bluuebunny/crossref_metadata_2025_split huggingface dataset:
The airways pharmacology of DNK333, a potent, selective, non‐peptide dual NK1/NK2 receptor antagonist
Authors: Lewis C.A. , El‐Hashim A.Z. , Gerspacher M. , Hoshiko K. , Mazzoni L. , Pfannkuche H.‐J. , Subramanian N. , Fozard J.R. 
Published: March 2005

AbstractThe airways' pharmacology of DNK333 ((1R,3R,2E)‐N‐[3,4‐dichlorobenzyl)]‐4‐[(hexahydro‐2‐oxo‐1H‐azepin‐3‐yl)amino]‐N‐methyl‐3,5bis(trifluoromethyl) benzamide), a potent and selective dual NK1/NK2 neurokinin receptor antagonist is described in the present paper. DNK333 bound with high and similar affinities to human NK1 and NK2 receptors. In guinea‐pig isolated trachea, DNK333 induced concentration‐dependent blockade of the contractile responses to NK1‐ or NK2‐receptor agonists. In anaesthetized guinea‐pigs, DNK333 shifted the bronchoconstrictor dose‐response curves induced by NK1‐ and NK2‐receptor agonists by 21.8‐ (3 mg/kg) and 6.8‐fold (10 mg/kg), respectively. At 10 mg/kg, a 12‐h duration of action was observed. Nasal perfusion of substance P and capsaicin to anaesthetized guinea‐pigs induced extravasation, which was inhibited dose‐dependently by DNK333 (ED50 values 72 and 70 µg/kg, respectively). Exposure of conscious guinea‐pigs to 0.6 M citric acid resulted in cough and an increase in enhanced pause of respiratory function (Penh). Oral administration of DNK333 (0.3, 3, or 10 mg/kg, −2 h) inhibited cough by 62, 63, and 82%, respectively and the increase in Penh by 85.5 and 77.2% (3 and 10 mg/kg, respectively). Bronchoconstrictor responses in anaesthetized guinea‐pigs to intravenous injections of methacholine and substance P were increased 60 min after LPS challenge (1 mg/kg, i.v.). DNK333 (1 and 10 mg/kg) dosed intraduodenally 30 min prior to LPS challenge inhibited airway hyperreactivity in a dose‐dependent manner. In conclusion, DNK333 is a potent, orally bioavailable, dual NK1/NK2 receptor antagonist with a long duration of action. It inhibits bronchoconstriction, extravasation, cough, and airway hyperreactivity induced by endogenous release of neuropeptides, which renders DNK333 suitable for exploring the role of tachykinins in respiratory disease. Drug Dev Res 63:161–173, 2004. © 2004 Wiley‐Liss, Inc.
Ethical Issues in the Biotechnology and Pharmaceutical Industries
Authors: Aronson Debra , Best Simon G. , Werner Michael J. , Moos Walter H. 
Published: March 2005

AbstractEthical topics come in many shapes and forms. When we set out to identify potential areas for the present special issue of this journal, we considered many areas that fit within a theme of “future challenges in bioethics.” We were interested in the impact of new technologies, how society will cope, how institutions will change to deal with the issues, and how different parts of the world will view the same issues differently. In this preface, we briefly describe selected issues, including scientific openness, genetics and related areas, informed consent and privacy, and human rights in the third world. We also mention corporate ethics, an area of much recent attention in the media, at corporations, with auditors, and on Wall Street. Finally, we describe the areas covered by the specific articles that follow. Drug Dev Res 63:89–92, 2004. © 2005 Wiley‐Liss, Inc.
Patenting the sun: Enclosing the scientific commons and transforming the university—ethical concerns
Authors: Triggle David J. 
Published: March 2005

AbstractUniversity and corporate interests have grown increasingly close during the past quarter century, particularly, but not exclusively so, in the life science areas. Legislation passed in 1980 specifically encouraged universities to seek patents on their basic science discoveries and to develop and license such patents. Universities are now significant players in the life sciences area, although the rewards are confined to a very small number of institutions. Questions arise concerning the influence of such commercial activities on the character of the universities, on their roles as public institutions, on the integrity of science and scientists, and on the progressive enclosing of the basic science commons, to which universities have traditionally been major contributors. Drug Dev Res 63:139–149, 2004. © 2005 Wiley‐Liss, Inc.
Closing the public health gap in Africa: Are we losing sight of our priorities?
Authors: Wasunna Angela Amondi 
Published: March 2005

AbstractGiven a plethora of data and information that show high mortality and morbidity in Africa from preventable diseases, it appears that the public health agenda in Africa is not being given the prominence and attention it deserves. This article provides background to the problem, and calls on communities, governments, and international stakeholders to refocus their health plans and funding priorities to ensure that primary care and public health are not relegated to the rear in the pursuit of better health in Africa. Drug Dev Res 63:134–138, 2004. © 2005 Wiley‐Liss, Inc.
Bioterrorism and the Responsible Conduct of Biomedical Research
Authors: Resnik David B. , Shamoo Adil E. 
Published: March 2005

AbstractThis article discusses the ethical responsibilities of biomedical researchers to prevent bioterrorism, including duties related to research, publication, editorial review, public education, expert opinion, advocacy, and reporting suspicious activity. Since actions taken to avert bioterrorism may also undermine important scientific norms, such as openness, freedom, and collegiality, and individual rights, such as privacy, biomedical scientists may encounter ethical dilemmas and problems when they consider taking steps against terrorism. This article proposes some policies and recommendations that attempt to strike a fair and reasonable balance between protecting scientific norms and individual rights and promoting national and international security. This article articulates policies and recommendations that will help ensure that the norms that govern biomedical research and individual rights are not casualties in the struggle against terrorism. Drug Dev Res 63:121–133, 2004. © 2005 Wiley‐Liss, Inc.
The Ethics of the F Word: Faith‐Based Science in a Faith‐Based World
Authors: Triggle David J. 
Published: March 2005

Abstract“And you never ask questions when god's on your side,”—Bob Dylan (1963). Science demands organized skepticism and the acknowledgement that science is a product of nature and not of a particular religion, culture, or political system. Faith‐based science that demands an unquestioning acceptance of a particular view or opinion is thus an oxymoronic discipline. Nonetheless, the incursion of faith‐based religious or political values into scientific disciplines and science‐based decision‐making is a persistent and increasing challenge. Religious values have always been a major part of American public and political life, but have assumed increased significance over the past two decades. In particular, the Presidency of George W. Bush has brought such issues to the forefront in many areas where science and science‐based decision‐making impacts the political decision‐making process. The current role of religion in impacting science‐based decision‐making in the United States is discussed. Drug Dev Res 63:112–120, 2004. © 2005 Wiley‐Liss, Inc.
Sponsored research and the public's right to know
Authors: Fersko Raymond S. , Merabet Hind 
Published: March 2005

AbstractTechnology transfer provides various protections and incentives for universities and federal research laboratories to develop and profit from their discoveries. However, the government, academic and private sectors may have conflicting, yet interrelated, values, interests, and practices when it comes to the gathering, recording, reporting, use, interpretation, and ownership of research data. The increasing commercialization of biomedical research has blurred some of these seeming divisions, and individuals and institutions occasionally find themselves succumbing to the financial pressures generated by their sponsors. This article discusses the ethical duty towards the public, and patients particularly, to present research results as accurately and objectively as possible, including in the specific context of human embryonic stem cell research. Drug Dev Res 63:103–111, 2004. © 2005 Wiley‐Liss, Inc.
Bioethics in biotechnology: from pain to gain
Authors: Dhanda Rahul K. 
Published: March 2005

AbstractAs the biotechnology industry grows, it will continually rely on the development of new technologies and the innovative use of mature scientific discoveries. These technologies will undoubtedly raise ethical issues challenging both their mode of development and intended use. Biotechnology companies are affected by the public debates and regulatory decisions that will ensure, but the ability of individual companies to address these challenges is, on the whole, insubstantial. Many companies are aware and appreciate the gravity of bioethics issues, but they lack the infrastructure and guidance to approach them. In this essay, a brief analysis is offered to help assess the impact of these issues on biotechnology firms, which is followed by suggested strategies for acting responsibly in the face of these important moral challenges. Drug. Dev Res 63:93–102, 2004. © 2005 Wily‐Liss, Inc.
Enhancement of dissolution rate of rofecoxib using solid dispersions with urea
Authors: Liu Chengsheng , Desai Kashappa Goud H. , Liu Chenguang , Park Hyun J. 
Published: March 2005

AbstractThe aim of this study was to enhance the dissolution rate of rofecoxib using solid dispersions (SDs) with urea. In preliminary studies, the solubility behavior of rofecoxib in the presence of polyethylene glycol (PEG)‐4000, polyvinylpyrrolidone (PVP) K30, mannitol, and urea in water was obtained at 37°C to choose an effective carrier for preparing its SDs. A systematic increase in the solubility behavior of rofecoxib was observed with increasing concentrations of these carriers in water except mannitol. The Gibbs free energy (ΔG) values were negative indicating the spontaneous nature of rofecoxib solubilization, and it decreased with increases in concentration, demonstrating that the reaction became more favorable as the concentration of these carriers increased. Since, urea exhibited higher solubilizing power than the other carriers, SDs of rofecoxib with urea were prepared at 1:1, 1:2, 1:5, and 1:10 (rofecoxib:urea) ratios by the fusion method. Evaluation of the properties of the SDs was performed using dissolution studies, fourier‐transform infrared (FTIR) spectroscopy, differential scanning calorimetry (DSC), X‐Ray diffraction (XRD), and scanning electron microscopy (SEM). The dissolution rate of rofecoxib was enhanced rapid by its SDs with urea and increased with increasing concentrations of urea in SDs. The mean dissolution time (MDT) of rofecoxib decreased after preparation of SDs and physical mixtures with urea. FTIR spectroscopic studies showed the stability of rofecoxib and the absence of a well‐defined rofecoxib‐urea interaction. DSC and XRD studies confirmed the amorphous state of rofecoxib in SDs of rofecoxib with urea. SEM pictures showed the formation of effective SDs of rofecoxib with urea since well‐defined changes in the surface nature of rofecoxib, SDs, and physical mixture were observed. Drug Dev Res 63:181–189, (2004). © 2004 Wiley‐Liss, Inc.
Epidermal lipids: thermotropic behavior and role in transcutaneous permeation of levodopa
Authors: Babita Kumar , Rana Vikas , Tiwary Ashok Kumar 
Published: March 2005

AbstractSkin lipids play a pivotal role in maintaining the barrier properties of skin. The present investigation aimed at studying the effect of skin lipid synthesis inhibitors on the transcutaneous delivery of levodopa (LD). Skin perturbation with ethanol was found to reduce the content of cholesterol, fatty acid, and sphingosine. Subsequent treatment with various doses of their respective synthesis inhibitors atorvastatin, cerulenin, and β‐chloroalanine sustained the reduced content of these lipids in viable rat skin. A maximum synthesis inhibition of approximately 80, 60, and 55% for cholesterol, triglycerides (an indicator of fatty acid), and sphingosine (a precursor of ceramide) was observed at 2, 2, and 8 h, respectively, after topical application of optimized dose of the inhibitors. Differential scanning calorimetric (DSC) analysis of treated rat epidermis revealed approximately 70, 52, and 50% reduction in enthalpy (ΔH) of the lipid endothermic transition peak by the corresponding doses of inhibitors. The effective plasma concentration (Ceff) of LD in rats was achieved by treatment with atorvastatin, cerulenin, and β‐chloroalanine within 2, 4, and 6 h, respectively. After application of a combination of these inhibitors, the lag time was reduced to 1 h and Ceff was maintained over 48 h. The inhibition of lipid synthesis in epidermis and concomitant decrease in enthalpy of lipid endothermic transition were directly correlated with enhanced in vitro and in vivo permeation of LD. These findings suggest that lipid synthesis inhibition can be exploited to enhance transcutaneous delivery of a polar drug, levodopa. Drug Dev Res 63:190–199, 2004. © 2004 Wiley‐Liss, Inc.
Effect of ascorbic acid, dihydrolipoic acid, t‐Butylhydroquinone, and phenylbutylnitrone on mortality and neurological impairment induced by sequential common carotid artery sectioning in mice
Authors: Santiago‐Mejia Jacinto , Fuentes‐Vargas Monica , Rios Camilo , Vidrio Horacio , Rodriguez Rodolfo 
Published: March 2005

AbstractThe efficacy of four antioxidant agents to reduce neurological deficits and mortality produced by sequential common carotid artery sectioning (SCAS) in mice was evaluated. Ascorbic acid (AA, 500 mg/kg), dihydrolipoic acid (DHLA, 100 mg/kg), tert‐butylhydroquinone (t‐BHQ, 100 mg/kg) or phenylbutylnitrone (PBN, 100 mg/kg) were injected ip 15 min after the second artery sectioning. Animals were evaluated at 24, 48, and 72 h after antioxidant or saline injection using two procedures: neurological examination and spontaneous motility. Based on neurological examination, a disability status scale was used to determine the degree of functional incapacity after brain ischemia for each animal. The scale comprised 10 progressive steps beyond 0 (normal) extending to status 10 (death due to SCAS). In this scale, the highest scores reflect greater neurological dysfunction. AA and DHLA but neither t‐BHQ nor PBN decreased mortality and reduced neurobehavioral deficits caused by SCAS in mice. The observed 24‐, 48‐, and 72‐h survival rates for AA were 86, 71, and 48% and for DHLA were 75, 65, and 65%, representing a significant prolongation of lifespan as compared with vehicle‐treated animals (60, 35, 35%). The 24‐, 48‐, and 72‐h neurological scores for AA of 5.2, 6.2, and 7.5 and for DHLA of 4.6, 5.3, and 5.8 as compared with the scores observed for the saline‐treated control group (7.6, 8.6, and 8.6) indicate that administration of these antioxidants is beneficial for the neurological output of surviving animals. These antioxidants may have important neuroprotective properties, and indicate that a clinical trial, mainly of DHLA, in stroke patients should be considered. Drug Dev. Res. 63:212–218, 2004. © 2004 Wiley‐Liss, Inc.
Cardiotoxin III induces apoptosis in T24 cells via reactive oxygen species‐independent mitochondrial death pathway
Authors: Chien Ching‐Ming , Yang Sheng‐Huei , Lu Mei‐Chin , Chang Long‐Sen , Lin Shinne‐Ren 
Published: March 2005

AbstractCardiotoxin III (CTX III), a basic polypeptide with 60 amino acid residues isolated from Naja naja atra venom, has been reported to have anticancer activity. CTX III inhibited the growth of T24 cells in a time‐ and dose‐dependent manner with an IC50value of 1.7 µg/mL and displayed several features of apoptosis including apoptotic body formation, increase of sub G1 population, DNA fragmentation, and poly (ADP‐ribose) polymerase (PARP) cleavage. Using apoptosis analysis, measurement of reactive oxygen species (ROS) and assessment of mitochondrial membrane potentials (ΔΨm), CTX III was found to be a potent inducer of apoptosis, transducing apoptotic signals via a decrease in mitochondrial membrane potential (ΔΨm) and release of cytochrome c from mitochondria into cytosol. However, CTX III did not generate reactive oxygen species (ROS). Taken together, the present data indicate that CTX III induces apoptosis in T24 cells through an ROS‐independent mitochondrial dysfunction pathway and resultant cytochrome c release. This is the first report on the mechanism of the anticancer effect of CTX III on T24 cells. Drug Dev. Res. 63:219–224, 2004. © 2004 Wiley‐Liss, Inc.
Flavonoid compounds: a review of anticancer properties and interactions with cis‐diamminedichloroplatinum(II)
Authors: Kosmider Beata , Osiecka Regina 
Published: March 2005

AbstractFlavonoid compounds, especially quercetin and genistein, have antitumor activity. These compounds are cytotoxic to cancer cells but have no or insignificant activity in normal cells. These beneficial properties prompted synthesis of flavonoid synthetic derivatives, e.g., flavopiridol; 5‐amino‐2,3‐fluorophenyl)‐6,8‐difluoro‐7‐methyl‐4H‐1‐benzopyran‐4‐one; B43‐genistein and EGF‐genistein). cis‐DDP (cis‐diamminedichloroplatinum(II)) is one of the most effective drugs used for chemotherapy, but its actions are limited by many side effects. Beneficial synergistic effects of flavonoids (e.g., quercetin, genistein, butein, tannic acid) and cis‐DDP were found in cis‐DDP‐sensitive and resistant cancer cells that resulted in a lower toxicity for cis‐DDP. Further studies focused on the synthesis of complexes of compounds belonging to different groups, e.g., cis‐bis(3‐aminoflavone)dichloroplatinum(II) where introduction of the flavone ligand altered the DNA‐binding properties of the complex as compared to cis‐DDP alone. The beneficial anticancer and antioxidant properties of flavonoids and their synthetic derivatives have prompted further research on the synergistic interactions of these compounds with routinely applied chemotherapeutic drugs, e.g. cis‐DDP. Drug Dev. Res. 63:200–211, 2004. © 2004 Wiley‐Liss, Inc.
Recent strategies and methods for improving insulin delivery
Authors: Lin Congrong , Gokhale Rajeev , Trivedi Jay S. , Ranade Vasant 
Published: March 2005

AbstractSubcutaneous insulin has been used to treat diabetes since the discovery of insulin itself. However, despite a number of different formulations and routes of administration, intensive insulin therapy without limitations, such as too low bioavailability, has not enjoyed widespread clinical acceptance. Attempts to find effective, well‐tolerated routes for delivering insulin began in the late 1920s and as of today, an ideal insulin delivery is still formidable. The most recent advances in insulin delivery are focused on using the inhalation route. The recent European filing of inhaled insulin (Exubera) is providing hope for alternative delivery routes, for example. This article reviews recent advances and approaches that hold promise toward the successful development of insulin delivery for the management of diabetes. Drug Dev. Res. 63:151–160, 2004. © 2004 Wiley‐Liss, Inc.
Proteomic fingerprints distinguish microglia, bone marrow, and spleen macrophage populations
Authors: Enose Yoshimi , Destache Christopher J. , Mack Andrea L. , Anderson James R. , Ullrich Fred , Ciborowski Pawel S. , Gendelman Howard E. 
Published: March 2005

AbstractMononuclear phagocytes (MP; dendritic cells, monocytes, tissue macrophages, and microglia) maintain tissue homeostasis and provide a first line of defense against invading pathogens. In specific circumstances, MPs also induce inflammatory responses and as such affect disease onset and progression. Despite intensive research into MP biology, little is known of the functional and molecular properties of individual MP subtypes. Using a novel proteomics platform, unique protein patterns and protein identities were observed among populations of spleen and bone marrow macrophages and microglia. Cells were obtained from C57BL/6 mice and were cultivated in macrophage colony‐stimulating factor. MP subtypes were indistinguishable by morphological or antigenic criteria. Protein profiling by Surface Enhanced Laser Desorption Ionization‐Time of Flight (SELDI‐TOF) ProteinChip® assays with weak cationic exchange chips showed unique MP spectral profiles. Corresponding protein fractions were recovered by high performance liquid chromatography and identified by liquid chromatography tandem mass spectrometry. The results provide a unique means to distinguish microglia from other MP subtypes. © 2005 Wiley‐Liss, Inc.
Inhibition of cysteine protease activity disturbs DNA replication and prevents mitosis in the early mitotic cell cycles of sea urchin embryos
Authors: Concha Carolina , Monardes Antonia , Even Yasmine , Morin Violeta , Puchi Marcia , Imschenetzky Maria , Marie Genevière Anne 
Published: March 2005

AbstractRecent findings suggested that the role of cysteine proteases would not be limited to protein degradation in lysosomes but would also play regulatory functions in more specific cell mechanisms. We analyzed here the role of these enzymes in the control of cell cycle during embryogenesis. The addition of the potent cysteine protease inhibitor E64d to newly fertilized sea urchin eggs disrupted cell cycle progression, affecting nuclear as well as cytoplasmic characteristic events. Monitoring BrdU incorporation in E64d treated eggs demonstrated that DNA replication is severely disturbed. Moreover, this drug treatment inhibited male histones degradation, a step that is necessary for sperm chromatin remodeling and precedes the initiation of DNA replication in control eggs. This inhibition likely explains the DNA replication disturbance and suggests that S phase initiation requires cysteine protease activity. In turn, activation of the DNA replication checkpoint could be responsible for the consecutive block of nuclear envelope breakdown (NEB). However, in sea urchin early embryos this checkpoint doesn't control the mitotic cytoplasmic events that are not tightly coupled with NEB. Thus the fact that microtubule spindle is not assembled and cyclin B‐cdk1 not activated under E64d treatment more likely rely on a distinct mechanism. Immunofluorescence experiments indicated that centrosome organization was deficient in absence of cysteine protease activity. This potentially accounts for mitotic spindle disruption and for cyclin B mis‐localization in E64d treated eggs. We conclude that cysteine proteases are essential to trigger S phase and to promote M phase entry in newly fertilized sea urchin eggs. © 2005 Wiley‐Liss, Inc.
Molecular mechanisms of glutamine action
Authors: Curi R. , Lagranha C.J. , Doi S.Q. , Sellitti D.F. , Procopio J. , Pithon‐Curi T.C. , Corless M. , Newsholme P. 
Published: March 2005

AbstractGlutamine is the most abundant free amino acid in the body and is known to play a regulatory role in several cell specific processes including metabolism (e.g., oxidative fuel, gluconeogenic precursor, and lipogenic precursor), cell integrity (apoptosis, cell proliferation), protein synthesis, and degradation, contractile protein mass, redox potential, respiratory burst, insulin resistance, insulin secretion, and extracellular matrix (ECM) synthesis. Glutamine has been shown to regulate the expression of many genes related to metabolism, signal transduction, cell defense and repair, and to activate intracellular signaling pathways. Thus, the function of glutamine goes beyond that of a simple metabolic fuel or protein precursor as previously assumed. In this review, we have attempted to identify some of the common mechanisms underlying the regulation of glutamine dependent cellular functions. © 2005 Wiley‐Liss, Inc.