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Pharmaceuticals, Volume 4, Issue 1 (January 2011), Pages 1-214

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Research

Jump to: Review

Open AccessArticle Molecular Therapies in Thyroid Cancer
Pharmaceuticals 2011, 4(1), 91-100; doi:10.3390/ph4010091
Received: 2 November 2010 / Revised: 9 December 2010 / Accepted: 22 December 2010 / Published: 24 December 2010
Cited by 1 | PDF Full-text (53 KB) | HTML Full-text | XML Full-text
Abstract
Thyroid cancer is a common diagnosis with greater than 34,000 cases per year in the United States. Early stage thyroid cancer is often managed with surgical intervention and radioactive iodine; however, for recurrent or metastatic disease, the treatment options, historically, have been [...] Read more.
Thyroid cancer is a common diagnosis with greater than 34,000 cases per year in the United States. Early stage thyroid cancer is often managed with surgical intervention and radioactive iodine; however, for recurrent or metastatic disease, the treatment options, historically, have been limited to chemotherapy. Chemotherapy for metastatic thyroid cancer has been of limited efficacy. Encouragingly, molecular therapeutics have played a greater role in managing patients with advanced disease. These agents work primarily through disruption of tyrosine kinase pathways. This review will discuss the expanding role of molecular targets in managing patients with advanced thyroid cancer. Full article
(This article belongs to the Special Issue Targeted Therapy)
Open AccessArticle Fentanyl and Spiradoline Interactions in a Place-Conditioning Black-White Shuttle-Box
Pharmaceuticals 2011, 4(1), 101-116; doi:10.3390/ph401101
Received: 5 November 2010 / Revised: 20 December 2010 / Accepted: 22 December 2010 / Published: 24 December 2010
Cited by 1 | PDF Full-text (350 KB) | HTML Full-text | XML Full-text
Abstract
Rats were trained for multiple sessions in a place-conditioning shuttle-box to explore motivational interactions of mu and kappa opioid agonists, specifically fentanyl reward and spiradoline aversion. In Phase 1, groups of rats received various doses of mu or kappa agonists, or placebo, [...] Read more.
Rats were trained for multiple sessions in a place-conditioning shuttle-box to explore motivational interactions of mu and kappa opioid agonists, specifically fentanyl reward and spiradoline aversion. In Phase 1, groups of rats received various doses of mu or kappa agonists, or placebo, testing for preference or aversion. Group A always received saline SC before 15-minute sessions. Group B received fentanyl SC (0.003, 0.006, 0.012 mg/kg), Group C received low and medium doses of agonists SC, and Group D received spiradoline (0.3, 0.6, 1.2 mg/kg) SC during Training Sessions 1-4, rats being restricted to the drug-associated compartment. Rats received saline when restricted to the placebo-associate compartment and on test days with access to both shuttle-box compartments. In Phase 2 of the study, Training Session 5, Combinations of mu and kappa agonists were substituted in Groups B, C, and D. Dose-related preference to fentanyl and aversion to spiradoline occurred during Test Sessions 1-4. During Test Session 5, fentanyl preference in Group B was suppressed by spiradoline, rats in Group C had a saline-like response to combined agonists, and spiradoline aversion in Group D was attenuated by fentanyl. These findings suggest that combined doses of mu and kappa agonists, while additive for antinociception, offset the rewarding and punishing effects of each other. Full article
(This article belongs to the Special Issue Opioids)
Open AccessArticle Bioequivalence of Two Intravenous Artesunate Products with Its Active Metabolite Following Single and Multiple Injections
Pharmaceuticals 2011, 4(1), 138-153; doi:10.3390/ph4010138
Received: 29 November 2010 / Revised: 22 December 2010 / Accepted: 5 January 2011 / Published: 7 January 2011
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Abstract
In animal species and humans, artesunate (AS) undergoes extensive and complex biotransformation to an active metabolite, dihydroartemisinin (DHA). The bioequivalence of two intravenous AS pharmaceutical products with 5% NaHCO3 (China Formulation) or 0.3 M PBS (WRAIR Formulation) was determined in rats [...] Read more.
In animal species and humans, artesunate (AS) undergoes extensive and complex biotransformation to an active metabolite, dihydroartemisinin (DHA). The bioequivalence of two intravenous AS pharmaceutical products with 5% NaHCO3 (China Formulation) or 0.3 M PBS (WRAIR Formulation) was determined in rats in a two-formulation, two-period, and two-sequence crossover experimental design. Following single and multiple intravenous administrations, a series of blood samples was collected by using an automated blood sampler and drug concentrations were analyzed by LC-MS/MS. The 90% CI of the difference between the two intravenous formulations was contained within 80–125% of the geometric mean of pharmacokinetic parameters for AS and DHA in all animals dosed. Hematological effects were studied on days 1 and 3 after the final dosing, and a rapidly reversible hematological toxicity (significant reductions in reticulocyte levels) was seen in the peripheral blood of the rats treated with each formulation. The results showed that bioequivalence with the parent compound and active metabolite was fulfilled in the 82.3–117.7% ranges of all parameters (AUC0–t, Cmax, concentration average and degree of fluctuation) in the two-period and two-sequence crossover studies following single and repeated intravenous injections. For the metabolite, the equivalence was satisfied in most pharmacokinetic parameters tested due to the variability in the hydrolysis rate of AS to DHA. The WRAIR formulation of AS was considered to be bioequivalent to the Chinese formulation at steady-state according to the total drug exposure, in terms of both parent drug and active metabolite, rapidly reversal in reticulocyte decline, and extension of single and multiple administrations. Therefore, the parent drug and active metabolites should play similar important roles in the determination of efficacy and safety of the drug. Full article
(This article belongs to the Special Issue New Antimalarial Drugs)
Open AccessArticle L-Arginine Supplementation and Metabolism in Asthma
Pharmaceuticals 2011, 4(1), 187-201; doi:10.3390/ph4010187
Received: 4 November 2010 / Revised: 3 January 2011 / Accepted: 10 January 2011 / Published: 12 January 2011
Cited by 5 | PDF Full-text (242 KB) | HTML Full-text | XML Full-text
Abstract
L-Arginine, the amino acid substrate for nitric oxide synthase, has been tested as a therapeutic intervention in a variety of chronic diseases and is commonly used as a nutritional supplement. In this study, we hypothesized that a subset of moderate to severe persistent asthma patients would benefit from supplementation with L-arginine by transiently increasing nitric oxide levels, resulting in bronchodilation and a reduction in inflammation. The pilot study consisted of a 3 month randomized, double-blind, placebo-controlled trial of L-arginine (0.05 g/kg twice daily) in patients with moderate to severe asthma. We measured spirometry, exhaled breath nitric oxide, serum arginine metabolites, questionnaire scores, daily medication use and PEFR with the primary endpoint being the number of minor exacerbations at three months. Interim analysis of the 20 subjects showed no difference in the number of exacerbations, exhaled nitric oxide levels or lung function between groups, though participants in the L-arginine group had higher serum L-arginine at day 60 (2.0 ± 0.6 × 10−3 vs. 1.1 ± 0.2 × 10−3 µmol/L, p < 0.05), ornithine at day 30 (2.4 ± 0.9 vs. 1.2 ± 0.3 µmol/L serum, p < 0.05) and ADMA at day 30 (6.0 ± 1.5 × 10−1 vs. 2.6 ± 0.6 × 10−1 µmol/L serum, p < 0.05) on average compared to the placebo group. The study was terminated prematurely. Supplementing asthma subjects with L-arginine increases plasma levels; whether subgroups might benefit from such supplementation requires further study. Full article
(This article belongs to the Special Issue Genes, Mechanisms and Drugs for Asthma)

Review

Jump to: Research

Open AccessReview Blood Pressure-Lowering Aspects of Lipid-Lowering and Anti-Diabetic Drugs
Pharmaceuticals 2011, 4(1), 1-6; doi:10.3390/ph4010001
Received: 20 December 2010 / Accepted: 22 December 2010 / Published: 23 December 2010
Cited by 1 | PDF Full-text (36 KB) | HTML Full-text | XML Full-text
Abstract
Several studies have shown that blood pressure can be lowered by the use of drugs that are not traditional antihypertensive drugs. This might be of clinical importance when many risk patients are treated by combination drug therapy in order to prevent cardiovascular [...] Read more.
Several studies have shown that blood pressure can be lowered by the use of drugs that are not traditional antihypertensive drugs. This might be of clinical importance when many risk patients are treated by combination drug therapy in order to prevent cardiovascular disease by way of improving the cardiovascular risk factor profile. Full article
(This article belongs to the Special Issue Antihypertensive Drugs)
Open AccessReview GPCR Conformations: Implications for Rational Drug Design
Pharmaceuticals 2011, 4(1), 7-43; doi:10.3390/ph4010007
Received: 24 November 2010 / Revised: 20 December 2010 / Accepted: 21 December 2010 / Published: 23 December 2010
Cited by 9 | PDF Full-text (1717 KB) | HTML Full-text | XML Full-text
Abstract
G protein-coupled receptors (GPCRs) comprise a large class of transmembrane proteins that play critical roles in both normal physiology and pathophysiology. These critical roles offer targets for therapeutic intervention, as exemplified by the substantial fraction of current pharmaceutical agents that target members [...] Read more.
G protein-coupled receptors (GPCRs) comprise a large class of transmembrane proteins that play critical roles in both normal physiology and pathophysiology. These critical roles offer targets for therapeutic intervention, as exemplified by the substantial fraction of current pharmaceutical agents that target members of this family. Tremendous contributions to our understanding of GPCR structure and dynamics have come from both indirect and direct structural characterization techniques. Key features of GPCR conformations derived from both types of characterization techniques are reviewed. Full article
(This article belongs to the Special Issue GPCR Based Drug Discovery)
Open AccessReview Blocking Plasmodium falciparum Malaria Transmission with Drugs: The Gametocytocidal and Sporontocidal Properties of Current and Prospective Antimalarials
Pharmaceuticals 2011, 4(1), 44-68; doi:10.3390/ph4010044
Received: 30 November 2010 / Revised: 14 December 2010 / Accepted: 21 December 2010 / Published: 23 December 2010
Cited by 12 | PDF Full-text (177 KB) | HTML Full-text | XML Full-text
Abstract
Drugs that kill or inhibit the sexual stages of Plasmodium could potentially amplify or synergize the impact of other interventions by blocking transmission to mosquitoes. Primaquine and other 8-aminoquinolines have long offered such potential, but safety and other concerns have limited their [...] Read more.
Drugs that kill or inhibit the sexual stages of Plasmodium could potentially amplify or synergize the impact of other interventions by blocking transmission to mosquitoes. Primaquine and other 8-aminoquinolines have long offered such potential, but safety and other concerns have limited their use. Although transmission-blocking properties are not often a priority of drug discovery efforts, a number of interesting gametocytocidal and/or sporontocidal drug candidates have emerged in recent years. Some still bear significant technical and safety concerns, while others have passed clinical trials and are on the verge of entering the antimalarial armamentarium. Recent advances in our knowledge of gametocyte differentiation, gametogenesis and sporogony have also led to the identification of a large array of potential new targets for drugs that might interfere with malaria transmission. This review examines the properties of existing and prospective drugs, mechanisms of action, counter-indications and their potential role in regional malaria elimination efforts. Full article
(This article belongs to the Special Issue New Antimalarial Drugs)
Open AccessReview Drug Induced Hypersensitivity and the HLA Complex
Pharmaceuticals 2011, 4(1), 69-90; doi:10.3390/ph4010069
Received: 27 October 2010 / Revised: 7 November 2010 / Accepted: 8 December 2010 / Published: 23 December 2010
Cited by 13 | PDF Full-text (152 KB) | HTML Full-text | XML Full-text
Abstract
Drug-induced hypersensitivity reactions are of major concern and present a burden for national healthcare systems due to their often severe nature, high rate of hospital admissions and high mortality. They manifest with a wide range of symptoms and signs, and can be [...] Read more.
Drug-induced hypersensitivity reactions are of major concern and present a burden for national healthcare systems due to their often severe nature, high rate of hospital admissions and high mortality. They manifest with a wide range of symptoms and signs, and can be initiated by a wide range of structurally diverse chemical compounds. The pathophysiological mechanisms underlying hypersensitivity reactions are not well understood, but it is thought that they are immune mediated. MHC region on Chromosome 6 contains many genes with immune function. Classical MHC molecules are highly polymorphic cell surface glycoproteins whose function is to present peptide antigens to T cells. In addition to conferring protection from some diseases, HLA alleles are also associated with an increased risk of other diseases, including drug-induced hypersensitivity. Pharmacogenetic approach to predict the risk of drug-induced hypersensitivity has been established for several drugs. We will discuss the progress of hypersensitivity pharmacogenetics over the last few years and focus on current efforts of the international community to develop consortia which aim to standardize disease phenotypes and to identify affected individuals through international collaborations. In addition, we will discuss the clinical utility of HLA typing as predictive or diagnostic testing for drug-induced hypersensitivity. Full article
(This article belongs to the Special Issue Personalized Medicine)
Open AccessReview Sphingosine-1-Phosphate-Specific G Protein-Coupled Receptors as Novel Therapeutic Targets for Atherosclerosis
Pharmaceuticals 2011, 4(1), 117-137; doi:10.3390/ph4010117
Received: 30 November 2010 / Revised: 25 December 2010 / Accepted: 4 January 2011 / Published: 4 January 2011
Cited by 3 | PDF Full-text (251 KB) | HTML Full-text | XML Full-text
Abstract
Atherosclerosis is a chronic inflammatory process involving complex interactions of modified lipoproteins, monocyte-derived macrophages or foam cells, lymphocytes, endothelial cells (ECs), and vascular smooth muscle cells. Sphingosine-1-phosphate (S1P), a biologically active blood-borne lipid mediator, exerts pleiotropic effects such as cell proliferation, migration [...] Read more.
Atherosclerosis is a chronic inflammatory process involving complex interactions of modified lipoproteins, monocyte-derived macrophages or foam cells, lymphocytes, endothelial cells (ECs), and vascular smooth muscle cells. Sphingosine-1-phosphate (S1P), a biologically active blood-borne lipid mediator, exerts pleiotropic effects such as cell proliferation, migration and cell-cell adhesion in a variety of cell types via five members of S1P-specific high-affinity G protein-coupled receptors (S1P1-S1P5). Among them, S1P1, S1P2 and S1P3 are major receptor subtypes which are widely expressed in various tissues. Available evidence suggest that S1P and HDL-bound S1P exert atheroprotective effects including inhibition of leukocyte adhesion and stimulation of endothelial nitric oxide synthase (eNOS) in endothelial cells (ECs) through the activation of Gi signaling pathway via S1P3 and probably S1P1, although there is still controversy. FTY720, the phosphorylation product of which is a high-affinity agonist for all S1P receptors except S1P2 and act as an immunosuppressant by downregulating S1P1 on lymphocytes, inhibits atherosclerosis in LDL receptor-null mice and apoE-null mice through the inhibition of lymphocyte and macrophage functions and probably stimulation of EC functions, without influencing plasma lipid concentrations. In contrast to S1P1 and S1P3, S1P2 facilitates atherosclerosis by activating G12/13-Rho-Rho kinase (ROCK) in apoE-null mice. S1P2 mediates transmigration of monocytes into the arterial intima, oxidized LDL accumulation and cytokine secretion in monocyte-derived macrophages, and eNOS inhibition and cytokine secretion in ECs through Rac inhibition, NF-kB activation and 3’-specific phosphoinositide phosphatase (PTEN) stimulation downstream of G12/13-Rho-ROCK. Systemic long-term administration of a selective S1P2-blocker remarkably inhibits atherosclerosis without overt toxicity. Thus, multiple S1P receptors positively and negatively regulate atherosclerosis through multitudes of mechanisms. Considering the essential and multi-faceted role of S1P2 in atherogenesis and the impact of S1P2 inactivation on atherosclerosis, S1P2 is a particularly promising therapeutic target for atherosclerosis. Full article
(This article belongs to the Special Issue GPCR Based Drug Discovery)
Open AccessReview Cardiorenal Effects of Kappa Opioid Peptides During Ontogeny
Pharmaceuticals 2011, 4(1), 154-168; doi:10.3390/ph4010154
Received: 9 December 2010 / Revised: 30 December 2010 / Accepted: 7 January 2011 / Published: 11 January 2011
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Abstract
This review focuses on the physiological roles for kappa opioid receptors (KORs) in adult animals and humans, as well as in the developing newborn animal. Our recent findings have provided new information that under physiological conditions in conscious newborn animals, activation of [...] Read more.
This review focuses on the physiological roles for kappa opioid receptors (KORs) in adult animals and humans, as well as in the developing newborn animal. Our recent findings have provided new information that under physiological conditions in conscious newborn animals, activation of KORs with the selective agonist, U-50488H, results in an aquaresis, as previously observed in adult animals and humans. In addition, we have shown in conscious lambs that KORs modulate systemic and renal haemodynamics as well as the arterial baroreflex control of heart rate, providing a previously unidentified role for KORs. Full article
(This article belongs to the Special Issue Opioids)
Open AccessReview Pathogenesis and Antifungal Drug Resistance of the Human Fungal Pathogen Candida glabrata
Pharmaceuticals 2011, 4(1), 169-186; doi:10.3390/ph4010169
Received: 14 December 2010 / Revised: 22 December 2010 / Accepted: 5 January 2011 / Published: 11 January 2011
Cited by 11 | PDF Full-text (194 KB) | HTML Full-text | XML Full-text
Abstract
Candida glabrata is a major opportunistic human fungal pathogen causing superficial as well as systemic infections in immunocompromised individuals and several other patient cohorts. C. glabrata represents the second most prevalent cause of candidemia and a better understanding of its virulence and [...] Read more.
Candida glabrata is a major opportunistic human fungal pathogen causing superficial as well as systemic infections in immunocompromised individuals and several other patient cohorts. C. glabrata represents the second most prevalent cause of candidemia and a better understanding of its virulence and drug resistance mechanisms is thus of high medical relevance. In contrast to the diploid dimorphic pathogen C. albicans, whose ability to undergo filamentation is considered a major virulence trait, C. glabrata has a haploid genome and lacks the ability to switch to filamentous growth. A major impediment for the clinical therapy of C. glabrata infections is its high intrinsic resistance to several antifungal drugs, especially azoles. Further, the development of antifungal resistance, particularly during prolonged and prophylactic therapies is diminishing efficacies of therapeutic interventions. In addition, C. glabrata harbors a large repertoire of adhesins involved in the adherence to host epithelia. Interestingly, genome plasticity, phenotypic switching or the remarkable ability to persist and survive inside host immune cells further contribute to the pathogenicity of C. glabrata. In this comprehensive review, we want to emphasize and discuss the mechanisms underlying virulence and drug resistance of C. glabrata, and discuss its ability to escape from the host immune surveillance or persist inside host cells. Full article
(This article belongs to the Special Issue Anti-Infective Agents)
Open AccessReview Original Fluorescent Ligand-Based Assays Open New Perspectives in G-Protein Coupled Receptor Drug Screening
Pharmaceuticals 2011, 4(1), 202-214; doi:10.3390/ph4010202
Received: 1 December 2010 / Revised: 23 December 2010 / Accepted: 24 December 2010 / Published: 18 January 2011
Cited by 9 | PDF Full-text (265 KB) | HTML Full-text | XML Full-text
Abstract
The identification of new drugs exhibiting reduced adverse side-effects constitutes a great challenge for the next decade. Various steps are needed to screen for good ligand candidates and one of them is the evaluation of their binding properties. New strategies based on [...] Read more.
The identification of new drugs exhibiting reduced adverse side-effects constitutes a great challenge for the next decade. Various steps are needed to screen for good ligand candidates and one of them is the evaluation of their binding properties. New strategies based on fluorescence measurement constitute excellent alternatives to the traditional radioactive assays. Less hazardous, faster and cheaper, these methods also exhibit very good sensitivity and can be used on various biological models such as heterologous expression systems or native tissues. Full article
(This article belongs to the Special Issue GPCR Based Drug Discovery)

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