Showing papers in "Pharmaceuticals in 2009"
TL;DR: Interestingly, an increased cytosolic distribution but also highly toxic activities in the micromolar range against several cell lines is observed, and structural analysis revealed that attachment of the fusion peptide had profound implications on the whole conformation of the peptide, which might be responsible for membrane interaction and endosome disruption.
Abstract: Cell-penetrating peptides (CPP) have become a widely used tool for efficient cargo delivery into cells. However, one limiting fact is their uptake by endocytosis causing the enclosure of the CPP-cargo construct within endosomes. One often used method to enhance the outflow into the cytosol is the fusion of endosome-disruptive peptide or protein sequences to CPP. But, until now, no studies exist investigating the effects of the fusion peptide to the cellular distribution, structural arrangements and cytotoxic behaviour of the CPP. In this study, we attached a short modified sequence of hemagglutinin subunit HA2 to different CPP and analysed the biologic activity of the new designed peptides. Interestingly, we observed an increased cytosolic distribution but also highly toxic activities in the micromolar range against several cell lines. Structural analysis revealed that attachment of the fusion peptide had profound implications on the whole conformation of the peptide, which might be responsible for membrane interaction and endosome disruption.
87 citations
TL;DR: The new system of classification will add to existing knowledge of prodrug classifications, and will provide improved insight into the contributory roles of both prodrug and active drug in the product’s efficacy and safety, and their risk-benefit assessment.
Abstract: Many therapeutic agents are manufactured and administered in prodrug forms. In this paper, a new classification system for prodrugs is proposed to provide useful information about where in the body a prodrug is converted to the active drug. In this system, prodrugs are classified into Type I or Type II and the respective Subtypes IA, IB, IIA, IIB or IIC based on their sites of conversion into the final active drug form. For Type I prodrugs, conversion occurs intracellularly (e.g., antiviral nucleoside analogs, lipid-lowering statins), whereas conversion of Type II prodrugs occurs extracellularly, for examples in digestive fluids, systemic circulation or other extracellular body fluids (e.g., etoposide phosphate, valganciclovir, fosamprenavir). Type IA prodrugs refer to those that are converted at the cellular targets of therapeutic actions, whereas Type IB prodrugs’ conversion occurs in the primary metabolic tissues such as liver, gut, or lung. For Type II prodrugs, the conversion process could either take place extracellularly in the milieu of gastrointestinal fluids (Type IIA), in the systemic circulation and/or other systemic extracellular fluid compartments (Type IIB), or near therapeutical target cells (Type IIC). A prodrug may belong to multiple categories and be recognized as a Mixed-Type prodrug. For example a prodrug may be converted both in target cells and metabolic tissues such as liver (i.e., named as a Type IA/IB prodrug), or one converted in both GI fluids and systemic circulations (i.e., named as a Type IIA/IIB prodrug). The Mixed-Type compound can be further distinguished as a Parallel Mixed-Type or Sequential Mixed-Type prodrug depending on the conversion processes that proceed with, either in concurrent or in sequential steps. Because traditional analysis of drug actions has always been focused on the site of action and mode of action, the proposed classification of prodrugs based on cellular locations of conversion is in line with current thought processes of regulatory review and risk assessment of both prodrug and active drug. By gaining insights regarding the site of action through prodrug nomenclature, risk benefit evaluation can be made more efficiently because both information on kinetics and impact of tissues involved are adequately revealed through prodrug subtype designated. In conclusion, the new system of classification will add to existing knowledge of prodrug classifications, and will provide improved insight into the contributory roles of both prodrug and active drug in the product’s efficacy and safety, and their risk-benefit assessment.
84 citations
TL;DR: The structural elucidation of the two new compounds 6,11, as well as an update of data for the already described prenylated derivatives 7,8,10 were accomplished by IR, UV, HRMS and NMR techniques.
Abstract: Pyranoxanthones 6-8 were obtained by dehydrogenation of the respective dihydropyranoxanthones 3-5 with DDQ in dry dioxane. Two prenylated xanthones 10,11 were obtained from the reaction of 1-hydroxyxanthone (9) with prenyl bromide in alkaline medium, or by condensation of xanthone 9 with isoprene in the presence of orthophosphoric acid. The structural elucidation of the two new compounds 6,11, as well as an update of data for the already described prenylated derivatives 7,8,10 were accomplished by IR, UV, HRMS and NMR (1H, 13C, HSQC and HMBC) techniques. The effect of the prenylated xanthone derivatives on the in vitro growth of human tumor cell lines MCF-7 (breast adenocarcinoma) and NCI-H460 (non-small cell lung cancer) is also reported. Compounds 10 and 11 have been found to exhibit a moderate growth inhibitory activity against the MCF-7 cell line.
34 citations
TL;DR: The physiological roles of CoQ10, as well as the rationale and the role in clinical practice of Coq10 supplementation in different neurological diseases, are reviewed, from primary CoQ 10 deficiency to neurodegenerative disorders.
Abstract: Coenzyme Q10 (CoQ10, or ubiquinone) is a small electron carrier of the mitochondrial respiratory chain with antioxidant properties. CoQ10 supplementation has been widely used for mitochondrial disorders. The rationale for using CoQ10 is very powerful when this compound is primary decreased because of defective synthesis. Primary CoQ10 deficiency is a treatable condition, so heightened "clinical awareness" about this diagnosis is essential. CoQ10 and its analogue, idebenone, have also been widely used in the treatment of other neurodegenerative disorders. These compounds could potentially play a therapeutic role in Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, Friedreich's ataxia, and other conditions which have been linked to mitochondrial dysfunction. This article reviews the physiological roles of CoQ10, as well as the rationale and the role in clinical practice of CoQ10 supplementation in different neurological diseases, from primary CoQ10 deficiency to neurodegenerative disorders.
34 citations
TL;DR: It is suggested that resveratrol may constitute a potential drug for prevention of ageing and for the treatment of several diseases due to its antioxidant properties and sirtuin activation.
Abstract: The prevention of aging is one of the most fascinating areas in biomedicine. The first step in the development of effective drugs for aging prevention is a knowledge of the biochemical pathways responsible for the cellular aging process. In this context it seems clear that free radicals play a key role in the aging process. However, in recent years it has been demonstrated that the families of enzymes called sirtuins, specifically situin 1 (SIRT1), have an anti-aging action. Thus, the natural compound resveratrol is a natural compound that shows a very strong activation of SIRT1 and also shows antioxidant effects. By activating sirtuin 1, resveratrol modulates the activity of numerous proteins, including peroxisome proliferator-activated receptor coactivator-1α (PGC-1 alpha), the FOXO family, Akt (protein kinase B) and NFκβ. In the present review, we suggest that resveratrol may constitute a potential drug for prevention of ageing and for the treatment of several diseases due to its antioxidant properties and sirtuin activation.
25 citations
TL;DR: The polymeric gum fraction was separated from the essential oil and the resin to assess and compare the anti-H.
Abstract: Mastic gum is a viscous light-green liquid obtained from the bark of Pistacia lentiscus var. chia. which belongs to the Anacardiaceae family. The gum has been fractionated to investigate the antimicrobial activity of the whole gum and its fractions against various strains of Helicobacter pylori. The polymeric gum fraction was separated from the essential oil and the resin (trunk exudates without essential oil) to assess and compare the anti-H. pylori activity of the polymer fraction against lower molecular weight fractions, the gum itself and masticated gum. The polymer fraction was also oxidized and assessed for antimicrobial activity.
23 citations
TL;DR: Treatment for aortic dissection should begin on arrival to the emergency department and continues in the intensive care unit, endovascular suite or the operating room, and diligent control of BP is of utmost importance in order to reduce the progression of dissection.
Abstract: Over the last few decades, treatment for aortic dissection and thoracic aortic aneurysms has evolved significantly with improvement in outcomes. Treatment paradigms include medical, endovascular and surgical options. As aortic dissection presents as a hypertensive emergency, diligent control of BP is of utmost importance in order to reduce the progression of dissection with possible aortic branch malperfusion. Treatment should begin on arrival to the emergency department and continues in the intensive care unit, endovascular suite or the operating room. Novel antihypertensive medications with improved pharmacological profile and improved surgical techniques, have improved the prognosis of patients with aortic aneurysm and/or aortic dissection. Nevertheless, morbidity and mortality remain high and hypertensive emergency poses a significant challenge in aortic dissection and thoracic aortic aneurysms.
21 citations
TL;DR: This review highlights the current state of the field and suggests new approaches that can be used to evaluate functional consequences associated with mutations and polymorphisms in the PAF-AH gene.
Abstract: In the past several years a number of alterations in the PAFAH/PLA₂G7/LpPLA₂ gene have been described. These include inactivating mutations, polymorphisms in the coding region, and other genetic changes located in promoter and intronic regions of the gene. The consequences associated with these genetic variations have been evaluated from different perspectives, including in vitro biochemical and molecular studies and clinical analyses in human subjects. This review highlights the current state of the field and suggests new approaches that can be used to evaluate functional consequences associated with mutations and polymorphisms in the PAF-AH gene.
18 citations
TL;DR: The interaction of cephalosporins with the metal ions could suggest negative effects of some metal ions on the clinical aspects of small intestinal peptide and drug transport.
Abstract: The effect of different metal ions on the intestinal transport and the antibacterial activity of cefadroxil [(6R,7R)-7-{[(2R)-2-amino-2-(4-hydroxyphenyl)acetyl]amino}-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid] was investigated. The [14C]Gly-Sar uptake via PEPT1 was inhibited by Zn2+ and Cu2+ treatment in a concentration-dependent manner (Ki values 107 ± 23 and 19 ± 5 μM, respectively). Kinetic analysis showed that the Kt of Gly-Sar uptake was increased 2-fold in the presence of zinc sulphate (150 μM) whereas the Vmax value were not affected suggesting that zinc ions inhibited Gly-Sar uptake by PEPT1 in a competitively manner. Ni2+ exhibited moderate inhibitory effect, whereas Co2+, Mg2+, Al3+ ions showed no inhibitory effect on Gly-Sar uptake via PEPT1. Subsequently, we examined the effect of Zn2+ and Al3+ ions on the transepithelial transport of cefadroxil across Caco-2 cells cultured on permeable supports. The results showed that zinc ions inhibited the transepithelial flux of cefadroxil at Caco-2 cell monolayers while Al3+ ions had no effect. The interaction of cephalosporins with the metal ions could suggest negative effects of some metal ions on the clinical aspects of small intestinal peptide and drug transport. Finally, the effect of Zn2+, Cu2+ and Al3+ ions on the antibacterial activity of cefadroxil was tested. It was found that there is no significant difference between the activity of cefadroxil and the cefadroxil metal ion complexes studied against the investigated sensitive bacterial species.
15 citations
TL;DR: The role of neuronal mitochondria in the pathogenesis of AD is reviewed and treatment strategies that utilize this upstream access point as a method for disease prevention are reviewed.
Abstract: Therapeutic strategies for Alzheimer disease (AD) have yet to offer a disease-modifying effect to stop the debilitating progression of neurodegeneration and cognitive decline. Rather, treatments thus far are limited to agents that slow disease progression without halting it, and although much work towards a cure is underway, a greater understanding of disease etiology is certainly necessary for any such achievement. Mitochondria, as the centers of cellular metabolic activity and the primary generators of reactive oxidative species in the cell, received particular attention especially given that mitochondrial defects are known to contribute to cellular damage. Furthermore, as oxidative stress has come to the forefront of AD as a causal theory, and as mitochondrial damage is known to precede much of the hallmark pathologies of AD, it seems increasingly apparent that this metabolic organelle is ultimately responsible for much, if not all of disease pathogenesis. In this review, we review the role of neuronal mitochondria in the pathogenesis of AD and critically assess treatment strategies that utilize this upstream access point as a method for disease prevention. We suspect that, with a revived focus on mitochondrial repair and protection, an effective and realistic therapeutic agent can be successfully developed.
12 citations
TL;DR: The role of mitochondria and insulin signaling in normal brain function and in neurodegeneration is discussed and the potential protective role of insulin and insulin sensitizers in Alzheimer´s, Parkinson´s and Huntington´s diseases and amyotrophic lateral sclerosis will be also discussed.
Abstract: Insulin, besides its glucose lowering effects, is involved in the modulation of lifespan, aging and memory and learning processes. As the population ages, neurodegenerative disorders become epidemic and a connection between insulin signaling dysregulation, cognitive decline and dementia has been established. Mitochondria are intracellular organelles that despite playing a critical role in cellular metabolism are also one of the major sources of reactive oxygen species. Mitochondrial dysfunction, oxidative stress and neuroinflammation, hallmarks of neurodegeneration, can result from impaired insulin signaling. Insulin-sensitizing drugs such as the thiazolidinediones are a new class of synthetic compounds that potentiate insulin action in the target tissues and act as specific agonists of the peroxisome proliferator-activated receptor gamma (PPAR-γ). Recently, several PPAR agonists have been proposed as novel and possible therapeutic agents for neurodegenerative disorders. Indeed, the literature shows that these agents are able to protect against mitochondrial dysfunction, oxidative damage, inflammation and apoptosis. This review discusses the role of mitochondria and insulin signaling in normal brain function and in neurodegeneration. Furthermore, the potential protective role of insulin and insulin sensitizers in Alzheimer´s, Parkinson´s and Huntington´s diseases and amyotrophic lateral sclerosis will be also discussed.
TL;DR: Combinations of olmesartan and amlodipine were significantly more effective at reducing blood pressure and realising guideline blood pressure goals in patients with mild to severe hypertension than monotherapy (with a placebo component).
Abstract: Background: Combination therapy with antihypertensive agents utilises different mechanisms of action and may be responsible for a more effective decrease in blood pressure. Objective: To review the recently published trials on efficacy and safety of the combination therapy with olmesartan and amlodipine. Results: The double-blind American COACH (Combination of Olmesartan Medoxomil and Amlopdine Besylate in Controlling High Blood Pressure) study (2008) showed in 1,940 patients that after eight weeks of treatment the BP goals were most frequently achieved in the ‘combination therapy group’, with 56.3% (54.1–58.5%) and 54.0% (51.8–56.2%) of patients reaching adequate blood pressure of
TL;DR: For more than 20 years after the excitement engendered by their discovery in 1957, there were no significant clinical uses of interferons; however, following their cloning they have been employed as effective treatment for several viral, autoimmune, and neoplastic diseases.
Abstract: For more than 20 years after the excitement engendered by their discovery in 1957 as antiviral agents, there were no significant clinical uses of interferons; however, following their cloning they have been employed as effective treatment for several viral, autoimmune, and neoplastic diseases.
TL;DR: Results showed that significant neurotransmitter peptide biomarkers in the dorsal striatal brain of endogenous and bromocriptine-treated PD animals are found, providing new pharmacotherapeutic strategies for PD patients.
Abstract: We used Neuromolecular Imaging (NMI) and trademarked BRODERICK PROBE® mini-implantable biosensors, to selectively and separately detect neurotransmitters in vivo, on line, within seconds in the dorsal striatal brain of the Parkinson's Disease (PD) animal model. We directly compared our results derived from PD to the normal striatal brain of the non-Parkinson's Disease (non-PD) animal. This advanced biotechnology enabled the imaging of dopamine (DA), serotonin (5-HT), homovanillic acid (HVA) a metabolite of DA, L-tryptophan (L-TP) a precursor to 5-HT and peptides, dynorphin A 1-17 (Dyn A) and somatostatin (somatostatin releasing inhibitory factor) (SRIF). Each neurotransmitter and neurochemical was imaged at a signature electroactive oxidation/half-wave potential in dorsal striatum of the PD as compared with the non-PD animal. Both endogenous and bromocriptine-treated neurochemical profiles in PD and non-PD were imaged using the same experimental paradigm and detection sensitivities. Results showed that we have found significant neurotransmitter peptide biomarkers in the dorsal striatal brain of endogenous and bromocriptine-treated PD animals. The peptide biomarkers were not imaged in dorsal striatal brain of non-PD animals, either endogenously or bromocriptine-treated. These findings provide new pharmacotherapeutic strategies for PD patients. Thus, our findings are highly applicable to the clinical treatment of PD.
TL;DR: Three thermally and hydrolytically stable silylamide trioxanes have been prepared from the natural trioxane artemisinin in only five simple chemical steps and in at least 56% overall yield.
Abstract: Three thermally and hydrolytically stable silylamide trioxanes have been prepared from the natural trioxane artemisinin in only five simple chemical steps and in at least 56% overall yield. Two of these new chemical entities completely cured malariainfected mice at a single oral dose of only 8 mg/kg combined with 24 mg/kg of mefloquine hydrochloride. The high efficacy of this ACT chemotherapy is considerably better than the efficacy using the popular trioxane drug artemether plus mefloquine hydrochloride.
TL;DR: This review analyzes and review the information already gained with Aliskiren, raises questions regarding the advantages of DRIs as monotherapy compared to marketed ACEIs and ARBs, their potential added value in combination with other RAAS modulators and other still unproven benefits in relation to prorenin and renin receptor biology.
Abstract: The renin-angiotensin-aldosterone system (RAAS) plays a dominant role in the pathophysiology of hypertension, diabetes mellitus, chronic kidney disease and chronic heart failure. Therefore, drugs that block key components of the RAAS such as ACE inhibitors (ACEI) and angiotensin receptor blockers (ARBs) have gained wide clinical use for these indications. Despite progress, the morbidity and mortality of patients treated with ACEI or ARBs remain high. Aliskiren (Tekturna, Rasilez) is the first orally active inhibitor of renin approved for clinical use as an antihypertensive agent. The development program has established that at the licensed doses of 150 mg and 300 mg. Aliskiren is effective either as monotherapy or in combination with drugs from the other major classes. In this review we analyze and review the information already gained with Aliskiren, raises questions regarding the advantages of DRIs as monotherapy compared to marketed ACEIs and ARBs, their potential added value in combination with other RAAS modulators and other still unproven benefits in relation to prorenin and renin receptor biology.
TL;DR: The main results of this study emphasize the fact that physicians need a guideline for the management of hypertensive patients and that most of physicians agree with them.
Abstract: Knowledge of guideline implementation pitfalls allows anticipation and solving of problems and may help to promote implementation. The aims of this study were: 1) to find out how much is known among medical professionals about the recommendations for the Management of Arterial Hypertension; 2) to study in depth the extent of implementation and 3) to evaluate the manner in which this guide will be applied to daily medical practice. The Delphi method was used for this work. The total estimated sample size was 2,250 physicians. The carefully selected experts answered questionnaires in two or more rounds. The final sample size was 2,475 physicians. Results of the study are detailed in the article. Among the resultsIt is noteworthy that the guide is viewed as needed among all those who have been interviewed and this agreement about its need is generalised and that the improvement in medical practice, together with individual treatment and cardiovascular risk stratification are viewed positively in opinions reached by consensus by the majority of physicians, regardless of whether they are specialists or general practitioners. The main results of this study emphasize the fact that physicians need a guideline for the management of hypertensive patients and that most of physicians agree with them. The new guidelines on arterial hypertension management are widely known among physicians and there appears to be a global agreement regarding the need for the implementation of the new recommendations.