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Pharmaceuticals
Volume 4
Issue 5
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Pharmaceuticals, Volume 4, Issue 5 (May 2011) – 6 articles , Pages 681-781

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170 KiB  
Review
The Role of Carvedilol in the Treatment of Dilated and Anthracyclines-Induced Cardiomyopathy
by Kenichi Watanabe, Wawaimuli Arozal, Flori R. Sari, Somasundaram Arumugam, Rajarajan A. Thandavarayan, Kenji Suzuki and Makoto Kodama
Pharmaceuticals 2011, 4(5), 770-781; https://doi.org/10.3390/ph4050770 - 24 May 2011
Cited by 4 | Viewed by 8655
Abstract
Although chronic sympathetic activation provides inotropic and chronotropic support to the failing heart, such activation may also have deleterious effects, including the direct cardiotoxic effects of catecholamines, activation of the renin-angiotensin-aldosterone system and an increase in myocardial oxygen demand. These observations indicate that [...] Read more.
Although chronic sympathetic activation provides inotropic and chronotropic support to the failing heart, such activation may also have deleterious effects, including the direct cardiotoxic effects of catecholamines, activation of the renin-angiotensin-aldosterone system and an increase in myocardial oxygen demand. These observations indicate that β-blockade might be beneficial in the treatment of heart failure resulting from dilated cardiomyopathy or ischaemic heart disease. Carvedilol is a non-selective β-blocker acting on β1-, β2-, and α1-adrenoceptors. It possesses potent anti-oxidant and anti-apoptotic properties, along with neuroprotective, vasculoprotective, cardioprotective effects, and it has reduced overall mortality in patients with heart failure in controlled clinical trials. Its role in treating cardiomyopathy requires focus. The fact that anthracyclines are cardiotoxic seriously narrows their therapeutic index in cancer therapy. The cardiotoxic risk increases with the cumulative dose and may lead to congestive heart failure and dilated cardiomyopathy in adults and in children. This review focuses on recent research regarding the beneficial effects of carvedilol in the treatment of dilated cardiomyopathy and to revisit the available evidence on the cardioprotection of carvedilol when associated with anthracycline and to explain the mechanisms underlying the benefits of their co-administration. Full article
(This article belongs to the Special Issue Betablockers)
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238 KiB  
Article
Prediction of Positions of Active Compounds Makes It Possible To Increase Activity in Fragment-Based Drug Development
by Yoshifumi Fukunishi
Pharmaceuticals 2011, 4(5), 758-769; https://doi.org/10.3390/ph4050758 - 20 May 2011
Cited by 1 | Viewed by 6587
Abstract
We have developed a computational method that predicts the positions of active compounds, making it possible to increase activity as a fragment evolution strategy. We refer to the positions of these compounds as the active position. When an active fragment compound is found, [...] Read more.
We have developed a computational method that predicts the positions of active compounds, making it possible to increase activity as a fragment evolution strategy. We refer to the positions of these compounds as the active position. When an active fragment compound is found, the following lead generation process is performed, primarily to increase activity. In the current method, to predict the location of the active position, hydrogen atoms are replaced by small side chains, generating virtual compounds. These virtual compounds are docked to a target protein, and the docking scores (affinities) are examined. The hydrogen atom that gives the virtual compound with good affinity should correspond to the active position and it should be replaced to generate a lead compound. This method was found to work well, with the prediction of the active position being 2 times more efficient than random synthesis. In the current study, 15 examples of lead generation were examined. The probability of finding active positions among all hydrogen atoms was 26%, and the current method accurately predicted 60% of the active positions. Full article
(This article belongs to the Special Issue Advances in Drug Design)
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161 KiB  
Review
Protein Traffic Is an Intracellular Target in Alcohol Toxicity
by Guillermo Esteban-Pretel, María Pilar Marín, Ana M. Romero, Xavier Ponsoda, Raul Ballestin, Juan J. Canales and Jaime Renau-Piqueras
Pharmaceuticals 2011, 4(5), 741-757; https://doi.org/10.3390/ph4050741 - 17 May 2011
Cited by 6 | Viewed by 6985
Abstract
Eukaryotic cells comprise a set of organelles, surrounded by membranes with a unique composition, which is maintained by a complex synthesis and transport system. Cells also synthesize the proteins destined for secretion. Together, these processes are known as the secretory pathway or exocytosis. [...] Read more.
Eukaryotic cells comprise a set of organelles, surrounded by membranes with a unique composition, which is maintained by a complex synthesis and transport system. Cells also synthesize the proteins destined for secretion. Together, these processes are known as the secretory pathway or exocytosis. In addition, many molecules can be internalized by cells through a process called endocytosis. Chronic and acute alcohol (ethanol) exposure alters the secretion of different essential products, such as hormones, neurotransmitters and others in a variety of cells, including central nervous system cells. This effect could be due to a range of mechanisms, including alcohol-induced alterations in the different steps involved in intracellular transport, such as glycosylation and vesicular transport along cytoskeleton elements. Moreover, alcohol consumption during pregnancy disrupts developmental processes in the central nervous system. No single mechanism has proved sufficient to account for these effects, and multiple factors are likely involved. One such mechanism indicates that ethanol also perturbs protein trafficking. The purpose of this review is to summarize our understanding of how ethanol exposure alters the trafficking of proteins in different cell systems, especially in central nervous system cells (neurons and astrocytes) in adult and developing brains. Full article
(This article belongs to the Special Issue Drug Abuse Targets)
205 KiB  
Review
Hormesis and Female Sex Hormones
by Jakob O. Strom, Annette Theodorsson and Elvar Theodorsson
Pharmaceuticals 2011, 4(5), 726-740; https://doi.org/10.3390/ph4050726 - 16 May 2011
Cited by 15 | Viewed by 8507
Abstract
Hormone replacement after menopause has in recent years been the subject of intense scientific debate and public interest and has sparked intense research efforts into the biological effects of estrogens and progestagens. However, there are reasons to believe that the doses used and [...] Read more.
Hormone replacement after menopause has in recent years been the subject of intense scientific debate and public interest and has sparked intense research efforts into the biological effects of estrogens and progestagens. However, there are reasons to believe that the doses used and plasma concentrations produced in a large number of studies casts doubt on important aspects of their validity. The concept of hormesis states that a substance can have diametrically different effects depending on the concentration. Even though estrogens and progestagens have proven prone to this kind of dose-response relation in a multitude of studies, the phenomenon remains clearly underappreciated as exemplified by the fact that it is common practice to only use one hormone dose in animal experiments. If care is not taken to adjust the concentrations of estrogens and progestagens to relevant biological conditions, the significance of the results may be questionable. Our aim is to review examples of female sexual steroids demonstrating bidirectional dose-response relations and to discuss this in the perspective of hormesis. Some examples are highlighted in detail, including the effects on cerebral ischemia, inflammation, cardiovascular diseases and anxiety. Hopefully, better understanding of the hormesis phenomenon may result in improved future designs of studies of female sexual steroids. Full article
(This article belongs to the Special Issue Hormone Therapy)
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455 KiB  
Article
Fluorescent β-Blockers as Tools to Study Presynaptic Mechanisms of Neurosecretion
by Beatriz Beltran, Romen Carrillo, Tomas Martin, Victor S. Martin, Jose D. Machado and Ricardo Borges
Pharmaceuticals 2011, 4(5), 713-725; https://doi.org/10.3390/ph4050713 - 28 Apr 2011
Cited by 6 | Viewed by 7521
Abstract
Several, if not all adrenergic β-blockers (β-Bs), accumulate progressively inside secretory vesicles in a time- and concentration-dependent manner, and could be considered to be false neurotransmitters. This transmitter effect is most likely unrelated to their ability to block adrenergic receptors, but it could [...] Read more.
Several, if not all adrenergic β-blockers (β-Bs), accumulate progressively inside secretory vesicles in a time- and concentration-dependent manner, and could be considered to be false neurotransmitters. This transmitter effect is most likely unrelated to their ability to block adrenergic receptors, but it could explain the delay in lowering arterial pressure in hypertensive patients. We have developed a new drug to monitor the accumulation of β-Bs inside living cells, RCTM-3, which fluoresces in the visible spectrum. Here we describe the procedure to synthesize this new compound, as well as its fluorescent properties, pharmacological profile and its accumulation inside the secretory vesicles of PC12 cells. Full article
(This article belongs to the Special Issue Betablockers)
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246 KiB  
Review
Expanding the Antimalarial Drug Arsenal—Now, But How?
by Brian T. Grimberg and Rajeev K. Mehlotra
Pharmaceuticals 2011, 4(5), 681-712; https://doi.org/10.3390/ph4050681 - 26 Apr 2011
Cited by 56 | Viewed by 10027
Abstract
The number of available and effective antimalarial drugs is quickly dwindling. This is mainly because a number of drug resistance-associated mutations in malaria parasite genes, such as crt, mdr1, dhfr/dhps, and others, have led to widespread resistance to [...] Read more.
The number of available and effective antimalarial drugs is quickly dwindling. This is mainly because a number of drug resistance-associated mutations in malaria parasite genes, such as crt, mdr1, dhfr/dhps, and others, have led to widespread resistance to all known classes of antimalarial compounds. Unfortunately, malaria parasites have started to exhibit some level of resistance in Southeast Asia even to the most recently introduced class of drugs, artemisinins. While there is much need, the antimalarial drug development pipeline remains woefully thin, with little chemical diversity, and there is currently no alternative to the precious artemisinins. It is difficult to predict where the next generation of antimalarial drugs will come from; however, there are six major approaches: (i) re-optimizing the use of existing antimalarials by either replacement/rotation or combination approach; (ii) repurposing drugs that are currently used to treat other infections or diseases; (iii) chemically modifying existing antimalarial compounds; (iv) exploring natural sources; (v) large-scale screening of diverse chemical libraries; and (vi) through parasite genome-based (“targeted”) discoveries. When any newly discovered effective antimalarial treatment is used by the populus, we must maintain constant vigilance for both parasite-specific and human-related factors that are likely to hamper its success. This article is neither comprehensive nor conclusive. Our purpose is to provide an overview of antimalarial drug resistance, associated parasite genetic factors (1. Introduction; 2. Emergence of artemisinin resistance in P. falciparum), and the antimalarial drug development pipeline (3. Overview of the global pipeline of antimalarial drugs), and highlight some examples of the aforementioned approaches to future antimalarial treatment. These approaches can be categorized into “short term” (4. Feasible options for now) and “long term” (5. Next generation of antimalarial treatment—Approaches and candidates). However, these two categories are interrelated, and the approaches in both should be implemented in parallel with focus on developing a successful, long-lasting antimalarial chemotherapy. Full article
(This article belongs to the Special Issue New Antimalarial Drugs)
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