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Pharmaceuticals
Volume 3
Issue 5
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Pharmaceuticals, Volume 3, Issue 5 (May 2010) – 25 articles , Pages 1286-1710

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101 KiB  
Review
Beneficial and Harmful Interactions of Antibiotics with Microbial Pathogens and the Host Innate Immune System
by Ronald Anderson, Gregory Tintinger, Riana Cockeran, Moliehi Potjo and Charles Feldman
Pharmaceuticals 2010, 3(5), 1694-1710; https://doi.org/10.3390/ph3051694 - 25 May 2010
Cited by 25 | Viewed by 10695
Abstract
In general antibiotics interact cooperatively with host defences, weakening and decreasing the virulence of microbial pathogens, thereby increasing vulnerability to phagocytosis and eradication by the intrinsic antimicrobial systems of the host. Antibiotics, however, also interact with host defences by several other mechanisms, some [...] Read more.
In general antibiotics interact cooperatively with host defences, weakening and decreasing the virulence of microbial pathogens, thereby increasing vulnerability to phagocytosis and eradication by the intrinsic antimicrobial systems of the host. Antibiotics, however, also interact with host defences by several other mechanisms, some harmful, others beneficial. Harmful activities include exacerbation of potentially damaging inflammatory responses, a property of cell-wall targeted agents, which promotes the release of pro-inflammatory microbial cytotoxins and cell-wall components. On the other hand, inhibitors of bacterial protein synthesis, especially macrolides, possess beneficial anti-inflammatory/cytoprotective activities, which result from interference with the production of microbial virulence factors/cytotoxins. In addition to these pathogen-directed, anti-inflammatory activities, some classes of antimicrobial agent possess secondary anti-inflammatory properties, unrelated to their conventional antimicrobial activities, which target cells of the innate immune system, particularly neutrophils. This is a relatively uncommon, potentially beneficial property of antibiotics, which has been described for macrolides, imidazole anti-mycotics, fluoroquinolones, and tetracyclines. Although of largely unproven significance in the clinical setting, increasing awareness of the pro-inflammatory and anti-inflammatory properties of antibiotics may contribute to a more discerning and effective use of these agents. Full article
(This article belongs to the Special Issue Antibiotics)
266 KiB  
Review
Effect of Non-Steroidal Anti-Inflammatory Drugs on Bone Healing
by Jessica Cottrell and J. Patrick O’Connor
Pharmaceuticals 2010, 3(5), 1668-1693; https://doi.org/10.3390/ph3051668 - 25 May 2010
Cited by 82 | Viewed by 18452
Abstract
Nonspecific and COX-2 selective nonsteroidal anti-inflammatory drugs (NSAIDs) function by inhibiting the cyclooxygenase isoenzymes and effectively reduce pain and inflammation attributed to acute or chronic musculoskeletal pathologies. However, use of NSAIDs as an analgesic is thought to negatively contribute to bone healing. This [...] Read more.
Nonspecific and COX-2 selective nonsteroidal anti-inflammatory drugs (NSAIDs) function by inhibiting the cyclooxygenase isoenzymes and effectively reduce pain and inflammation attributed to acute or chronic musculoskeletal pathologies. However, use of NSAIDs as an analgesic is thought to negatively contribute to bone healing. This review strived to provide a thorough unbiased analysis of the current research conducted on animals and humans regarding NSAIDs and their effect on bone healing. Specifically, this review discusses the role of animal models, dosing regiments, and outcome parameters when examining discrepancies about NSAIDS and their effects on bone regeneration. The role of COX-2 in bone regeneration needs to be better defined in order to further elucidate the impact of NSAIDs on bone healing. Full article
(This article belongs to the Special Issue Non-Steroidal Anti-Inflammatory Drugs)
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443 KiB  
Review
NSAIDs: Old Drugs Reveal New Anticancer Targets
by Gary A. Piazza, Adam B. Keeton, Heather N. Tinsley, Jason D. Whitt, Bernard D. Gary, Bini Mathew, Raj Singh, William E. Grizzle and Robert C. Reynolds
Pharmaceuticals 2010, 3(5), 1652-1667; https://doi.org/10.3390/ph3051652 - 25 May 2010
Cited by 57 | Viewed by 20045
Abstract
There is compelling evidence that nonsteroidal anti-inflammatory drugs (NSAIDs) and cyclooxygenase-2 selective inhibitors have antineoplastic activity, but toxicity from cyclooxygenase (COX) inhibition and the suppression of physiologically important prostaglandins limits their use for cancer chemoprevention. Previous studies as reviewed here suggest that the [...] Read more.
There is compelling evidence that nonsteroidal anti-inflammatory drugs (NSAIDs) and cyclooxygenase-2 selective inhibitors have antineoplastic activity, but toxicity from cyclooxygenase (COX) inhibition and the suppression of physiologically important prostaglandins limits their use for cancer chemoprevention. Previous studies as reviewed here suggest that the mechanism for their anticancer properties does not require COX inhibition, but instead involves an off-target effect. In support of this possibility, recent molecular modeling studies have shown that the NSAID sulindac can be chemically modified to selectively design out its COX-1 and COX-2 inhibitory activity. Unexpectedly, certain derivatives that were synthesized based on in silico modeling displayed increased potency to inhibit tumor cell growth. Other experiments have shown that sulindac can inhibit phosphodiesterase to increase intracellular cyclic GMP levels and that this activity is closely associated with its ability to selectively induce apoptosis of tumor cells. Together, these studies suggest that COX-independent mechanisms can be targeted to develop safer and more efficacious drugs for cancer chemoprevention. Full article
(This article belongs to the Special Issue Non-Steroidal Anti-Inflammatory Drugs)
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127 KiB  
Review
Beyond Genetics—Stratified and Personalised Medicines Using Multiple Parameters
by Richard Peck and Patrick Smith
Pharmaceuticals 2010, 3(5), 1637-1651; https://doi.org/10.3390/ph3051637 - 25 May 2010
Cited by 5 | Viewed by 10222
Abstract
Prescribers have been practicing stratified medicine for many years. Patient characteristics, usually non-genetic, including age, comorbidities and concomitant medications are taken into account when deciding which drug to prescribe. In addition, the majority of drugs require dose adjustments across patient subgroups, usually determined [...] Read more.
Prescribers have been practicing stratified medicine for many years. Patient characteristics, usually non-genetic, including age, comorbidities and concomitant medications are taken into account when deciding which drug to prescribe. In addition, the majority of drugs require dose adjustments across patient subgroups, usually determined by non-genetic differences between the subgroups. Whilst pharmacogenetics hold promise for enhancing treatment stratification and even treatment individualisation, non-genetic factors will continue to be very important. Both non-genetic and genetic factors must be considered to improve understanding and quantification of the variability in treatment outcomes and to guide stratification and targeting of patient subgroups to the right drug and also to the right range of doses within that subgroup. Development of stratified medicines must consider non-genetic as well as genetic factors and, where appropriate, include stratification through optimising the dose for each patient or subgroup as well as by choosing the drug most likely to deliver efficacy to that patient or group. Full article
(This article belongs to the Special Issue Personalized Medicine)
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543 KiB  
Review
Molecular Mechanism for Various Pharmacological Activities of NSAIDS
by Tohru Mizushima
Pharmaceuticals 2010, 3(5), 1614-1636; https://doi.org/10.3390/ph3051614 - 25 May 2010
Cited by 19 | Viewed by 13279
Abstract
The anti-inflammatory action of non-steroidal anti-inflammatory drugs (NSAIDs) is mediated through their inhibitory effects on cyclooxygenase (COX) activity. On the other hand, NSAID use is often associated with gastrointestinal complications. The inhibition of COX by NSAIDs is not the sole explanation for the [...] Read more.
The anti-inflammatory action of non-steroidal anti-inflammatory drugs (NSAIDs) is mediated through their inhibitory effects on cyclooxygenase (COX) activity. On the other hand, NSAID use is often associated with gastrointestinal complications. The inhibition of COX by NSAIDs is not the sole explanation for the gastrointestinal side effects of NSAIDs. Furthermore, recent epidemiological studies have revealed that prolonged NSAID use reduces the risk of cancer and Alzheimer’s disease (AD) and a COX-independent unknown mechanism is suggested to be involved in these activities of NSAIDs. In this article, I review our recent work on the COX-independent mechanism involved in NSAID-induced gastric lesions and anti-tumor and anti-AD activities of NSAIDs. Using DNA microarray analysis, we found that NSAIDs affect expression of various genes in a COX-independent manner. We found that membrane permeabilization activity of NSAIDs and resulting NSAID-induced apoptosis are involved in NSAID-induced gastric lesions. On the other hand, induction of expression of tight junction-related genes and endoplasmic reticulum chaperones were suggested to be involved in anti-tumor and anti-AD, respectively, activities of NSAIDs. These results suggest that NSAIDs affect expression of various genes in a COX-independent manner, which is involved in various pharmacological activities of NSAIDs. Full article
(This article belongs to the Special Issue Non-Steroidal Anti-Inflammatory Drugs)
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739 KiB  
Review
NSAIDs, Mitochondria and Calcium Signaling: Special Focus on Aspirin/Salicylates
by Yoshihiro Suzuki, Toshio Inoue and Chisei Ra
Pharmaceuticals 2010, 3(5), 1594-1613; https://doi.org/10.3390/ph3051594 - 19 May 2010
Cited by 23 | Viewed by 14355
Abstract
Aspirin (acetylsalicylic acid) is a well-known nonsteroidal anti-inflammatory drug (NSAID) that has long been used as an anti-pyretic and analgesic drug. Recently, much attention has been paid to the chemopreventive and apoptosis-inducing effects of NSAIDs in cancer cells. These effects have been thought [...] Read more.
Aspirin (acetylsalicylic acid) is a well-known nonsteroidal anti-inflammatory drug (NSAID) that has long been used as an anti-pyretic and analgesic drug. Recently, much attention has been paid to the chemopreventive and apoptosis-inducing effects of NSAIDs in cancer cells. These effects have been thought to be primarily attributed to the inhibition of cyclooxygenase activity and prostaglandin synthesis. However, recent studies have demonstrated unequivocally that certain NSAIDs, including aspirin and its metabolite salicylic acid, exert their anti-inflammatory and chemopreventive effects independently of cyclooxygenase activity and prostaglandin synthesis inhibition. It is becoming increasingly evident that two potential common targets of NSAIDs are mitochondria and the Ca2+ signaling pathway. In this review, we provide an overview of the current knowledge regarding the roles of mitochondria and Ca2+ in the apoptosis-inducing effects as well as some side effects of aspirin, salicylates and other NSAIDs, and introducing the emerging role of L-type Ca2+ channels, a new Ca2+ entry pathway in non-excitable cells that is up-regulated in human cancer cells. Full article
(This article belongs to the Special Issue Non-Steroidal Anti-Inflammatory Drugs)
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Review
Controlling the Mdm2-Mdmx-p53 Circuit
by David L. Waning, Jason A. Lehman, Christopher N. Batuello and Lindsey D. Mayo
Pharmaceuticals 2010, 3(5), 1576-1593; https://doi.org/10.3390/ph3051576 - 18 May 2010
Cited by 24 | Viewed by 10372
Abstract
The p53 tumor suppressor is a key protein in maintaining the integrity of the genome by inducing either cell cycle arrest or apoptosis following cellular stress signals. Two human family members, Mdm2 and Mdmx, are primarily responsible for inactivating p53 transcription and targeting [...] Read more.
The p53 tumor suppressor is a key protein in maintaining the integrity of the genome by inducing either cell cycle arrest or apoptosis following cellular stress signals. Two human family members, Mdm2 and Mdmx, are primarily responsible for inactivating p53 transcription and targeting p53 protein for ubiquitin-mediated degradation. In response to genotoxic stress, post-translational modifications to p53, Mdm2 and Mdmx stabilize and activate p53. The role that phosphorylation of these molecules plays in the cellular response to genotoxic agents has been extensively studied with respect to cancer biology. In this review, we discuss the main phosphorylation events of p53, Mdm2 and Mdmx in response to DNA damage that are important for p53 stability and activity. In tumors that harbor wild-type p53, reactivation of p53 by modulating both Mdm2 and Mdmx signaling is well suited as a therapeutic strategy. However, the rationale for development of kinase inhibitors that target the Mdm2-Mdmx-p53 axis must be carefully considered since modulation of certain kinase signaling pathways has the potential to destabilize and inactivate p53. Full article
(This article belongs to the Special Issue Protein Kinase Inhibitors)
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Review
Chemoprophylaxis of Tropical Infectious Diseases
by William J. H. McBride
Pharmaceuticals 2010, 3(5), 1561-1575; https://doi.org/10.3390/ph3051561 - 18 May 2010
Cited by 5 | Viewed by 10256
Abstract
Travelers to tropical countries are at risk for a variety of infectious diseases. In some cases effective vaccinations are available, but for other infections chemoprophylaxis can be offered. Malaria prevention has become increasingly complex as Plasmodium species become resistant to available drugs. In [...] Read more.
Travelers to tropical countries are at risk for a variety of infectious diseases. In some cases effective vaccinations are available, but for other infections chemoprophylaxis can be offered. Malaria prevention has become increasingly complex as Plasmodium species become resistant to available drugs. In certain high risk settings, antibiotics can be used to prevent leptospirosis, scrub typhus and other infections. Post-exposure prophylaxis is appropriate for selected virulent infections. In this article the evidence for chemoprophylaxis will be reviewed. Full article
(This article belongs to the Special Issue Tropical Medicine)
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Review
The Role of Non-Steroidal Anti-Inflammatory Drugs in the Chemoprevention of Breast Cancer
by Sarah L. Horn and Ian S. Fentiman
Pharmaceuticals 2010, 3(5), 1550-1560; https://doi.org/10.3390/ph3051550 - 17 May 2010
Cited by 6 | Viewed by 8296
Abstract
Epidemiological evidence suggests that non-steroidal anti-inflammatory drugs (NSAIDs) which act as cyclooxygenase (COX-2) inhibitors may reduce breast cancer incidence by up to 20%. These agents are often taken for pain relief by older women with osteoarthritis. Age is the major risk factor for [...] Read more.
Epidemiological evidence suggests that non-steroidal anti-inflammatory drugs (NSAIDs) which act as cyclooxygenase (COX-2) inhibitors may reduce breast cancer incidence by up to 20%. These agents are often taken for pain relief by older women with osteoarthritis. Age is the major risk factor for breast cancer in women with 50% cases being diagnosed in those aged >65 years. NSAIDs reduce serum estradiol by 17% in post-menopausal women and since most of these who develop breast cancers have estrogen receptor positive tumours; this suggests a possible preventative role. Careful use of these agents could provide a strategy for both relief of symptoms of osteoarthritis and also breast cancer prevention. Instead of conducting a randomised trial, proof of efficacy could be from an adequately powered cohort study within the breast screening programme. Full article
(This article belongs to the Special Issue Non-Steroidal Anti-Inflammatory Drugs)
395 KiB  
Review
Nonsteroidal Anti-Inflammatory Drugs (NSAIDs): Progress in Small Molecule Drug Development
by Praveen P. N. Rao, Saad N. Kabir and Tarek Mohamed
Pharmaceuticals 2010, 3(5), 1530-1549; https://doi.org/10.3390/ph3051530 - 14 May 2010
Cited by 88 | Viewed by 23424
Abstract
Ever since the discovery of aspirin, small molecule therapeutics have been widely prescribed to treat inflammation and pain. Aspirin and several small molecule NSAIDs are known to inhibit the enzymes cyclooxygenase-1 (COX-1) and -2 (COX-2). Despite the success of NSAIDs to treat inflammatory [...] Read more.
Ever since the discovery of aspirin, small molecule therapeutics have been widely prescribed to treat inflammation and pain. Aspirin and several small molecule NSAIDs are known to inhibit the enzymes cyclooxygenase-1 (COX-1) and -2 (COX-2). Despite the success of NSAIDs to treat inflammatory disorders, the development of a clinically useful small molecule NSAIDs with decreased side effect profiles is an ongoing effort. The recent discovery and development of selective COX-2 inhibitors was a step toward this direction. Emerging trends are represented by the progress in the development of hybrid agents such as nitric oxide donor-NSAIDs (NO-NSAIDs) and dual COX/lipoxygenase (LOX) inhibitors. This review focuses on the recent advances in the rational design of small molecule NSAIDs in therapy. Full article
(This article belongs to the Special Issue Non-Steroidal Anti-Inflammatory Drugs)
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375 KiB  
Review
Targeted Therapy of Cancer Using Photodynamic Therapy in Combination with Multi-faceted Anti-Tumor Modalities
by Malini Olivo, Ramaswamy Bhuvaneswari, Sasidharan Swarnalatha Lucky, Nagamani Dendukuri and Patricia Soo-Ping Thong
Pharmaceuticals 2010, 3(5), 1507-1529; https://doi.org/10.3390/ph3051507 - 14 May 2010
Cited by 142 | Viewed by 17323
Abstract
Photodynamic therapy (PDT) has emerged as one of the important therapeutic options in the management of cancer and other diseases. PDT involves a tumor-localized photosensitizer (PS), which when appropriately illuminated by visible light converts oxygen into cytotoxic reactive oxygen species (ROS), that attack [...] Read more.
Photodynamic therapy (PDT) has emerged as one of the important therapeutic options in the management of cancer and other diseases. PDT involves a tumor-localized photosensitizer (PS), which when appropriately illuminated by visible light converts oxygen into cytotoxic reactive oxygen species (ROS), that attack key structural entities within the targeted cells, ultimately resulting in necrosis or apoptosis. Though PDT is a selective modality, it can be further enhanced by combining other targeted therapeutic strategies that include the use of synthetic peptides and nanoparticles for selective delivery of photosensitizers. Another potentially promising strategy is the application of targeted therapeutics that exploit a myriad of critical pathways involved in tumorigenesis and metastasis. Vascular disrupting agents that eradicate tumor vasculature during PDT and anti-angiogenic agents that targets specific molecular pathways and prevent the formation of new blood vessels are novel therapeutic approaches that have been shown to improve treatment outcome. In addition to the well-documented mechanisms of direct cell killing and damage to the tumor vasculature, PDT can also activate the body’s immune response against tumors. Numerous pre-clinical studies and clinical observations have demonstrated the immuno-stimulatory capability of PDT. Herein, we aim to integrate the most important findings with regard to the combination of PDT and other novel targeted therapy approaches, detailing its potential in cancer photomedicine. Full article
(This article belongs to the Special Issue Targeted Therapy)
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Review
Critical Overview on the Benefits and Harms of Aspirin
by Chun Shing Kwok and Yoon K. Loke
Pharmaceuticals 2010, 3(5), 1491-1506; https://doi.org/10.3390/ph3051491 - 14 May 2010
Cited by 14 | Viewed by 10837
Abstract
Aspirin is widely used internationally for a variety of indications, with the most prominent one being that of cardiovascular disease. However, aspirin has also been proposed as a treatment option in a diverse range of conditions such as diabetes mellitus, cancer prevention, and [...] Read more.
Aspirin is widely used internationally for a variety of indications, with the most prominent one being that of cardiovascular disease. However, aspirin has also been proposed as a treatment option in a diverse range of conditions such as diabetes mellitus, cancer prevention, and obstetrics. In our overview, we critically appraise the current evidence from recent systematic reviews and meta-analyses covering the benefits of aspirin across these conditions. We also look at evidence that some patients may not derive benefit due to the concept of aspirin resistance. Aspirin is also associated with the potential for significant harm, principally from haemorrhagic adverse events. We critically appraise the threat of haemorrhagic complications, and weigh up these risks against that of any potential benefit. Full article
(This article belongs to the Special Issue Non-Steroidal Anti-Inflammatory Drugs)
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1368 KiB  
Review
Building Cell Selectivity into CPP-Mediated Strategies
by Irene Martín, Meritxell Teixidó and Ernest Giralt
Pharmaceuticals 2010, 3(5), 1456-1490; https://doi.org/10.3390/ph3051456 - 14 May 2010
Cited by 45 | Viewed by 14444
Abstract
There is a pressing need for more effective and selective therapies for cancer and other diseases. Consequently, much effort is being devoted to the development of alternative experimental approaches based on selective systems, which are designed to be specifically directed against target cells. [...] Read more.
There is a pressing need for more effective and selective therapies for cancer and other diseases. Consequently, much effort is being devoted to the development of alternative experimental approaches based on selective systems, which are designed to be specifically directed against target cells. In addition, a large number of highly potent therapeutic molecules are being discovered. However, they do not reach clinical trials because of their low delivery, poor specificity or their incapacity to bypass the plasma membrane. Cell-penetrating peptides (CPPs) are an open door for cell-impermeable compounds to reach intracellular targets. Putting all these together, research is sailing in the direction of the design of systems with the capacity to transport new drugs into a target cell. Some CPPs show cell type specificity while others require modifications or form part of more sophisticated drug delivery systems. In this review article we summarize several strategies for directed drug delivery involving CPPs that have been reported in the literature. Full article
(This article belongs to the Special Issue Cell-penetrating Peptides 2012)
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Review
Suppression of Autoimmune Arthritis by Small Molecule Inhibitors of the JAK/STAT Pathway
by Charles J. Malemud
Pharmaceuticals 2010, 3(5), 1446-1455; https://doi.org/10.3390/ph3051446 - 12 May 2010
Cited by 13 | Viewed by 10976
Abstract
A skewed ratio of pro-inflammatory to anti-inflammatory cytokines, elevated growth factor synthesis and T- and B-lymphocyte activation are 3 hallmarks of rheumatoid arthritis (RA) pathology. Interleukin-6 (IL-6), IL-7, IL-17, IL-12/IL-23 and growth factors, granulocyte macrophage-colony stimulating factor, IL-3, and erythropoietin activate the Janus [...] Read more.
A skewed ratio of pro-inflammatory to anti-inflammatory cytokines, elevated growth factor synthesis and T- and B-lymphocyte activation are 3 hallmarks of rheumatoid arthritis (RA) pathology. Interleukin-6 (IL-6), IL-7, IL-17, IL-12/IL-23 and growth factors, granulocyte macrophage-colony stimulating factor, IL-3, and erythropoietin activate the Janus Kinase/Signal Transducers and Activators of Transcription (JAK/STAT) pathway. Evidence showed that STAT protein phosphorylation (p-STAT) by activated JAKs is permissive for p-STAT to act as transcription factors by binding to STAT-responsive gene promoter sequences. This event is critical for perpetuating RA, in part, by up-regulating pro-inflammatory cytokine gene transcription. Activation of JAK/STAT by cytokines and growth factors can induce ‘cross-talk’ with other signaling pathways by which Stress-Activated Protein/Mitogen-Activated Protein Kinase (SAP/MAPK) and Phosphatidylinositide-3-Kinase (PI3K)-mediated signaling are also activated. JAK-specific small molecule inhibitors (SMIs) were developed to test whether JAK/STAT pathway blockade would regulate autoimmune-mediated inflammation. JAK-specific SMI blockade inhibited p-STAT induced by pro-inflammatory cytokines in vitro. Systemically administered JAK-specific SMI blockade also ameliorated biomarkers of inflammation in well-validated arthritis animal models. A few JAK-specific SMIs have made their way into RA clinical trials. In fact, the JAK3-specific SMI, CP-690,500 is the first JAK/STAT SMI to be assessed for clinical efficacy in a Phase III RA trial. Full article
(This article belongs to the Special Issue Protein Kinase Inhibitors)
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Review
Natural Products in Epilepsy—the Present Situation and Perspectives for the Future
by Dana Ekstein and Steven C. Schachter
Pharmaceuticals 2010, 3(5), 1426-1445; https://doi.org/10.3390/ph3051426 - 12 May 2010
Cited by 29 | Viewed by 11730
Abstract
More efficacious and better tolerated treatments for epilepsy are clearly needed. Complementary and alternative medicine (CAM) has a long history of use in certain parts of the world and has gained increasing interest over the last decades in Western countries. In countries with [...] Read more.
More efficacious and better tolerated treatments for epilepsy are clearly needed. Complementary and alternative medicine (CAM) has a long history of use in certain parts of the world and has gained increasing interest over the last decades in Western countries. In countries with a Western-based type of medical system, people with epilepsy (PWE) take natural products or engage in other forms of CAM mainly to enhance general health, but also to prevent seizures or to alleviate symptoms of comorbidities or side effects of antiepileptic medications. In other countries, well developed medical systems, such as traditional Chinese Medicine and Ayurveda, are often the basis for treating PWE. Based on anecdotal reports of efficacy in PWE, natural products from these and other traditions are increasingly being studied in animal models of epilepsy, and candidates for further clinical development have been identified. It is likely, therefore, that natural products will be further evaluated for safety, tolerability and efficacy in PWE with drug-resistant seizures. Full article
(This article belongs to the Special Issue Antiepileptic Drugs)
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Review
Acid-Sensing Ion Channels and Pain
by Qihai Gu and Lu-Yuan Lee
Pharmaceuticals 2010, 3(5), 1411-1425; https://doi.org/10.3390/ph3051411 - 11 May 2010
Cited by 27 | Viewed by 11013
Abstract
Pathophysiological conditions such as inflammation, ischemia, infection and tissue injury can all evoke pain, and each is accompanied by local acidosis. Acid sensing ion channels (ASICs) are proton-gated cation channels expressed in both central and peripheral nervous systems. Increasing evidence suggests that ASICs [...] Read more.
Pathophysiological conditions such as inflammation, ischemia, infection and tissue injury can all evoke pain, and each is accompanied by local acidosis. Acid sensing ion channels (ASICs) are proton-gated cation channels expressed in both central and peripheral nervous systems. Increasing evidence suggests that ASICs represent essential sensors for tissue acidosis-related pain. This review provides an update on the role of ASICs in pain sensation and discusses their therapeutic potential for pain management. Full article
(This article belongs to the Special Issue Ion Channels as Therapeutic Targets for Pain)
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1064 KiB  
Review
Effects of NSAIDs on Differentiation and Function of Human and Murine Osteoclasts – Crucial ‘Human Osteoclastology’
by Shigeru Kotake, Toru Yago, Manabu Kawamoto and Yuki Nanke
Pharmaceuticals 2010, 3(5), 1394-1410; https://doi.org/10.3390/ph3051394 - 11 May 2010
Cited by 18 | Viewed by 13005
Abstract
Osteoclasts play a critical role in both normal bone metabolism and bone resorption in the joints of patients with rheumatoid arthritis. It has been reported that non-steroidal anti-inflammatory drugs (NSAIDs) inhibit murine osteoclastogenesis in vitro and murine arthritis models in vivo, but [...] Read more.
Osteoclasts play a critical role in both normal bone metabolism and bone resorption in the joints of patients with rheumatoid arthritis. It has been reported that non-steroidal anti-inflammatory drugs (NSAIDs) inhibit murine osteoclastogenesis in vitro and murine arthritis models in vivo, but not the destruction of joints of patients with rheumatoid arthritis. In the current review article, we review the recent findings in the effect of NSAIDs on the formation and function of human and murine osteoclasts both in vitro and in vivo, underlining the importance of studies using human osteoclasts. Since 2009, we have suggested a novel term ‘human osteoclastology’. Full article
(This article belongs to the Special Issue Non-Steroidal Anti-Inflammatory Drugs)
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210 KiB  
Review
Combining Biofilm-Controlling Compounds and Antibiotics as a Promising New Way to Control Biofilm Infections
by Andréia Bergamo Estrela and Wolf-Rainer Abraham
Pharmaceuticals 2010, 3(5), 1374-1393; https://doi.org/10.3390/ph3051374 - 11 May 2010
Cited by 60 | Viewed by 15104
Abstract
Many bacteria grow on surfaces forming biofilms. In this structure, they are well protected and often high dosages of antibiotics cannot clear infectious biofilms. The formation and stabilization of biofilms are mediated by diffusible autoinducers (e.g. N-acyl homoserine lactones, small peptides, furanosyl [...] Read more.
Many bacteria grow on surfaces forming biofilms. In this structure, they are well protected and often high dosages of antibiotics cannot clear infectious biofilms. The formation and stabilization of biofilms are mediated by diffusible autoinducers (e.g. N-acyl homoserine lactones, small peptides, furanosyl borate diester). Metabolites interfering with this process have been identified in plants, animals and microbes, and synthetic analogues are known. Additionally, this seems to be not the only way to control biofilms. Enzymes capable of cleaving essential components of the biofilm matrix, e.g. polysaccharides or extracellular DNA, and thus weakening the biofilm architecture have been identified. Bacteria also have mechanisms to dissolve their biofilms and return to planktonic lifestyle. Only a few compounds responsible for the signalling of these processes are known, but they may open a completely novel line of biofilm control. All these approaches lead to the destruction of the biofilm but not the killing of the pathogens. Therefore, a combination of biofilm-destroying compounds and antibiotics to handle biofilm infections is proposed. In this article, different approaches to combine biofilm-controlling compounds and antibiotics to fight biofilm infections are discussed, as well as the balance between biofilm formation and virulence. Full article
(This article belongs to the Special Issue Antibiotics)
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260 KiB  
Review
Lp-PLA2 Inhibition—The Atherosclerosis Panacea?
by Mahir Karakas and Wolfgang Koenig
Pharmaceuticals 2010, 3(5), 1360-1373; https://doi.org/10.3390/ph3051360 - 29 Apr 2010
Cited by 16 | Viewed by 15571
Abstract
Based on the complex pathophysiology of atherosclerosis, a large number of biomarkers that relate to lipids, inflammation, immunity, thrombosis and hemostasis, have been investigated experimentally, in epidemiologic studies and in clinical trials. Interest focuses on their potential role to aid in risk stratification, [...] Read more.
Based on the complex pathophysiology of atherosclerosis, a large number of biomarkers that relate to lipids, inflammation, immunity, thrombosis and hemostasis, have been investigated experimentally, in epidemiologic studies and in clinical trials. Interest focuses on their potential role to aid in risk stratification, as possible surrogate markers of atherosclerosis, and potential targets for therapy. More recently, one lipid associated biomarker, lipoprotein-associated phospholipase A2 (Lp-PLA2), has gained considerable interest. In addition to a plausible pathophysiological role by generating pro-inflammatory and pro-atherogenic compounds from oxidized LDL in the vessel wall, there is a large, fairly consistent epidemiological database indicating that increased levels of Lp-PLA2 mass or activity are associated with increased risk for cardiovascular outcomes; such data further suggest that it might improve risk stratification. In addition, clinical studies indicate that increased Lp-PLA2 levels are associated with endothelial dysfunction. Moreover, it may also serve as an interesting therapeutic target, since a specific inhibitor of the enzyme is available with promising animal data and initial positive data in humans. Recent experimental data from a hyperlipidemic diabetic pig model strongly suggest that increased Lp-PLA2 in the vessel wall is associated with a more vulnerable plaque phenotype which can be modulated by inhibiting Lp-PLA2 activity. A biomarker study in more than 1,000 patients with CHD over three months has demonstrated a positive effect on various inflammatory molecules. In addition, an imaging study using IVUS based modalities (greyscale, virtual histology, and palpography) together with a panel of biomarkers (IBIS-2) has been done in more than 300 patients with CHD treated over 12 months and results indicate that the progression of the necrotic core of the plaque can be retarded. Inhibition of the pro-atherogenic and pro-inflammatory effects of Lp-PLA2 may therefore contribute to decrease the residual risk in high risk patients already on polypharmacotherapy. This hypothesis is now being tested in two large phase 3 clinical trials. Thus, Lp-PLA2 indeed may represent a biomarker and a promising target for intervention. Full article
(This article belongs to the Special Issue Biomarkers)
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Review
Health Economics of Antibiotics
by Steven Simoens
Pharmaceuticals 2010, 3(5), 1348-1359; https://doi.org/10.3390/ph3051348 - 29 Apr 2010
Cited by 4 | Viewed by 10964
Abstract
Antibiotics have made a significant contribution to improving patient health, but policy makers and health care payers are concerned about the costs of antibiotics in addition to their effectiveness. This paper aims to assess the value of antibiotics by examining incremental cost-utility ratios [...] Read more.
Antibiotics have made a significant contribution to improving patient health, but policy makers and health care payers are concerned about the costs of antibiotics in addition to their effectiveness. This paper aims to assess the value of antibiotics by examining incremental cost-utility ratios of antibiotics. Evidence was derived from cost-utility analyses of antibiotics included in the Tufts-New England Center Cost-Effectiveness Analysis Registry through September 2009. The analysis included 85 incremental cost-utility ratios from 23 cost-utility analyses. The findings showed that 38.8% of incremental cost-utility ratios related to dominant antibiotics (i.e., more effective and less costly than the comparator); 45.9% referred to antibiotics that improved effectiveness, but also increased costs; and 15.3% related to dominated antibiotics (i.e., less effective and more costly than the comparator). The median ratio was 748 € per quality-adjusted life year. Using threshold values of 20,000 € per quality-adjusted life year and 50,000 € per quality-adjusted life year, the probability that an antibiotic provides value for money was 64% and 67%, respectively. The current evidence base suggests that the majority of antibiotics provide value for money and that antibiotics can aid decision makers to attain further population health improvements, whilst containing pharmaceutical expenditures. Full article
(This article belongs to the Special Issue Antibiotics)
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Review
NSAIDs, Opioids, Cannabinoids and the Control of Pain by the Central Nervous System
by Horacio Vanegas, Enrique Vazquez and Victor Tortorici
Pharmaceuticals 2010, 3(5), 1335-1347; https://doi.org/10.3390/ph3051335 - 29 Apr 2010
Cited by 45 | Viewed by 18683
Abstract
Nonsteroidal anti-inflammatory drugs (NSAIDs) act upon peripheral tissues and upon the central nervous system to produce analgesia. A major central target of NSAIDs is the descending pain control system. The rostral structures of the descending pain control system send impulses towards the spinal [...] Read more.
Nonsteroidal anti-inflammatory drugs (NSAIDs) act upon peripheral tissues and upon the central nervous system to produce analgesia. A major central target of NSAIDs is the descending pain control system. The rostral structures of the descending pain control system send impulses towards the spinal cord and regulate the transmission of pain messages. Key structures of the descending pain control system are the periaqueductal gray matter (PAG) and the rostral ventromedial region of the medulla (RVM), both of which are critical targets for endogenous opioids and opiate pharmaceuticals. NSAIDs also act upon PAG and RVM to produce analgesia and, if repeatedly administered, induce tolerance to themselves and cross-tolerance to opioids. Experimental evidence shows that this is due to an interaction of NSAIDs with endogenous opioids along the descending pain control system. Analgesia by NSAIDs along the descending pain control system also requires an activation of the CB1 endocannabinoid receptor. Several experimental approaches suggest that opioids, NSAIDs and cannabinoids in PAG and RVM cooperate to decrease GABAergic inhibition and thus enhance the descending flow of impulses that inhibit pain. Full article
(This article belongs to the Special Issue Non-Steroidal Anti-Inflammatory Drugs)
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Review
Prospects for the Use of ATR Inhibitors to Treat Cancer
by Jill M. Wagner and Scott H. Kaufmann
Pharmaceuticals 2010, 3(5), 1311-1334; https://doi.org/10.3390/ph3051311 - 28 Apr 2010
Cited by 52 | Viewed by 17791
Abstract
ATR is an apical kinase in one of the DNA-damage induced checkpoint pathways. Despite the development of inhibitors of kinases structurally related to ATR, as well as inhibitors of the ATR substrate Chk1, no ATR inhibitors have yet been developed. Here we review [...] Read more.
ATR is an apical kinase in one of the DNA-damage induced checkpoint pathways. Despite the development of inhibitors of kinases structurally related to ATR, as well as inhibitors of the ATR substrate Chk1, no ATR inhibitors have yet been developed. Here we review the effects of ATR downregulation in cancer cells and discuss the potential for development of ATR inhibitors for clinical use. Full article
(This article belongs to the Special Issue Protein Kinase Inhibitors)
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Review
The Role of Non-Steroidal Anti-Inflammatory Drugs in Renal Colic
by Kim Davenport and Elizabeth Waine
Pharmaceuticals 2010, 3(5), 1304-1310; https://doi.org/10.3390/ph3051304 - 28 Apr 2010
Cited by 27 | Viewed by 18590
Abstract
NSAIDs provide optimal analgesia in renal colic due to the reduction in glomerular filtration and renal pelvic pressure, ureteric peristalsis and ureteric oedema. Prevention of glomerular afferent arteriolar vasodilatation renders these patients at risk of renal impairment. NSAIDs have the additional benefit of [...] Read more.
NSAIDs provide optimal analgesia in renal colic due to the reduction in glomerular filtration and renal pelvic pressure, ureteric peristalsis and ureteric oedema. Prevention of glomerular afferent arteriolar vasodilatation renders these patients at risk of renal impairment. NSAIDs have the additional benefit of reducing the number of new colic episodes and preventing subsequent readmission to hospital. Despite recent work promoting the use of pharmacological agents to improve stone passage rates, NSAIDs do not appear to reduce the time to stone passage or increase the likelihood of stone passage in renal colic. Full article
(This article belongs to the Special Issue Non-Steroidal Anti-Inflammatory Drugs)
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Review
The Treatment of Melioidosis
by Timothy J.J. Inglis
Pharmaceuticals 2010, 3(5), 1296-1303; https://doi.org/10.3390/ph3051296 - 27 Apr 2010
Cited by 39 | Viewed by 14180
Abstract
Melioidosis is a complex bacterial infection, treatment of which combines the urgency of treating rapidly fatal Gram negative septicaemia with the need for eradication of long-term persistent disease in pulmonary, soft tissue, skeletal and other organ systems. Incremental improvements in treatment have been [...] Read more.
Melioidosis is a complex bacterial infection, treatment of which combines the urgency of treating rapidly fatal Gram negative septicaemia with the need for eradication of long-term persistent disease in pulmonary, soft tissue, skeletal and other organ systems. Incremental improvements in treatment have been made as a result of multicentre collaboration across the main endemic region of Southeast Asia and northern Australia. There is an emerging consensus on the three main patterns of antimicrobial chemotherapy; initial (Phase 1) treatment, subsequent eradication (Phase 2) therapy and most recently post-exposure (Phase 0) prophylaxis. The combination of agents used, duration of therapy and need for adjunct modalities depends on the type, severity and antimicrobial susceptibility of infection. New antibiotic and adjunct therapies are at an investigational stage but on currently available data are unlikely to make a significant impact on this potentially fatal infection. Full article
(This article belongs to the Special Issue Tropical Medicine)
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Review
Effects of NSAIDs on the Inner Ear: Possible Involvement in Cochlear Protection
by Tomofumi Hoshino, Keiji Tabuchi and Akira Hara
Pharmaceuticals 2010, 3(5), 1286-1295; https://doi.org/10.3390/ph3051286 - 27 Apr 2010
Cited by 18 | Viewed by 11087
Abstract
Cyclooxygenase and lipoxygenase, two important enzymes involved in arachidonic acid metabolism, are major targets of non-steroidal anti-inflammatory drugs (NSAIDs). Recent investigations suggest that arachidonic cascades and their metabolites may be involved in maintaining inner ear functions. The excessive use of aspirin may cause [...] Read more.
Cyclooxygenase and lipoxygenase, two important enzymes involved in arachidonic acid metabolism, are major targets of non-steroidal anti-inflammatory drugs (NSAIDs). Recent investigations suggest that arachidonic cascades and their metabolites may be involved in maintaining inner ear functions. The excessive use of aspirin may cause tinnitus in humans and impairment of the outer hair cell functions in experimental animals. On the other hand, NSAIDs reportedly exhibit protective effects against various kinds of inner ear disorder. The present review summarizes the effects of NSAIDs on cochlear pathophysiology. NSAIDs are a useful ameliorative adjunct in the management of inner ear disorders. Full article
(This article belongs to the Special Issue Non-Steroidal Anti-Inflammatory Drugs)
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