Pharmaceuticals

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Open AccessReview

NSAIDs in the Acute Treatment of Migraine: A Review of Clinical and Experimental Data

by Arpad Pardutz and Jean Schoenen

Pharmaceuticals 2010, 3(6), 1966-1987; https://doi.org/10.3390/ph3061966 - 17 Jun 2010

Cited by 47 | Viewed by 17135

Migraine is a common disabling neurological disorder with a serious socio-economical burden. By blocking cyclooxygenase nonsteroidal anti-inflammatory drugs (NSAIDs) decrease the synthesis of prostaglandins, which are involved in the pathophysiology of migraine headaches. Despite the introduction more than a decade ago of a [...] Read more.

Migraine is a common disabling neurological disorder with a serious socio-economical burden. By blocking cyclooxygenase nonsteroidal anti-inflammatory drugs (NSAIDs) decrease the synthesis of prostaglandins, which are involved in the pathophysiology of migraine headaches. Despite the introduction more than a decade ago of a new class of migraine-specific drugs with superior efficacy, the triptans, NSAIDs remain the most commonly used therapies for the migraine attack. This is in part due to their wide availability as over-the-counter drugs and their pharmaco-economic advantages, but also to a favorable efficacy/side effect profile at least in attacks of mild and moderate intensity. We summarize here both the experimental data showing that NSAIDs are able to influence several pathophysiological facets of the migraine headache and the clinical studies providing evidence for the therapeutic efficacy of various subclasses of NSAIDs in migraine therapy. Taken together these data indicate that there are several targets for NSAIDs in migraine pathophysiology and that on the spectrum of clinical potency acetaminophen is at the lower end while ibuprofen is among the most effective drugs. Acetaminophen and aspirin excluded, comparative trials between the other NSAIDs are missing. Since evidence-based criteria are scarce, the selection of an NSAID should take into account proof and degree of efficacy, rapid GI absorption, gastric ulcer risk and previous experience of each individual patient. If selected and prescribed wisely, NSAIDs are precious, safe and cost-efficient drugs for the treatment of migraine attacks. Full article

(This article belongs to the Special Issue Non-Steroidal Anti-Inflammatory Drugs)

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Open AccessReview

Non-Steroidal Anti-Inflammatory Drugs and Brain Inflammation: Effects on Microglial Functions

by Maria Antonietta Ajmone-Cat, Antonietta Bernardo, Anita Greco and Luisa Minghetti

Pharmaceuticals 2010, 3(6), 1949-1965; https://doi.org/10.3390/ph3061949 - 14 Jun 2010

Cited by 96 | Viewed by 20569

Abstract

The term NSAID refers to structurally diverse chemical compounds that share the ability to inhibit the activity of the prostaglandin (PG) biosynthetic enzymes, the cyclooxygenase (COX) isoforms 1 and 2. The suppression of PG synthesis at sites of inflammation has been regarded as [...] Read more.

The term NSAID refers to structurally diverse chemical compounds that share the ability to inhibit the activity of the prostaglandin (PG) biosynthetic enzymes, the cyclooxygenase (COX) isoforms 1 and 2. The suppression of PG synthesis at sites of inflammation has been regarded as primarily responsible for the beneficial properties of NSAIDs, but several COX-independent effects have been described in recent years. Epidemiological studies indicate that NSAIDs are neuroprotective, although the mechanisms underlying their beneficial effect remain largely unknown. Microglial cells play a major role in brain inflammation and are often viewed as major contributors to the neurodegeneration. Therefore, microglia represent a likely target for NSAIDs within the brain. In the present review, we focused on the direct effects of NSAIDs and selective COX-2 inhibitors on microglial functions and discuss the potential efficacy in controlling brain inflammation. Full article

(This article belongs to the Special Issue Non-Steroidal Anti-Inflammatory Drugs)

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Open AccessReview

Unlocking the Door to Neuronal Woes in Alzheimer’s Disease: Aβ and Mitochondrial Permeability Transition Pore

by Heng Du and Shirley ShiDu Yan

Pharmaceuticals 2010, 3(6), 1936-1948; https://doi.org/10.3390/ph3061936 - 14 Jun 2010

Cited by 12 | Viewed by 10055

Abstract

Mitochondrial dysfunction occurs early in the progression of Alzheimer’s disease. Amyloid-β peptide has deleterious effects on mitochondrial function and contributes to energy failure, respiratory chain impairment, neuronal apoptosis, and generation of reactive oxygen species in Alzheimer’s disease. The mechanisms underlying amyloid-β [...] Read more.

Mitochondrial dysfunction occurs early in the progression of Alzheimer’s disease. Amyloid-β peptide has deleterious effects on mitochondrial function and contributes to energy failure, respiratory chain impairment, neuronal apoptosis, and generation of reactive oxygen species in Alzheimer’s disease. The mechanisms underlying amyloid-β induced mitochondrial stress remain unclear. Emerging evidence indicates that mitochondrial permeability transition pore is important for maintenance of mitochondrial and neuronal function in aging and neurodegenerative disease. Cyclophilin D (Cyp D) plays a central role in opening mitochondrial permeability transition pores, ultimately leading to cell death. Interaction of amyloid-β with cyclophilin D triggers or enhances the formation of mitochondrial permeability transition pores, consequently exacerbating mitochondrial and neuronal dysfunction, as shown by decreased mitochondrial membrane potential, impaired mitochondrial respiration function, and increased oxidative stress and cytochrome c release. Blockade of cyclophilin D by genetic abrogation or pharmacologic inhibition protects mitochondria and neurons from amyloid-β induced toxicity, suggesting that cyclophilin D dependent mitochondrial transition pores are a therapeutic target for Alzheimer’s disease. Full article

(This article belongs to the Special Issue Mitochondrial Drugs for Neurodegenerative Diseases)

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Open AccessReview

Therapeutic Drug Monitoring of the Newer Anti-Epilepsy Medications

by Matthew D. Krasowski

Pharmaceuticals 2010, 3(6), 1909-1935; https://doi.org/10.3390/ph3061909 - 11 Jun 2010

Cited by 77 | Viewed by 17502

Abstract

In the past twenty years, 14 new antiepileptic drugs have been approved for use in the United States and/or Europe. These drugs are eslicarbazepine acetate, felbamate, gabapentin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, rufinamide, stiripentol, tiagabine, topiramate, vigabatrin and zonisamide. In general, the clinical [...] Read more.

In the past twenty years, 14 new antiepileptic drugs have been approved for use in the United States and/or Europe. These drugs are eslicarbazepine acetate, felbamate, gabapentin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, rufinamide, stiripentol, tiagabine, topiramate, vigabatrin and zonisamide. In general, the clinical utility of therapeutic drug monitoring has not been established in clinical trials for these new anticonvulsants, and clear guidelines for drug monitoring have yet to be defined. The antiepileptic drugs with the strongest justifications for drug monitoring are lamotrigine, oxcarbazepine, stiripentol, and zonisamide. Stiripentol and tiagabine are strongly protein bound and are candidates for free drug monitoring. Therapeutic drug monitoring has lower utility for gabapentin, pregabalin, and vigabatrin. Measurement of salivary drug concentrations has potential utility for therapeutic drug monitoring of lamotrigine, levetiracetam, and topiramate. Therapeutic drug monitoring of the new antiepileptic drugs will be discussed in managing patients with epilepsy. Full article

(This article belongs to the Special Issue Antiepileptic Drugs)

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Open AccessReview

A Review of Topical Diclofenac Use in Musculoskeletal Disease

by Bindu Nair and Regina Taylor-Gjevre

Pharmaceuticals 2010, 3(6), 1892-1908; https://doi.org/10.3390/ph3061892 - 11 Jun 2010

Cited by 40 | Viewed by 15008

Abstract

Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly prescribed medications for the treatment of musculoskeletal disorders. Osteoarthritis is the most common form of arthritis in humans and its prevalence rises with age. Oral NSAIDs have potential associated toxicities that must be monitored for and can [...] Read more.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly prescribed medications for the treatment of musculoskeletal disorders. Osteoarthritis is the most common form of arthritis in humans and its prevalence rises with age. Oral NSAIDs have potential associated toxicities that must be monitored for and can limit the use of these drugs in certain populations including people of older age. Topical NSAIDs are now being recognized as an option for the treatment strategy of osteoarthritis. We review the efficacy and safety of one of the most common topical NSAIDS, topical diclofenac, for the treatment of osteoarthritis. Full article

(This article belongs to the Special Issue Non-Steroidal Anti-Inflammatory Drugs)

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Open AccessCommentary

In Response to: ‘Impact of Glycosylation on Effector Functions of Therapeutic IgG’ (Pharmaceuticals 2010, 3, 146–157)

by Andreas Nechansky, Iris Koller and Ralf Kircheis

Pharmaceuticals 2010, 3(6), 1887-1891; https://doi.org/10.3390/ph3061887 - 10 Jun 2010

Cited by 1 | Viewed by 6685

Abstract

To complete the review article by Abes and colleagues (Pharmaceuticals 2010, 3, 146–157) which provides a good overview on recently developed approaches for generation of glyco-modified antibodies and the impact of glyco-modification of antibodies on their effector functions, important information [...] Read more.

To complete the review article by Abes and colleagues (Pharmaceuticals 2010, 3, 146–157) which provides a good overview on recently developed approaches for generation of glyco-modified antibodies and the impact of glyco-modification of antibodies on their effector functions, important information should be added, namely that — besides the Glycart and the Biowa approach to generate de-fucosylated antibodies — innovative, moss derived methods have been shown to generate glyco-modified antibodies with improved effector function profile. Full article

(This article belongs to the Special Issue Monoclonal Antibody)

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Open AccessReview

Cannabinoids and Viral Infections

by Carol Shoshkes Reiss

Pharmaceuticals 2010, 3(6), 1873-1886; https://doi.org/10.3390/ph3061873 - 09 Jun 2010

Cited by 47 | Viewed by 10672

Abstract

Exogenous cannabinoids or receptor antagonists may influence many cellular and systemic host responses. The anti-inflammatory activity of cannabinoids may compromise host inflammatory responses to acute viral infections, but may be beneficial in persistent infections. In neurons, where innate antiviral/pro-resolution responses include the activation [...] Read more.

Exogenous cannabinoids or receptor antagonists may influence many cellular and systemic host responses. The anti-inflammatory activity of cannabinoids may compromise host inflammatory responses to acute viral infections, but may be beneficial in persistent infections. In neurons, where innate antiviral/pro-resolution responses include the activation of NOS-1, inhibition of Ca²⁺ activity by cannabinoids, increased viral replication and disease. This review examines the effect(s) of cannabinoids and their antagonists in viral infections. Full article

(This article belongs to the Special Issue Cannabinoids)

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Open AccessReview

Use of p38 MAPK Inhibitors for the Treatment of Werner Syndrome

by Mark C. Bagley, Terence Davis, Paola G. S. Murziani, Caroline S. Widdowson and David Kipling

Pharmaceuticals 2010, 3(6), 1842-1872; https://doi.org/10.3390/ph3061842 - 04 Jun 2010

Cited by 35 | Viewed by 16523

Abstract

Werner syndrome provides a convincing model for aspects of the normal ageing phenotype and may provide a suitable model for therapeutic interventions designed to combat the ageing process. Cultured primary fibroblast cells from Werner syndrome patients provide a powerful model system to study [...] Read more.

Werner syndrome provides a convincing model for aspects of the normal ageing phenotype and may provide a suitable model for therapeutic interventions designed to combat the ageing process. Cultured primary fibroblast cells from Werner syndrome patients provide a powerful model system to study the link between replicative senescence in vitro and in vivo pathophysiology. Genome instability, together with an increased pro-oxidant state, and frequent replication fork stalling, all provide plausible triggers for intracellular stress in Werner syndrome cells, and implicates p38 MAPK signaling in their shortened replicative lifespan. A number of different p38 MAPK inhibitor chemotypes have been prepared rapidly and efficiently using microwave heating techniques for biological study in Werner syndrome cells, including SB203580, VX-745, RO3201195, UR-13756 and BIRB 796, and their selectivity and potency evaluated in this cellular context. Werner syndrome fibroblasts treated with a p38 MAPK inhibitor reveal an unexpected reversal of the accelerated ageing phenotype. Thus the study of p38 inhibition and its effect upon Werner pathophysiology is likely to provide new revelations into the biological mechanisms operating in cellular senescence and human ageing in the future. Full article

(This article belongs to the Special Issue Protein Kinase Inhibitors)

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Open AccessReview

Non-Steroidal Anti-Inflammatory Drugs in Alzheimer's Disease and Parkinson's Disease: Reconsidering the Role of Neuroinflammation

by Amy H. Moore, Matthew J. Bigbee, Grace E. Boynton, Colin M. Wakeham, Hilary M. Rosenheim, Christopher J. Staral, James L. Morrissey and Amanda K. Hund

Pharmaceuticals 2010, 3(6), 1812-1841; https://doi.org/10.3390/ph3061812 - 02 Jun 2010

Cited by 76 | Viewed by 16954

Abstract

Alzheimer's disease (AD) and Parkinson's disease (PD) are the most common neurodegenerative diseases with age as the greatest risk factor. As the general population experiences extended life span, preparation for the prevention and treatment of these and other age-associated neurological diseases are warranted. [...] Read more.

Alzheimer's disease (AD) and Parkinson's disease (PD) are the most common neurodegenerative diseases with age as the greatest risk factor. As the general population experiences extended life span, preparation for the prevention and treatment of these and other age-associated neurological diseases are warranted. Since epidemiological studies suggested that non-steroidal anti-inflammatory drug (NSAID) use decreased risk for AD and PD, increasing attention has been devoted to understanding the costs and benefits of the innate neuroinflammatory response to functional recovery following pathology onset. This review will provide a general overview on the role of neuroinflammation in these neurodegenerative diseases and an update on NSAID treatment in recent experimental animal models, epidemiological analyses, and clinical trials. Full article

(This article belongs to the Special Issue Non-Steroidal Anti-Inflammatory Drugs)

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Open AccessReview

Role of Leukotrienes and Leukotriene Modifiers in Asthma

by Paolo Montuschi

Pharmaceuticals 2010, 3(6), 1792-1811; https://doi.org/10.3390/ph3061792 - 02 Jun 2010

Cited by 41 | Viewed by 16378

Abstract

Leukotrienes (LTs), including cysteinyl LTs (CysLTs) and LTB₄, are potent lipid mediators that are pivotal in the pathophysiology of asthma phenotypes. At least two receptor subtypes for CysLTs – CysLT₁and CysLT₂ – have been identified. Most of the [...] Read more.

Leukotrienes (LTs), including cysteinyl LTs (CysLTs) and LTB₄, are potent lipid mediators that are pivotal in the pathophysiology of asthma phenotypes. At least two receptor subtypes for CysLTs – CysLT₁and CysLT₂ – have been identified. Most of the pathophysiological effects of CysLTs in asthma, including increased airway smooth muscle activity, microvascular permeability and airway mucus secretion, are mediated by the activation of the CysLT₁receptor. LTB₄ may have a role in the development of airway hyperresponsiveness, severe asthma and asthma exacerbations. Although generally less effective than inhaled glucocorticoids, CysLT₁ receptor antagonists can be given orally as monotherapy in patients with persistent mild asthma. In patients with more severe asthma, CysLT₁ receptor antagonists can be combined with inhaled glucocorticoids. This therapeutic strategy improves asthma control and enables the dose of inhaled glucocorticoids to be reduced, while maintaining similar efficacy. The identification of subgroups of patients with asthma who respond to CysLT₁ receptor antagonists is relevant for asthma management, as the response to these drugs is variable. The potential anti-remodeling effect of CysLT₁ receptor antagonists might be important for preventing or reversing airway structural changes in patients with asthma. This review discusses the role of LTs in asthma and the therapeutic implications of the pharmacological modulation of the LT pathway for asthma. Full article

(This article belongs to the Special Issue Antiasthmatic Drugs)

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Open AccessReview

The Pharmacogenomics of Anti-Hypertensive Therapy

by Sandosh Padmanabhan, Laura Paul and Anna F. Dominczak

Pharmaceuticals 2010, 3(6), 1779-1791; https://doi.org/10.3390/ph3061779 - 01 Jun 2010

Cited by 11 | Viewed by 11499

Abstract

Hypertension is a major public health problem, but measures to reduce blood pressure and thus cardiovascular risk are complicated by the high prevalence of treatment resistance, despite the availability of multiple drugs. Drug side-effects contribute considerably to suboptimal blood pressure control. Clinicians must [...] Read more.

Hypertension is a major public health problem, but measures to reduce blood pressure and thus cardiovascular risk are complicated by the high prevalence of treatment resistance, despite the availability of multiple drugs. Drug side-effects contribute considerably to suboptimal blood pressure control. Clinicians must often rely on empirical methods to match patients with effective drug treatment. Hypertension pharmacogenomics seeks to find genetic predictors of response to drugs that lower blood pressure and to translate this knowledge into clinical practice. In this review we summarise the current status of hypertension pharmacogenetics from monogenic hypertension to essential hypertension and discuss the issues that need to be considered in a hypertension pharmacogenomic study. Full article

(This article belongs to the Special Issue Personalized Medicine)

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Open AccessReview

Aptamers for Targeted Drug Delivery

by Partha Ray and Rebekah R. White

Pharmaceuticals 2010, 3(6), 1761-1778; https://doi.org/10.3390/ph3061761 - 27 May 2010

Cited by 100 | Viewed by 16513

Abstract

Aptamers are a class of therapeutic oligonucleotides that form specific three-dimensional structures that are dictated by their sequences. They are typically generated by an iterative screening process of complex nucleic acid libraries employing a process termed Systemic Evolution of Ligands by Exponential Enrichment [...] Read more.

Aptamers are a class of therapeutic oligonucleotides that form specific three-dimensional structures that are dictated by their sequences. They are typically generated by an iterative screening process of complex nucleic acid libraries employing a process termed Systemic Evolution of Ligands by Exponential Enrichment (SELEX). SELEX has traditionally been performed using purified proteins, and cell surface receptors may be challenging to purify in their properly folded and modified conformations. Therefore, relatively few aptamers have been generated that bind cell surface receptors. However, improvements in recombinant fusion protein technology have increased the availability of receptor extracellular domains as purified protein targets, and the development of cell-based selection techniques has allowed selection against surface proteins in their native configuration on the cell surface. With cell-based selection, a specific protein target is not always chosen, but selection is performed against a target cell type with the goal of letting the aptamer choose the target. Several studies have demonstrated that aptamers that bind cell surface receptors may have functions other than just blocking receptor-ligand interactions. All cell surface proteins cycle intracellularly to some extent, and many surface receptors are actively internalized in response to ligand binding. Therefore, aptamers that bind cell surface receptors have been exploited for the delivery of a variety of cargoes into cells. This review focuses on recent progress and current challenges in the field of aptamer-mediated delivery. Full article

(This article belongs to the Special Issue Targeted Therapy)

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Open AccessReview

Opportunities to Target Specific Contractile Abnormalities with Smooth Muscle Protein Kinase Inhibitors

by Annegret Ulke-Lemée and Justin A. MacDonald

Pharmaceuticals 2010, 3(6), 1739-1760; https://doi.org/10.3390/ph3061739 - 26 May 2010

Cited by 7 | Viewed by 12295

Abstract

Smooth muscle is a major component of most hollow organ systems (e.g., airways, vasculature, bladder and gut/gastrointestine); therefore, the coordinated regulation of contraction is a key property of smooth muscle. When smooth muscle functions normally, it contributes to general health and wellness, but [...] Read more.

Smooth muscle is a major component of most hollow organ systems (e.g., airways, vasculature, bladder and gut/gastrointestine); therefore, the coordinated regulation of contraction is a key property of smooth muscle. When smooth muscle functions normally, it contributes to general health and wellness, but its dysfunction is associated with morbidity and mortality. Rho-associated protein kinase (ROCK) is central to calcium-independent, actomyosin-mediated contractile force generation in the vasculature, thereby playing a role in smooth muscle contraction, cell motility and adhesion. Recent evidence supports an important role for ROCK in the increased vasoconstriction and remodeling observed in various models of hypertension. This review will provide a commentary on the development of specific ROCK inhibitors and their clinical application. Fasudil will be discussed as an example of bench-to-bedside development of a clinical therapeutic that is used to treat conditions of vascular hypercontractility. Due to the wide spectrum of biological processes regulated by ROCK, many additional clinical indications might also benefit from ROCK inhibition. Apart from the importance of ROCK in smooth muscle contraction, a variety of other protein kinases are known to play similar roles in regulating contractile force. The zipper-interacting protein kinase (ZIPK) and integrin-linked kinase (ILK) are two well-described regulators of contraction. The relative contribution of each kinase to contraction depends on the muscle bed as well as hormonal and neuronal stimulation. Unfortunately, specific inhibitors for ZIPK and ILK are still in the development phase, but the success of fasudil suggests that inhibitors for these other kinases may also have valuable clinical applications. Notably, the directed inhibition of ZIPK with a pseudosubstrate molecule shows unexpected effects on the contractility of gastrointestinal smooth muscle. Full article

(This article belongs to the Special Issue Protein Kinase Inhibitors)

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Open AccessReview

The Role of Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) in the Management of the Post-Embolization Symptoms after Uterine Artery Embolization

by Tiago Bilhim and João Martins Pisco

Pharmaceuticals 2010, 3(6), 1729-1738; https://doi.org/10.3390/ph3061729 - 26 May 2010

Cited by 16 | Viewed by 10228

Abstract

Uterine artery embolization (UAE) is usually a very painful procedure. Although pain after the procedure can occur as a single symptom, it usually is associated with other symptoms such as nausea, vomiting, pelvic pain, general malaise, fever and leukocytosis that characterize the post-embolization [...] Read more.

Uterine artery embolization (UAE) is usually a very painful procedure. Although pain after the procedure can occur as a single symptom, it usually is associated with other symptoms such as nausea, vomiting, pelvic pain, general malaise, fever and leukocytosis that characterize the post-embolization syndrome. Management of the post-embolization symptoms and of pain in particular, is paramount if UAE is to be performed as an outpatient procedure. Different protocols have used analgesic and/or anti-inflammatory agents to control these symptoms. Nonsteroidal anti-inflammatory drugs (NSAIDs) are frequently used in association with analgesic drugs to control post-embolization symptoms. In our institution the patients start oral medication with NSAIDs the day before the procedure and continue it during and after UAE. We also mix NSAIDs with the embolizing particles. This enables a reduction in the inflammation present in the uterine fibroids and helps controlling the pain. The purpose of this paper is to review the importance of NSAIDs in the management of the post-embolization symptoms. We describe the protocol that we use in our institution that enables us to perform the procedure on an outpatient basis with same day discharge and good control of the post-embolization symptoms with oral NSAIDs and analgesics. Full article

(This article belongs to the Special Issue Non-Steroidal Anti-Inflammatory Drugs)

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Open AccessReview

Cobalt Complexes as Antiviral and Antibacterial Agents

by Eddie L. Chang, Christa Simmers and D. Andrew Knight

Pharmaceuticals 2010, 3(6), 1711-1728; https://doi.org/10.3390/ph3061711 - 26 May 2010

Cited by 245 | Viewed by 28170

Abstract

Metal ion complexes are playing an increasing role in the development of antimicrobials. We review here the antimicrobial properties of cobalt coordination complexes in oxidation state 3+. In addition to reviewing the cobalt complexes containing polydentate donor ligands, we also focus on the [...] Read more.

Metal ion complexes are playing an increasing role in the development of antimicrobials. We review here the antimicrobial properties of cobalt coordination complexes in oxidation state 3+. In addition to reviewing the cobalt complexes containing polydentate donor ligands, we also focus on the antimicrobial activity of the homoleptic [Co(NH₃)₆]³⁺ ion. Full article

(This article belongs to the Special Issue Anti-Infective Agents)

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Pharmaceuticals, Volume 3, Issue 6 (June 2010) – 15 articles , Pages 1711-1987

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