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Pharmaceuticals, Volume 3, Issue 4 (April 2010), Pages 782-1285

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Research

Jump to: Review

Open AccessArticle Implications of Inter-Individual Differences in Clopidogrel Metabolism, with Focus on Pharmacogenetics
Pharmaceuticals 2010, 3(4), 782-794; doi:10.3390/ph3040782
Received: 18 January 2010 / Revised: 9 March 2010 / Accepted: 22 March 2010 / Published: 24 March 2010
Cited by 3 | PDF Full-text (125 KB) | HTML Full-text | XML Full-text
Abstract
Increasing evidence for the role of pharmacogenetics in treatment resistance to the antiplatelet agent clopidogrel has been gained during the last years. Apart from CYP2C19 genetic polymorphisms, nongenetic factors, particularly drug-drug interactions, age and other clinical characteristics influence the interindividual variability in [...] Read more.
Increasing evidence for the role of pharmacogenetics in treatment resistance to the antiplatelet agent clopidogrel has been gained during the last years. Apart from CYP2C19 genetic polymorphisms, nongenetic factors, particularly drug-drug interactions, age and other clinical characteristics influence the interindividual variability in clopidogrel response to varying degrees. The present article reviews the so far accumulated evidence on the role of pharmacogenetic traits influencing CYP-activity as determinants of the antiplatelet response to clopidogrel, and its clinical implications. The genetic variation in CYP2C19 activity seems to influence short- and long-term antithrombotic effects of clopidogrel to a substantial extent. Prediction models for clopidogrel non-responsiveness that include CYP2C19 genotyping together with relevant non-genetic risk factors are needed to be verified for their potential benefit in individualization of antithrombotic therapy. Full article
(This article belongs to the Special Issue Personalized Medicine)
Open AccessArticle Cell-Penetrating Peptides: A Comparative Study on Lipid Affinity and Cargo Delivery Properties
Pharmaceuticals 2010, 3(4), 1045-1062; doi:10.3390/ph3041045
Received: 22 December 2009 / Revised: 23 March 2010 / Accepted: 29 March 2010 / Published: 30 March 2010
Cited by 9 | PDF Full-text (399 KB) | HTML Full-text | XML Full-text
Abstract
A growing number of natural and/or synthetic peptides with cell membrane penetrating capability have been identified and described in the past years. These molecules have been considered promising tools for delivering bioactive compounds into various cell types. Although the mechanism of uptake [...] Read more.
A growing number of natural and/or synthetic peptides with cell membrane penetrating capability have been identified and described in the past years. These molecules have been considered promising tools for delivering bioactive compounds into various cell types. Although the mechanism of uptake is still unclear, it is reasonable to assume that the relative contribute of each proposed mechanism could differ for the same peptide, depending on experimental protocol and cargo molecule composition. In this work we try to connect the capability to interact with model lipid membrane and structural and chemical characteristics of CPPs in order to obtain a biophysical classification that predicts the behavior of CPP-cargo molecules in cell systems. Indeed, the binding with cell membrane is one of the primary step in the interaction of CPPs with cells, and consequently the studies on model membrane could become important for understanding peptide-membrane interaction on a molecular level, explaining how CPPs may translocate a membrane without destroying it and how this interactions come into play in shuttling CPPs via different routes with different efficiency. We analyzed by CD and fluorescence spectroscopies the binding properties of six different CPPs (kFGF, Nle54-Antp and Tat derived peptides, and oligoarginine peptides containing 6, 8 or 10 residues) in absence or presence of the same cargo peptide (the 392-401pTyr396 fragment of HS1 protein). The phospholipid binding properties were correlated to the conformational and chemical characteristics of peptides, as well as to the cell penetrating properties of the CPP-cargo conjugates. Results show that even if certain physico-chemical properties (conformation, positive charge) govern CPP capability to interact with the model membrane, these cannot fully explain cell-permeability properties. Full article
(This article belongs to the Special Issue Cell-penetrating Peptides 2012)
Open AccessArticle Synthesis and Neuroprotective Action of Optically Pure Neoechinulin A and Its Analogs
Pharmaceuticals 2010, 3(4), 1063-1069; doi:10.3390/ph3041063
Received: 21 December 2009 / Revised: 5 January 2010 / Accepted: 29 March 2010 / Published: 31 March 2010
Cited by 3 | PDF Full-text (207 KB) | HTML Full-text | XML Full-text
Abstract
We developed an efficient, stereoselective synthetic method for the diketopiperazine moiety of neoechinulin A and its derivatives. The intramolecular cyclization at 80 ºC proceeded with minimal racemization of the stereogenic center at C-12 on neoechinulin A, even though the cyclization at 110 [...] Read more.
We developed an efficient, stereoselective synthetic method for the diketopiperazine moiety of neoechinulin A and its derivatives. The intramolecular cyclization at 80 ºC proceeded with minimal racemization of the stereogenic center at C-12 on neoechinulin A, even though the cyclization at 110 ºC caused partial racemization. In contrast with these results, the cyclization on diketopiperazine of 8,9-dihydroneoechinulin A derivatives did not cause epimerization of the stereogenic centers, even at 110 °C. We examined the structure-activity relationships for the cytoprotective activity against cytotoxicity induced by 3-morpholinosydnonimine (SIN-1) in nerve growth factor (NGF)-differentiated PC12 cells. The C-8/C-9 double bond, but not the stereogenic center derived from alanine, was found to play a key role in the cytoprotective activity. Full article
(This article belongs to the Special Issue Asymmetric Synthesis and Medicinal Chemistry)
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Open AccessArticle Lessons Learned from Surveillance of Antimicrobial Susceptibilities of Pseudomonas aeruginosa at a Large Academic Medical Center
Pharmaceuticals 2010, 3(4), 1070-1083; doi:10.3390/ph3041070
Received: 17 December 2009 / Revised: 22 March 2010 / Accepted: 1 April 2010 / Published: 1 April 2010
Cited by 1 | PDF Full-text (153 KB) | HTML Full-text | XML Full-text
Abstract
This research report assessed the differences in resistance rates and antimicrobial usage-versus-susceptibility relationships of Pseudomonas aeruginosa found in various hospital patient care areas. A simplified case control study was also performed to identify patient-specific risk factors associated with cefepime-resistant P. aeruginosa isolates. [...] Read more.
This research report assessed the differences in resistance rates and antimicrobial usage-versus-susceptibility relationships of Pseudomonas aeruginosa found in various hospital patient care areas. A simplified case control study was also performed to identify patient-specific risk factors associated with cefepime-resistant P. aeruginosa isolates. Last, we determined the consequence of combining mucoid and non-mucoid derived antimicrobial susceptibilities of P. aeruginosa into hospital antibiograms. Overall, susceptibility rates remained lower in the intensive care units (ICUs) compared to the non-ICU patient care areas, except for cefepime over the last time period. Cefepime utilization and antimicrobial-resistance rates among P. aeruginosa isolates had a significant relationship. Decreased meropenem exposure was associated with lower resistance rates relative to cefepime. Risk factors independently associated with cefepime-resistant P. aeruginosa were structural lung disease, ICU admission, recent third generation cephalosporin use, frequent hospital admission and non-urine isolates. Large and statistically significant differences were observed between non-mucoid and combined percent susceptibility data for aminoglycosides. To control antimicrobial resistance and optimize initial empiric antimicrobial therapy, antimicrobial susceptibility and utilization patterns in specific patient care areas should be monitored and risk factors for antimicrobial resistance should be assessed. Mucoid strains of P. aeruginosa should not be included into antimicrobial susceptibility data as this may underestimate activity of most antipseudomonal agents. Full article
(This article belongs to the Special Issue Antibiotics)
Open AccessArticle Imperatoxin A, a Cell-Penetrating Peptide from Scorpion Venom, as a Probe of Ca2+-Release Channels/Ryanodine Receptors
Pharmaceuticals 2010, 3(4), 1093-1107; doi:10.3390/ph3041093
Received: 18 March 2010 / Accepted: 11 April 2010 / Published: 13 April 2010
Cited by 12 | PDF Full-text (1216 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Scorpion venoms are rich in ion channel-modifying peptides, which have proven to be invaluable probes of ion channel structure-function relationship. We previously isolated imperatoxin A (IpTxa), a 3.7 kDa peptide activator of Ca2+-release channels/ryanodine receptors (RyRs) [1,2,3] and founding member [...] Read more.
Scorpion venoms are rich in ion channel-modifying peptides, which have proven to be invaluable probes of ion channel structure-function relationship. We previously isolated imperatoxin A (IpTxa), a 3.7 kDa peptide activator of Ca2+-release channels/ryanodine receptors (RyRs) [1,2,3] and founding member of the calcin family of scorpion peptides. IpTxa folds into a compact, mostly hydrophobic molecule with a cluster of positively-charged, basic residues polarized on one side of the molecule that possibly interacts with the phospholipids of cell membranes. To investigate whether IpTxa permeates external cellular membranes and targets RyRs in vivo, we perfused IpTxa on intact cardiomyocytes while recording field-stimulated intracellular Ca2+ transients. To further investigate the cell-penetrating capabilities of the toxin, we prepared thiolated, fluorescent derivatives of IpTxa. Biological activity and spectroscopic properties indicate that these derivatives retain high affinity for RyRs and are only 5- to 10-fold less active than native IpTxa. Our results demonstrate that IpTxa is capable of crossing cell membranes to alter the release of Ca2+ in vivo, and has the capacity to carry a large, membrane-impermeable cargo across the plasma membrane, a finding with exciting implications for novel drug delivery. Full article
(This article belongs to the Special Issue Cell-penetrating Peptides 2012)
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Open AccessArticle Ingested Type I Interferon—State of the Art as Treatment for Autoimmunity Part 2
Pharmaceuticals 2010, 3(4), 1108-1121; doi:10.3390/ph3041108
Received: 25 January 2010 / Revised: 19 March 2010 / Accepted: 1 April 2010 / Published: 14 April 2010
Cited by 1 | PDF Full-text (244 KB) | HTML Full-text | XML Full-text
Abstract
We have proposed a unifying hypothesis of the etiopathogenesis of autoimmunity that defines autoimmunity as a type I interferon (IFN) immunodeficiency syndrome. We have examined toxicity and potential efficacy in two phase I (type 1 diabetes [T1D], multiple sclerosis [MS]) and phase [...] Read more.
We have proposed a unifying hypothesis of the etiopathogenesis of autoimmunity that defines autoimmunity as a type I interferon (IFN) immunodeficiency syndrome. We have examined toxicity and potential efficacy in two phase I (type 1 diabetes [T1D], multiple sclerosis [MS]) and phase II clinical trials in T1D and MS. In a phase I open label trial in T1D, ingested IFN-alpha preserved residual beta-cell function in recent onset patients. In a second phase I trial in MS, there was a significant decrease in peripheral blood mononuclear cell IL-2 and IFN-gamma production after ingesting IFN-alpha. In a phase II randomized, placebo-controlled, double-blind trial in MS, 10,000 IU ingested IFN-alpha significantly decreased gadolinium enhancements compared to the placebo group at month 5. TNF-alpha and IFN-gamma cytokine secretion in the 10,000 IU group at month 5 showed a significant decrease that corresponded with the effect of ingested IFN-alpha on decreasing gadolinium enhancements. In a phase II randomized, placebo-controlled, double-blind trial in T1D, patients in the 5,000 unit hrIFN-alpha treatment group maintained more beta-cell function one year after study enrollment compared to individuals in the placebo group. Ingested IFN-alpha was not toxic in these clinical trials. These studies suggest that ingested IFN-alpha may have a potential role in the treatment of autoimmunity. Full article
(This article belongs to the Special Issue Interferons)
Open AccessArticle Cell-Penetrating Fragments of the Cdk5 Regulatory Subunit Are Protective in Models of Neurodegeneration
Pharmaceuticals 2010, 3(4), 1232-1240; doi:10.3390/ph3041232
Received: 11 February 2010 / Revised: 16 April 2010 / Accepted: 21 April 2010 / Published: 23 April 2010
PDF Full-text (640 KB) | HTML Full-text | XML Full-text
Abstract
Cdk5 is essential for neuronal differentiation processes in the brain. Activation of Cdk5 requires the association with the mostly neuron-specific p35 or p39. Overactivation of CDK5 by cleavage of p35 into p25 is thought to be involved in neurodegenerative processes. Here, we [...] Read more.
Cdk5 is essential for neuronal differentiation processes in the brain. Activation of Cdk5 requires the association with the mostly neuron-specific p35 or p39. Overactivation of CDK5 by cleavage of p35 into p25 is thought to be involved in neurodegenerative processes. Here, we have tested an approach to inhibit pathological Cdk5 activation with a Tat-linked dominant-negative fragment of p25. It reduced cell death induced by staurosporine and showed a tendency to alleviate manganese-induced cell death, while it did not protect against 6-OHDA toxicity. Our results suggest that the Tat technique is a suitable tool to inhibit dysregulated CDK5. Full article
(This article belongs to the Special Issue Cell-penetrating Peptides 2012)
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Open AccessArticle Significant Acute Kidney Injury Due to Non-steroidal Anti-inflammatory Drugs: Inpatient Setting
Pharmaceuticals 2010, 3(4), 1279-1285; doi:10.3390/ph3041279
Received: 5 February 2010 / Revised: 14 April 2010 / Accepted: 19 April 2010 / Published: 26 April 2010
Cited by 1 | PDF Full-text (42 KB) | HTML Full-text | XML Full-text
Abstract
In the United States non-steroidal anti-inflammatory drugs (NSAID) are freely available over-the-counter. Because of the adverse effects on the kidneys and the popularity of these drugs, unregulated use of NSAIDs is an under recognized and potentially dangerous problem. Fifteen inpatients, mean age of 15.2 ± 2.3 years (five males, 10 females), were referred to nephrology for acute kidney injury. All patients admitted to taking ibuprofen and six also consumed naproxen. None of the patients had underlying renal diseases at the time of admission. Nine patients had proteinuria and 12 had hematuria (including one with gross hematuria). One patient had nephrotic syndrome but the condition resolved spontaneously without steroids and has remained in remission for four years. Two patients required dialysis. Only one of the dialyzed patients required steroid therapy for recovery of renal function. The mean duration of hospitalization was 7.4 ± 5.5 days. The serum creatinine peaked at 4.09 ± 4.24 (range 1.2-15.3) mg/dL. All patients recovered renal function with normalization of serum creatinine to 0.71 ± 0.15 mg/dL. The estimated GFR (glomerular filtration rate) at peak of renal failure was 38.2 ± 20.5 mL/min but did improve to a baseline of 134 ± 26.2 mL/min (range 89-177, p < 0.01). However, the duration from onset to normalization of serum creatinine was 37 ± 42 days indicating that majority of patients had abnormal renal function for a prolonged period. In conclusion, NSAIDs pose a significant risk of renal failure for significant duration and as an entity may be under recognized. Full article
(This article belongs to the collection Non-Steroidal Anti-Inflammatory Drugs)

Review

Jump to: Research

Open AccessReview Lambda Interferons: New Cytokines with Old Functions
Pharmaceuticals 2010, 3(4), 795-809; doi:10.3390/ph3040795
Received: 5 February 2010 / Revised: 24 March 2010 / Accepted: 24 March 2010 / Published: 25 March 2010
Cited by 4 | PDF Full-text (1337 KB) | HTML Full-text | XML Full-text
Abstract
Interferon lambda (IFN-λ) is a member of the class II cytokine family, and like the other members of this family, they are small helical proteins. Since their discovery significant efforts have been made to determine their role in innate and adaptive immunity. [...] Read more.
Interferon lambda (IFN-λ) is a member of the class II cytokine family, and like the other members of this family, they are small helical proteins. Since their discovery significant efforts have been made to determine their role in innate and adaptive immunity. Their strong antiviral activity, both in vitro and in vivo, has firmly established their interferon status. However, in contrast to type I interferon, only a very limited subset of cells/tissues responds to interferon lambda. In addition to inducing an antiviral state in responsive cells, recent data suggest that IFN-l plays a role in shaping the adaptive immune response. However, the data is not in complete agreement regarding the effect of IFN-λ on the adaptive immune system. Recently IFN-l has entered clinical trials against hepatitis C Virus and IFN-l is a promising future therapeutic, against different viruses replicating in responsive tissues, like that of the airway epithelia. In this review we describe the knowledge acquired during the past six years about the structure and function of interferon lambda. Full article
(This article belongs to the Special Issue Interferons)
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Open AccessReview Synthetic Medicinal Chemistry in Chagas’ Disease: Compounds at The Final Stage of “Hit-To-Lead” Phase
Pharmaceuticals 2010, 3(4), 810-838; doi:10.3390/ph3040810
Received: 1 February 2010 / Revised: 15 March 2010 / Accepted: 19 March 2010 / Published: 25 March 2010
Cited by 39 | PDF Full-text (638 KB) | HTML Full-text | XML Full-text
Abstract
Chagas’ disease, or American trypanosomosiasis, has been the most relevant illness produced by protozoa in Latin America. Synthetic medicinal chemistry efforts have provided an extensive number of chemodiverse hits at the “active-to-hit” stage. However, only a more limited number of these have [...] Read more.
Chagas’ disease, or American trypanosomosiasis, has been the most relevant illness produced by protozoa in Latin America. Synthetic medicinal chemistry efforts have provided an extensive number of chemodiverse hits at the “active-to-hit” stage. However, only a more limited number of these have been studied in vivo in models of Chagas’ disease. Herein, we survey some of the cantidates able to surpass the “hit-to-lead” stage discussing their limitations or merit to enter in clinical trials in the short term. Full article
(This article belongs to the Special Issue Tropical Medicine)
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Open AccessReview Mitochondrial and Cell Death Mechanisms in Neurodegenerative Diseases
Pharmaceuticals 2010, 3(4), 839-915; doi:10.3390/ph3040839
Received: 31 December 2009 / Revised: 22 March 2010 / Accepted: 23 March 2010 / Published: 25 March 2010
Cited by 54 | PDF Full-text (810 KB) | HTML Full-text | XML Full-text
Abstract
Alzheimer’s disease (AD), Parkinson’s disease (PD) and amyotrophic lateral sclerosis (ALS) are the most common human adult-onset neurodegenerative diseases. They are characterized by prominent age-related neurodegeneration in selectively vulnerable neural systems. Some forms of AD, PD, and ALS are inherited, and genes [...] Read more.
Alzheimer’s disease (AD), Parkinson’s disease (PD) and amyotrophic lateral sclerosis (ALS) are the most common human adult-onset neurodegenerative diseases. They are characterized by prominent age-related neurodegeneration in selectively vulnerable neural systems. Some forms of AD, PD, and ALS are inherited, and genes causing these diseases have been identified. Nevertheless, the mechanisms of the neuronal cell death are unresolved. Morphological, biochemical, genetic, as well as cell and animal model studies reveal that mitochondria could have roles in this neurodegeneration. The functions and properties of mitochondria might render subsets of selectively vulnerable neurons intrinsically susceptible to cellular aging and stress and overlying genetic variations, triggering neurodegeneration according to a cell death matrix theory. In AD, alterations in enzymes involved in oxidative phosphorylation, oxidative damage, and mitochondrial binding of Aβ and amyloid precursor protein have been reported. In PD, mutations in putative mitochondrial proteins have been identified and mitochondrial DNA mutations have been found in neurons in the substantia nigra. In ALS, changes occur in mitochondrial respiratory chain enzymes and mitochondrial cell death proteins. Transgenic mouse models of human neurodegenerative disease are beginning to reveal possible principles governing the biology of selective neuronal vulnerability that implicate mitochondria and the mitochondrial permeability transition pore. This review summarizes how mitochondrial pathobiology might contribute to neuronal death in AD, PD, and ALS and could serve as a target for drug therapy. Full article
(This article belongs to the Special Issue Mitochondrial Drugs for Neurodegenerative Diseases)
Open AccessReview Combating Combination of Hypertension and Diabetes in Different Rat Models
Pharmaceuticals 2010, 3(4), 916-939; doi:10.3390/ph3040916
Received: 5 January 2010 / Revised: 4 March 2010 / Accepted: 18 March 2010 / Published: 26 March 2010
Cited by 1 | PDF Full-text (206 KB) | HTML Full-text | XML Full-text
Abstract
Rat experimental models are used extensively for studying physiological mechanisms and treatments of hypertension and diabetes co-existence. Each one of these conditions is a major risk factor for cardiovascular disease (CVD), and the combination of the two conditions is a potent enhancer [...] Read more.
Rat experimental models are used extensively for studying physiological mechanisms and treatments of hypertension and diabetes co-existence. Each one of these conditions is a major risk factor for cardiovascular disease (CVD), and the combination of the two conditions is a potent enhancer of CVD. Five major animal models that advanced our understanding of the mechanisms and therapeutic approaches in humans are discussed in this review: Zucker, Goto-Kakizaki, SHROB, SHR/NDmcr-cp and Cohen Rosenthal diabetic hypertensive (CRDH) rats. The use of various drugs, such as angiotensin-converting enzyme (ACE) inhibitors (ACEIs), various angiotensin receptor blockers (ARBs), and calcium channel blockers (CCBs), to combat the effects of concomitant pathologies on the combination of diabetes and hypertension, as well as the non-pharmacological approach are reviewed in detail for each rat model. Results from experiments on these models indicate that classical factors contributing to the pathology of hypertension and diabetes combination—Including hypertension, hyperglycemia, hyperinsulinemia and hyperlipidemia—can now be treated, although these treatments do not completely prevent renal complications. Animal studies have focused on several mechanisms involved in hypertension/diabetes that remain to be translated into clinical medicine, including hypoxia, oxidative stress, and advanced glycation. Several target molecules have been identified that need to be incorporated into a treatment modality. The challenge continues to be the identification and interpretation of the clinical evidence from the animal models and their application to human treatment. Full article
(This article belongs to the Special Issue Antihypertensive Drugs)
Open AccessReview The Renin-Angiotensin System in the Development of Salt-Sensitive Hypertension in Animal Models and Humans
Pharmaceuticals 2010, 3(4), 940-960; doi:10.3390/ph3040940
Received: 22 December 2009 / Revised: 25 February 2010 / Accepted: 8 March 2010 / Published: 29 March 2010
Cited by 4 | PDF Full-text (98 KB) | HTML Full-text | XML Full-text
Abstract
Hypertension is still one of the major causes of death from cardiovascular failure. Increased salt intake may aggravate the rise in blood pressure and the development of consequential damage of the heart, the vessels and other organs. The general necessity of restricted [...] Read more.
Hypertension is still one of the major causes of death from cardiovascular failure. Increased salt intake may aggravate the rise in blood pressure and the development of consequential damage of the heart, the vessels and other organs. The general necessity of restricted salt intake regardless of blood pressure or salt sensitivity has been a matter of debate over the past decades. This review summarizes the main pathogenic mechanisms of hypertension and salt sensitivity in rat models, particularly in the spontaneously hypertensive rat (SHR), and in patients with essential hypertension (EH). Although SHRs are commonly considered to be salt-resistant, there is much evidence that salt loading may deteriorate blood pressure and cardiovascular function even in these animals. Similarly, EH is not a homogenous disorder – some patients, but not all, exhibit pronounced salt sensitivity. The renin-angiotensin system (RAS) plays a key role in the regulation of blood pressure and salt and fluid homeostasis and thus is one of the main targets of antihypertensive therapy. This review focuses on the contribution of the RAS to the pathogenesis of salt-sensitive hypertension in SHRs and patients with EH. Full article
(This article belongs to the Special Issue Antihypertensive Drugs)
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Open AccessReview Cell-Penetrating Peptides—Mechanisms of Cellular Uptake and Generation of Delivery Systems
Pharmaceuticals 2010, 3(4), 961-993; doi:10.3390/ph3040961
Received: 22 December 2009 / Revised: 20 February 2010 / Accepted: 29 March 2010 / Published: 30 March 2010
Cited by 84 | PDF Full-text (330 KB) | HTML Full-text | XML Full-text
Abstract
The successful clinical application of nucleic acid-based therapeutic strategies has been limited by the poor delivery efficiency achieved by existing vectors. The development of alternative delivery systems for improved biological activity is, therefore, mandatory. Since the seminal observations two decades ago that [...] Read more.
The successful clinical application of nucleic acid-based therapeutic strategies has been limited by the poor delivery efficiency achieved by existing vectors. The development of alternative delivery systems for improved biological activity is, therefore, mandatory. Since the seminal observations two decades ago that the Tat protein, and derived peptides, can translocate across biological membranes, cell-penetrating peptides (CPPs) have been considered one of the most promising tools to improve non-invasive cellular delivery of therapeutic molecules. Despite extensive research on the use of CPPs for this purpose, the exact mechanisms underlying their cellular uptake and that of peptide conjugates remain controversial. Over the last years, our research group has been focused on the S413-PV cell-penetrating peptide, a prototype of this class of peptides that results from the combination of 13-amino-acid cell penetrating sequence derived from the Dermaseptin S4 peptide with the SV40 large T antigen nuclear localization signal. By performing an extensive biophysical and biochemical characterization of this peptide and its analogs, we have gained important insights into the mechanisms governing the interaction of CPPs with cells and their translocation across biological membranes. More recently, we have started to explore this peptide for the intracellular delivery of nucleic acids (plasmid DNA, siRNA and oligonucleotides). In this review we discuss the current knowledge of the mechanisms responsible for the cellular uptake of cell-penetrating peptides, including the S413-PV peptide, and the potential of peptide-based formulations to mediate nucleic acid delivery. Full article
(This article belongs to the Special Issue Cell-penetrating Peptides 2012)
Open AccessReview Antiproliferative Properties of Type I and Type II Interferon
Pharmaceuticals 2010, 3(4), 994-1015; doi:10.3390/ph3040994
Received: 2 March 2010 / Revised: 15 March 2010 / Accepted: 29 March 2010 / Published: 30 March 2010
Cited by 44 | PDF Full-text (588 KB) | HTML Full-text | XML Full-text
Abstract
The clinical possibilities of interferon (IFN) became apparent with early studies demonstrating that it was capable of inhibiting tumor cells in culture and in vivo using animal models. IFN gained the distinction of being the first recombinant cytokine to be licensed in [...] Read more.
The clinical possibilities of interferon (IFN) became apparent with early studies demonstrating that it was capable of inhibiting tumor cells in culture and in vivo using animal models. IFN gained the distinction of being the first recombinant cytokine to be licensed in the USA for the treatment of a malignancy in 1986, with the approval of IFN-α2a (Hoffman-La Roche) and IFN-α2b (Schering-Plough) for the treatment of Hairy Cell Leukemia. In addition to this application, other approved antitumor applications for IFN-α2a are AIDS-related Kaposi’s Sarcoma and Chronic Myelogenous Leukemia (CML) and other approved antitumor applications for IFN-α2b are Malignant Melanoma, Follicular Lymphoma, and AIDS-related Kapoisi’s Sarcoma. In the ensuing years, a considerable number of studies have been conducted to establish the mechanisms of the induction and action of IFN’s anti-tumor activity. These include identifying the role of Interferon Regulatory Factor 9 (IRF9) as a key factor in eliciting the antiproliferative effects of IFN-α as well as identifying genes induced by IFN that are involved in recognition of tumor cells. Recent studies also show that IFN-activated human monocytes can be used to achieve >95% eradication of select tumor cells. The signaling pathways by which IFN induces apoptosis can vary. IFN treatment induces the tumor suppressor gene p53, which plays a role in apoptosis for some tumors, but it is not essential for the apoptotic response. IFN-α also activates phosphatidylinositol 3-kinase (PI3K), which is associated with cell survival. Downstream of PI3K is the mammalian target of rapamycin (mTOR) which, in conjunction with PI3K, may act in signaling induced by growth factors after IFN treatment. This paper will explore the mechanisms by which IFN acts to elicit its antiproliferative effects and more closely examine the clinical applications for the anti-tumor potential of IFN. Full article
(This article belongs to the Special Issue Interferons)
Open AccessReview Beta-Adrenergic Agonists
Pharmaceuticals 2010, 3(4), 1016-1044; doi:10.3390/ph3041016
Received: 2 February 2010 / Revised: 15 March 2010 / Accepted: 26 March 2010 / Published: 30 March 2010
Cited by 5 | PDF Full-text (1162 KB) | HTML Full-text | XML Full-text
Abstract
Inhaled β2-adrenoceptor (β2-AR) agonists are considered essential bronchodilator drugs in the treatment of bronchial asthma, both as symptoms-relievers and, in combination with inhaled corticosteroids, as disease-controllers. In this article, we first review the basic mechanisms by which the [...] Read more.
Inhaled β2-adrenoceptor (β2-AR) agonists are considered essential bronchodilator drugs in the treatment of bronchial asthma, both as symptoms-relievers and, in combination with inhaled corticosteroids, as disease-controllers. In this article, we first review the basic mechanisms by which the β2-adrenergic system contributes to the control of airway smooth muscle tone. Then, we go on describing the structural characteristics of β2-AR and the molecular basis of G-protein-coupled receptor signaling and mechanisms of its desensitization/ dysfunction. In particular, phosphorylation mediated by protein kinase A and β-adrenergic receptor kinase are examined in detail. Finally, we discuss the pivotal role of inhaled β2-AR agonists in the treatment of asthma and the concerns about their safety that have been recently raised. Full article
(This article belongs to the Special Issue Antiasthmatic Drugs)
Open AccessReview Non Steroidal Anti-Inflammatory Drugs and Inflammatory Bowel Disease
Pharmaceuticals 2010, 3(4), 1084-1092; doi:10.3390/ph3041084
Received: 13 January 2010 / Revised: 1 April 2010 / Accepted: 9 April 2010 / Published: 12 April 2010
Cited by 4 | PDF Full-text (155 KB) | HTML Full-text | XML Full-text
Abstract
Inflammatory Bowel Diseases (IBD) are an immune mediated chronic or relapsing disorders of the gastrointestinal (GI) tract. IBD is characterized by a chronic intestinal inflammatory process with various components contributing to the pathogenesis of the disease including environmental factors such as smoking [...] Read more.
Inflammatory Bowel Diseases (IBD) are an immune mediated chronic or relapsing disorders of the gastrointestinal (GI) tract. IBD is characterized by a chronic intestinal inflammatory process with various components contributing to the pathogenesis of the disease including environmental factors such as smoking or use of Non Steroidal Anti-Inflammatory Drugs (NSAIDS). NSAIDS are among the most commonly used medications for the treatment of various inflammatory conditions. The main factor limiting NSAIDS use is the concern for the development of gastrointestinal toxicity including mucosal injury. A possible association between the use of NSAIDS and the onset or relapse of IBD has been repeatedly suggested. This article will review the current concepts and evidence of the relationship between IBD and NSAIDS. Full article
(This article belongs to the collection Non-Steroidal Anti-Inflammatory Drugs)
Open AccessReview The Impact of CYP2D6 Genotyping on Tamoxifen Treatment
Pharmaceuticals 2010, 3(4), 1122-1138; doi:10.3390/ph3041122
Received: 30 December 2009 / Revised: 12 March 2010 / Accepted: 9 April 2010 / Published: 15 April 2010
Cited by 9 | PDF Full-text (241 KB) | HTML Full-text | XML Full-text
Abstract
Tamoxifen remains a cornerstone of treatment for patients with oestrogen-receptor-positive breast cancer. Tamoxifen efficacy depends on the biotransformation, predominantly via the cytochrome P450 2D6 (CYP2D6) isoform, to the active metabolite endoxifen. Both genetic and environmental (drug-induced) factors may alter CYP2D6 enzyme activity [...] Read more.
Tamoxifen remains a cornerstone of treatment for patients with oestrogen-receptor-positive breast cancer. Tamoxifen efficacy depends on the biotransformation, predominantly via the cytochrome P450 2D6 (CYP2D6) isoform, to the active metabolite endoxifen. Both genetic and environmental (drug-induced) factors may alter CYP2D6 enzyme activity directly affecting the concentrations of active tamoxifen metabolites. Several studies suggest that germline genetic variants in CYP2D6 influence the clinical outcomes of patients treated with adjuvant tamoxifen. Here, we review the existing data relating CYP2D6 genotypes to tamoxifen efficacy. Full article
(This article belongs to the Special Issue Personalized Medicine)
Open AccessReview Lysostaphin: A Staphylococcal Bacteriolysin with Potential Clinical Applications
Pharmaceuticals 2010, 3(4), 1139-1161; doi:10.3390/ph3041139
Received: 24 March 2010 / Revised: 8 April 2010 / Accepted: 14 April 2010 / Published: 19 April 2010
Cited by 22 | PDF Full-text (439 KB) | HTML Full-text | XML Full-text
Abstract
Lysostaphin is an antimicrobial agent belonging to a major class of antimicrobial peptides and proteins known as the bacteriocins. Bacteriocins are bacterial antimicrobial peptides which generally exhibit bactericidal activity against other bacteria. Bacteriocin production is a self-protection mechanism that helps the microorganisms [...] Read more.
Lysostaphin is an antimicrobial agent belonging to a major class of antimicrobial peptides and proteins known as the bacteriocins. Bacteriocins are bacterial antimicrobial peptides which generally exhibit bactericidal activity against other bacteria. Bacteriocin production is a self-protection mechanism that helps the microorganisms to survive in their natural habitats. Bacteriocins are currently distributed into three main classes. Staphylococcins are bacteriocins produced by staphylococci, which are Gram-positive bacteria of medical and veterinary importance. Lysostaphin is the only class III staphylococcin described so far. It exhibits a high degree of antistaphylococcal bacteriolytic activity, being inactive against bacteria of all other genera. Infections caused by staphylococci continue to be a problem worldwide not only in healthcare environments but also in the community, requiring effective measures for controlling their spread. Since lysostaphin kills human and animal staphylococcal pathogens, it has potential biotechnological applications in the treatment of staphylococcal infections. In vitro and in vivo studies performed with lysostaphin have shown that this staphylococcin has potential to be used, solely or in combination with other antibacterial agents, to prevent or treat bacterial staphylococcal infectious diseases. Full article
(This article belongs to the Special Issue Antibiotics)
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Open AccessReview Safety, Tolerability, and Immunogenicity of Interferons
Pharmaceuticals 2010, 3(4), 1162-1186; doi:10.3390/ph3041162
Received: 9 March 2010 / Revised: 3 April 2010 / Accepted: 12 April 2010 / Published: 20 April 2010
Cited by 5 | PDF Full-text (203 KB) | HTML Full-text | XML Full-text
Abstract
Interferons (IFNs) are class II cytokines that are key components of the innate immune response to virus infection. Three IFN sub-families, type I, II, and III IFNs have been identified in man, Recombinant analogues of type I IFNs, in particular IFNα2 and [...] Read more.
Interferons (IFNs) are class II cytokines that are key components of the innate immune response to virus infection. Three IFN sub-families, type I, II, and III IFNs have been identified in man, Recombinant analogues of type I IFNs, in particular IFNα2 and IFNβ1, have found wide application for the treatment of chronic viral hepatitis and remitting relapsing multiple sclerosis respectively. Type II IFN, or IFN gamma, is used principally for the treatment of chronic granulomatous disease, while the recently discovered type III IFNs, also known as IFN lambda or IL-28/29, are currently being evaluated for the treatment of chronic viral hepatitis. IFNs are in general well tolerated and the most common adverse events observed with IFNα or IFNβ therapy are “flu-like” symptoms such as fever, headache, chills, and myalgia. Prolonged treatment is associated with more serious adverse events including leucopenia, thrombocytopenia, increased hepatic transaminases, and neuropsychiatric effects. Type I IFNs bind to high-affinity cell surface receptors, composed of two transmembrane polypeptides IFNAR1 and IFNAR2, resulting in activation of the Janus kinases Jak1 and Tyk2, phosphorylation and activation of the latent cytoplasmic signal transducers and activators of transcription (STAT1) and STAT2, formation of a transcription complex together with IRF9, and activation of a specific set of genes that encode the effector molecules responsible for mediating the biological activities of type I IFNs. Systemic administration of type I IFN results in activation of IFN receptors present on essentially all types of nucleated cells, including neurons and hematopoietic stem cells, in addition to target cells. This may well explain the wide spectrum of IFN associated toxicities. Recent reports suggest that certain polymorphisms in type I IFN signaling molecules are associated with IFN-induced neutropenia and thrombocytopenia in patients with chronic hepatitis C. IFNγ binds to a cell-surface receptor composed of two transmembrane polypeptides IFGR1 and IFGR2 resulting in activation of the Janus kinases Jak1 and Jak2, phosphorylation of STAT1, formation of STAT1 homodimers, and activation of a specific set of genes that encode the effector molecules responsible for mediating its biological activity. In common with type I IFNs, IFNγ receptors are ubiquitous and a number of the genes activated by IFNγ are also activated by type I IFNs that may well account for a spectrum of toxicities similar to that associated with type I IFNs including “flu-like” symptoms, neutropenia, thrombocytopenia, and increased hepatic transaminases. Although type III IFNs share the major components of the signal transduction pathway and activate a similar set of IFN-stimulated genes (ISGs) as type I IFNs, distribution of the IFNλ receptor is restricted to certain cell types suggesting that IFNλ therapy may be associated with a reduced spectrum of toxicities relative to type I or type II IFNs. Repeated administration of recombinant IFNs can cause in a break in immune tolerance to self-antigens in some patients resulting in the production of neutralizing antibodies (NABs) to the recombinant protein homologue. Appearance of NABs is associated with reduced pharmacokinetics, pharmacodynamics, and a reduced clinical response. The lack of cross-neutralization of IFNβ by anti-IFNα NABs and vice versa, undoubtedly accounts for the apparent lack of toxicity associated with the presence of anti-IFN NABs with the exception of relatively mild infusion/injection reactions. Full article
(This article belongs to the Special Issue Interferons)
Open AccessReview A Review of Anti-Inflammatory Drug-Induced Gastrointestinal Injury: Focus on Prevention of Small Intestinal Injury
Pharmaceuticals 2010, 3(4), 1187-1201; doi:10.3390/ph3041187
Received: 16 March 2010 / Revised: 15 April 2010 / Accepted: 19 April 2010 / Published: 20 April 2010
Cited by 3 | PDF Full-text (3648 KB) | HTML Full-text | XML Full-text
Abstract
Capsule endoscopy and balloon endoscopy, advanced modalities that allow full investigation of the entire small intestine, have revealed that nonsteroidal anti-inflammatory drugs (NSAIDs) can cause a variety of abnormalities in the small intestine. Recently, several reports show that traditional NSAIDs (tNSAIDs) and [...] Read more.
Capsule endoscopy and balloon endoscopy, advanced modalities that allow full investigation of the entire small intestine, have revealed that nonsteroidal anti-inflammatory drugs (NSAIDs) can cause a variety of abnormalities in the small intestine. Recently, several reports show that traditional NSAIDs (tNSAIDs) and acetylsalicylic acid (ASA) can induce small intestinal injuries. These reports have shown that the preventive effect of proton pump inhibitors (PPIs) does not extend to the small intestine, suggesting that concomitant therapy may be required to prevent small intestinal side effects associated with tNSAID/ASA use. Recently, several randomized controlled trials used capsule endoscopy to evaluate the preventive effect of mucoprotective drugs against tNSAID/ASA-induced small intestinal injury. These studies show that misoprostol and rebamipide reduce the number and types of tNSAID-induced small intestinal mucosal injuries. However, those studies were limited to a small number of subjects and tested short-term tNSAID/ ASA treatment. Therefore, further extensive studies are clearly required to ascertain the beneficial effect of these drugs. Full article
(This article belongs to the collection Non-Steroidal Anti-Inflammatory Drugs)
Open AccessReview New Trends in Cancer Therapy: Targeting Ion Channels and Transporters
Pharmaceuticals 2010, 3(4), 1202-1224; doi:10.3390/ph3041202
Received: 16 February 2010 / Revised: 25 March 2010 / Accepted: 29 March 2010 / Published: 20 April 2010
Cited by 16 | PDF Full-text (312 KB) | HTML Full-text | XML Full-text
Abstract
The expression and activity of different channel types mark and regulate specific stages of cancer establishment and progression. Blocking channel activity impairs the growth of some tumors, both in vitro and in vivo, which opens a new field for pharmaceutical research. [...] Read more.
The expression and activity of different channel types mark and regulate specific stages of cancer establishment and progression. Blocking channel activity impairs the growth of some tumors, both in vitro and in vivo, which opens a new field for pharmaceutical research. However, ion channel blockers may produce serious side effects, such as cardiac arrhythmias. For instance, Kv11.1 (hERG1) channels are aberrantly expressed in several human cancers, in which they control different aspects of the neoplastic cell behaviour. hERG1 blockers tend to inhibit cancer growth. However they also retard the cardiac repolarization, thus lengthening the electrocardiographic QT interval, which can lead to life-threatening ventricular arrhythmias. Several possibilities exist to produce less harmful compounds, such as developing specific drugs that bind hERG1 channels in the open state or disassemble the ion channel/integrin complex which appears to be crucial in certain stages of neoplastic progression. The potential approaches to improve the efficacy and safety of ion channel targeting in oncology include: (1) targeting specific conformational channel states; (2) finding ever more specific inhibitors, including peptide toxins, for channel subtypes mainly expressed in well-identified tumors; (3) using specific ligands to convey traceable or cytotoxic compounds; (4) developing channel blocking antibodies; (5) designing new molecular tools to decrease channel expression in selected cancer types. Similar concepts apply to ion transporters such as the Na+/K+ pump and the Na+/H+ exchanger. Pharmacological targeting of these transporters is also currently being considered in anti-neoplastic therapy. Full article
(This article belongs to the Special Issue Targeted Therapy)
Open AccessReview Tyrosine Kinase Inhibitors as Antiangiogenic Drugs in Multiple Myeloma
Pharmaceuticals 2010, 3(4), 1225-1231; doi:10.3390/ph3041225
Received: 9 March 2010 / Revised: 21 April 2010 / Accepted: 22 April 2010 / Published: 22 April 2010
Cited by 6 | PDF Full-text (169 KB) | HTML Full-text | XML Full-text
Abstract
Tyrosine kinase inhibitors are a new class of anticancer drugs, that are capable of directly interacting with the catalytic site of the target enzyme and thereby inhibiting catalysis. Therapeutically useful tyrosine kinase inhibitors are not specific for a single tyrosine kinase, but [...] Read more.
Tyrosine kinase inhibitors are a new class of anticancer drugs, that are capable of directly interacting with the catalytic site of the target enzyme and thereby inhibiting catalysis. Therapeutically useful tyrosine kinase inhibitors are not specific for a single tyrosine kinase, but rather they are selective against a limited number of tyrosine kinases. The success of imatinib-mesylate (Gleevec®) for the treatment of patients with chronic myeloid leukemia has opened a intensive search for new small molecular compounds able to target other protein tyrosine kinases involved in the malignant transformation. This review article is focused on the use of tyrosine kinase inhibitors as antiangiogenic molecules in the treatment of multiple myeloma. Full article
(This article belongs to the Special Issue Protein Kinase Inhibitors)
Open AccessReview Thrombospondin-1 as a Paradigm for the Development of Antiangiogenic Agents Endowed with Multiple Mechanisms of Action
Pharmaceuticals 2010, 3(4), 1241-1278; doi:10.3390/ph3041241
Received: 14 February 2010 / Revised: 20 April 2010 / Accepted: 22 April 2010 / Published: 23 April 2010
Cited by 8 | PDF Full-text (1390 KB) | HTML Full-text | XML Full-text
Abstract
Uncontrolled neovascularization occurs in several angiogenesis-dependent diseases, including cancer. Neovascularization is tightly controlled by the balance between angiogenic growth factors and antiangiogenic agents. The various natural angiogenesis inhibitors identified so far affect neovascularization by different mechanisms of action. Thrombospondin-1 (TSP-1) is a [...] Read more.
Uncontrolled neovascularization occurs in several angiogenesis-dependent diseases, including cancer. Neovascularization is tightly controlled by the balance between angiogenic growth factors and antiangiogenic agents. The various natural angiogenesis inhibitors identified so far affect neovascularization by different mechanisms of action. Thrombospondin-1 (TSP-1) is a matricellular modular glycoprotein that acts as a powerful endogenous inhibitor of angiogenesis. It acts both indirectly, by sequestering angiogenic growth factors and effectors in the extracellular environment, and directly, by inducing an antiangiogenic program in endothelial cells following engagement of specific receptors including CD36, CD47, integrins and proteoglycans (all involved in angiogenesis ). In view of its central, multifaceted role in angiogenesis, TSP-1 has served as a source of antiangiogenic tools, including TSP-1 fragments, synthetic peptides and peptidomimetics, gene therapy strategies, and agents that up-regulate TSP-1 expression. This review discusses TSP-1-based inhibitors of angiogenesis, their mechanisms of action and therapeutic potential, drawing our experience with angiogenic growth factor-interacting TSP-1 peptides, and the possibility of exploiting them to design novel antiangiogenic agents. Full article
(This article belongs to the Special Issue Angiogenesis Inhibitors)
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