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Pharmaceuticals, Volume 3, Issue 12 (December 2010), Pages 3494-3632

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Research

Jump to: Review, Other

Open AccessArticle Effects of Moxifloxacin on Human Neutrophil and T-Lymphocyte Functions in Vitro
Pharmaceuticals 2010, 3(12), 3570-3580; doi:10.3390/ph3123570
Received: 14 September 2010 / Revised: 29 November 2010 / Accepted: 8 December 2010 / Published: 13 December 2010
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Abstract
Moxifloxacin is useful in the treatment of respiratory infections, including community-acquired pneumonia, and also shows promise in the treatment of tuberculosis, a clinical setting which necessitates extended administration of this agent. Relatively little is known, however, about the effects of this agent on the antimicrobial and proliferative activities of human neutrophils and T-lymphocytes, respectively. In the current study, we have investigated the effects of moxifloxacin at therapeutic concentrations and greater (1–20 µg/mL) on cytosolic Ca2+ fluxes, generation of antimicrobial reactive oxygen species (ROS), and release of the primary granule protease, elastase, following activation of the cells with the chemoattractant, fMLP (1 µM), or the phorbol ester, PMA (25 ng/mL), using radiometric, chemiluminescence, and colourimetric procedures, respectively. The effects of moxifloxacin on mitogen-activated proliferation of T cells and expression of the interleukin-2 (IL-2) receptor (CD25) were measured using radiometric and flow cytometric procedures respectively. With the exception of elastase release, which was significantly increased (P < 0.05) by treatment of the cells with moxifloxacin at 10 and 20 µg/mL, none of the other neutrophil or lymphocyte functions was affected by moxifloxacin. These observations suggest that extended use of this agent is unlikely to compromise the protective functions of neutrophils and T-lymphocytes and may even potentiate neutrophil-mediated antimicrobial activity by increasing the release of elastase. Full article
Open AccessArticle Cell-Penetrating Penta-Peptides (CPP5s): Measurement of Cell Entry and Protein-Transduction Activity
Pharmaceuticals 2010, 3(12), 3594-3613; doi:10.3390/ph3123594
Received: 17 November 2010 / Accepted: 1 December 2010 / Published: 15 December 2010
Cited by 18 | PDF Full-text (2972 KB) | HTML Full-text | XML Full-text
Abstract
Previously, we developed cell-penetrating penta-peptides (CPP5s). In the present study, VPTLK and KLPVM, two representative CPP5s, were used to characterize the cell-penetration and protein-transduction activities of these small molecules. Various inhibitors of endocytosis and pinocytosis (chlorpromazine, cytochalasin D, Filipin III, amiloride, methyl-b-cyclodextrin, [...] Read more.
Previously, we developed cell-penetrating penta-peptides (CPP5s). In the present study, VPTLK and KLPVM, two representative CPP5s, were used to characterize the cell-penetration and protein-transduction activities of these small molecules. Various inhibitors of endocytosis and pinocytosis (chlorpromazine, cytochalasin D, Filipin III, amiloride, methyl-b-cyclodextrin, and nocodazole) were tested. Only cytochalasin D showed suppression of CPP5 entry, though the effect was partial. In addition, CPP5s were able to enter a proteoglycan-deficient CHO cell line. These results suggest that pinocytosis and endocytosis may play only a minor role in the cell entry of CPP5s. By mass spectrometry, we determined that the intracellular concentration of VPTLK ranged from 20 nM to 6.0 mM when the cells were cultured in medium containing 1 mM – 1.6 mM VPTLK. To determine the protein-transduction activity of CPP5s, the Tex-LoxP EG cell line, which has a Cre-inducible green fluorescent protein (GFP) gene, was used. VPTLK and KLPVM were added to the N-terminus of Cre, and these fusion proteins were added to the culture medium of Tex-LoxP EG cells. Both VPTLK-Cre and KLPVM-Cre were able to turn on GFP expression in these cells, suggesting that CPP5s have protein-transduction activity. Since CPP5s have very low cytotoxic activity, even at a concentration of 1.6 mM in the medium, CPP5s could be utilized as a new tool for drug delivery into cells. Full article
(This article belongs to the Special Issue Cell-penetrating Peptides 2012)

Review

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Open AccessReview Obesity Drug Update: The Lost Decade?
Pharmaceuticals 2010, 3(12), 3494-3521; doi:10.3390/ph3123494
Received: 5 October 2010 / Revised: 17 November 2010 / Accepted: 23 November 2010 / Published: 24 November 2010
Cited by 9 | PDF Full-text (294 KB) | HTML Full-text | XML Full-text
Abstract
The growing worldwide obesity epidemic and obesity-related disorders present a huge unmet medical need for safe and effective anti-obesity medications. The discovery of leptin in 1994 was rapidly succeeded by a wave of related discoveries leading to the elaboration of a hypothalamic [...] Read more.
The growing worldwide obesity epidemic and obesity-related disorders present a huge unmet medical need for safe and effective anti-obesity medications. The discovery of leptin in 1994 was rapidly succeeded by a wave of related discoveries leading to the elaboration of a hypothalamic melanocortinergic neuronal circuit regulated by leptin and other central and peripheral signaling molecules to control energy homeostasis. The identification of specific neuronal subtypes along with their unique connections and expression products generated a rich target menu for anti-obesity drug discovery programs. Over the course of the last decade, several new chemical entities aimed at these targets have reached various stages or successfully completed the drug discovery/regulatory process only to be dropped or taken off the market. There are now in fact fewer options for anti-obesity drug therapies in late 2010 than were available in 2000. The challenge to discover safe and effective anti-obesity drugs is alive and well. Full article
(This article belongs to the Special Issue Anti-Obesity Drugs)
Open AccessReview Atypical Antipsychotics and Other Therapeutic Options for Treatment of Resistant Major Depressive Disorder
Pharmaceuticals 2010, 3(12), 3522-3542; doi:10.3390/ph3123522
Received: 1 November 2010 / Revised: 24 November 2010 / Accepted: 2 December 2010 / Published: 3 December 2010
Cited by 2 | PDF Full-text (161 KB) | HTML Full-text | XML Full-text
Abstract
Antidepressant therapies, such as selective serotonin reuptake inhibitors (SSRIs), are current first-line treatments for Major Depressive Disorder. However, over 50% of treated patients show an inadequate response to initial antidepressant therapy. If the therapeutic outcomes from two antidepressant therapies are suboptimal, potentially [...] Read more.
Antidepressant therapies, such as selective serotonin reuptake inhibitors (SSRIs), are current first-line treatments for Major Depressive Disorder. However, over 50% of treated patients show an inadequate response to initial antidepressant therapy. If the therapeutic outcomes from two antidepressant therapies are suboptimal, potentially resulting in Treatment Resistant Depression, subsequent strategies include switching to another antidepressant or augmenting treatment by combining with other agents. When combined with SSRIs, atypical antipsychotics have supplementary action on dopaminergic and noradrenergic systems. Studies on combined treatment with atypical antipsychotics have shown significantly increased remission rates, shortened response times, and favorable side effects. Augmentation of antidepressants with atypical antipsychotics is now an acceptable treatment strategy which leads to increased remission rates and better outcomes for patients. Full article
(This article belongs to the Special Issue Antidepressants)
Open AccessReview Anticoagulation in the Elderly
Pharmaceuticals 2010, 3(12), 3543-3569; doi:10.3390/ph3123543
Received: 7 October 2010 / Revised: 7 December 2010 / Accepted: 9 December 2010 / Published: 10 December 2010
Cited by 8 | PDF Full-text (240 KB) | HTML Full-text | XML Full-text
Abstract
Management of anticoagulation in elderly patients represents a particularly challenging issue. Indeed, this patient population is at high thromboembolic risk, but also at high hemorrhagic risk. Assessment of the benefit-risk balance of anticoagulation is the key point when decisions are made about [...] Read more.
Management of anticoagulation in elderly patients represents a particularly challenging issue. Indeed, this patient population is at high thromboembolic risk, but also at high hemorrhagic risk. Assessment of the benefit-risk balance of anticoagulation is the key point when decisions are made about introducing and/or continuing such treatments in the individual elderly patient. In order to maximise the safety of anticoagulation in the elderly, some specific considerations need to be taken into account, including renal insufficiency, modified pharmacodynamics of anticoagulants, especially vitamin K antagonists, and the presence of multiple comorbidities and concomitant medications. New anticoagulants could greatly simplify and possibly increase the safety of anticoagulation in the elderly in the near future. Full article
(This article belongs to the Special Issue Anticoagulants)
Open AccessReview Artemisinin-Naphthoquine Combination (ARCO®): An Overview of the Progress
Pharmaceuticals 2010, 3(12), 3581-3593; doi:10.3390/ph3123581
Received: 15 November 2010 / Revised: 8 December 2010 / Accepted: 9 December 2010 / Published: 14 December 2010
Cited by 13 | PDF Full-text (205 KB) | HTML Full-text | XML Full-text
Abstract
With the rapidly spreading resistance of Plasmodium falciparum to available non-artemisinin antimalarial drugs, new and novel pharmaceuticals are needed. ARCO® is a new generation ACT, one of several artemisinin-based combinations developed in China to counter antimalarial drug resistance. ARCO® is [...] Read more.
With the rapidly spreading resistance of Plasmodium falciparum to available non-artemisinin antimalarial drugs, new and novel pharmaceuticals are needed. ARCO® is a new generation ACT, one of several artemisinin-based combinations developed in China to counter antimalarial drug resistance. ARCO® is a derivative of two independently developed antimalarials, artemisinin and naphthoquine phosphate, which were combined to form the artemisinin-naphthoquine combination. Both artemisinin and naphthoquine drugs have proven to be efficacious, safe and well tolerated as monotherapies. The artemisinin-naphthoquine combination offers a novel advantage over existing ACTs: it can be administered as a single oral dose (or a 1-day treatment). Several therapeutic studies conducted recently indicate that a single oral dose administration of artemisinin-naphthoquine combination is equally effective and safe as the 3-day treatment with artemether-lumefantrine combination and other existing ACTs. This would make ARCO® the next generation ACT for the treatment of uncomplicated falciparum malaria. Full article
(This article belongs to the Special Issue New Antimalarial Drugs)
Open AccessReview Pharmacogenetics of SSRIs and Sexual Dysfunction
Pharmaceuticals 2010, 3(12), 3614-3628; doi:10.3390/ph3123614
Received: 1 November 2010 / Revised: 30 November 2010 / Accepted: 9 December 2010 / Published: 15 December 2010
Cited by 4 | PDF Full-text (74 KB) | HTML Full-text | XML Full-text
Abstract
Sexual dysfunction (SD) is a common and disconcerting side effect of selective serotonin reuptake inhibitors (SSRIs) that often influences a patient’s desire to continue long-term antidepressant treatment. Studies specifically assessing changes in sexual well-being over time illustrate that the incidence of sexual [...] Read more.
Sexual dysfunction (SD) is a common and disconcerting side effect of selective serotonin reuptake inhibitors (SSRIs) that often influences a patient’s desire to continue long-term antidepressant treatment. Studies specifically assessing changes in sexual well-being over time illustrate that the incidence of sexual side effects from SSRIs ranges from 20% to 70%, depending on the characteristics of the study sample assessed. Developing strategies to predict who may be at the highest risk for adverse changes in their sexual well-being is an important step in improving the quality of life and treatment of patients who require antidepressant therapy. Pharmacogenetic studies of SSRI-associated SD have identified associations between serotonin and glutamate system genes with aspects of SD. The results of studies investigating genetic variations in drug metabolism enzymes and their relationships to antidepressant-associated adverse effects have been mixed. Continued efforts to characterize the relationships between genetic markers and antidepressant outcomes, and to translate this knowledge to patient care, have the potential to significantly improve the empiric selection of antidepressant agents and to minimize the risk for intolerable side effects. Full article
(This article belongs to the Special Issue Antidepressants)

Other

Jump to: Research, Review

Open AccessCommentary Comments on the Eslicarbazepine Acetate Section of the Article ‘Therapeutic Drug Monitoring of the Newer Anti-Epilepsy Medications’
Pharmaceuticals 2010, 3(12), 3629-3632; doi:10.3390/ph3123629
Received: 9 November 2010 / Accepted: 16 December 2010 / Published: 17 December 2010
Cited by 1 | PDF Full-text (49 KB) | HTML Full-text | XML Full-text
Abstract
The recent review of Matthew D. Krasowski on ‘Therapeutic Drug Monitoring of the Newer Anti-Epilepsy Medications’ is a useful foundation of comparative interpretations on our current knowledge about therapeutic drug monitoring. Within the review, the statement that therapeutic drug monitoring has a [...] Read more.
The recent review of Matthew D. Krasowski on ‘Therapeutic Drug Monitoring of the Newer Anti-Epilepsy Medications’ is a useful foundation of comparative interpretations on our current knowledge about therapeutic drug monitoring. Within the review, the statement that therapeutic drug monitoring has a minimal role in the therapeutic use of eslicarbazepine acetate due to its relatively predictable pharmacokinetics reflects the existing body of evidence although some information such as eslicarbazepine acetate’s chemical structure, proportions of its metabolites, their pharmacokinetics and chiral method of plasma level measurement need to be revised. These critical characteristics differentiate the novel compound from former dibenzazepines such as carbamazepine and oxcarbazepine in its clinical effects and needs for therapeutic drug monitoring. Full article
(This article belongs to the Special Issue Antiepileptic Drugs)
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