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Pharmaceuticals, Volume 5, Issue 10 (October 2012), Pages 1045-1146

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Research

Jump to: Review

Open AccessArticle Statistical Estimation of the Protein-Ligand Binding Free Energy Based On Direct Protein-Ligand Interaction Obtained by Molecular Dynamics Simulation
Pharmaceuticals 2012, 5(10), 1064-1079; doi:10.3390/ph5101064
Received: 29 August 2012 / Revised: 19 September 2012 / Accepted: 21 September 2012 / Published: 28 September 2012
Cited by 1 | PDF Full-text (305 KB) | HTML Full-text | XML Full-text
Abstract
We have developed a method for estimating protein-ligand binding free energy (DG) based on the direct protein-ligand interaction obtained by a molecular dynamics simulation. Using this method, we estimated the DG value statistically by the average values of the van der Waals [...] Read more.
We have developed a method for estimating protein-ligand binding free energy (DG) based on the direct protein-ligand interaction obtained by a molecular dynamics simulation. Using this method, we estimated the DG value statistically by the average values of the van der Waals and electrostatic interactions between each amino acid of the target protein and the ligand molecule. In addition, we introduced fluctuations in the accessible surface area (ASA) and dihedral angles of the protein-ligand complex system as the entropy terms of the DG estimation. The present method included the fluctuation term of structural change of the protein and the effective dielectric constant. We applied this method to 34 protein-ligand complex structures. As a result, the correlation coefficient between the experimental and calculated DG values was 0.81, and the average error of DG was 1.2 kcal/mol with the use of the fixed parameters. These results were obtained from a 2 nsec molecular dynamics simulation. Full article
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Open AccessArticle Design, Synthesis and Hydrolytic Behavior of Mutual Prodrugs of NSAIDs with Gabapentin Using Glycol Spacers
Pharmaceuticals 2012, 5(10), 1080-1091; doi:10.3390/ph5101080
Received: 3 September 2012 / Revised: 30 September 2012 / Accepted: 8 October 2012 / Published: 12 October 2012
Cited by 4 | PDF Full-text (336 KB) | HTML Full-text | XML Full-text
Abstract
The free –COOH present in NSAIDs is thought to be responsible for the GI irritation associated with all traditional NSAIDs. Exploitation of mutual prodrugs is an approach wherein the NSAID is covalently bounded to a second pharmacologically active carrier/drug with the ultimate aim of reducing the gastric irritation. In this study some NSAIDs were conjugated with gabapentin via ester bonds using glycol spacers with the expectation of reducing gastric adverse effects and obtaining synergistic analgesic effects. The kinetics of ester hydrolysis were studied in two different non enzymatic buffer solutions at pH 1.2 and 7.4, as well as in 80% human plasma using HPLC with chloroform -methanol as mobile phase. Compounds 9ac with ethylene glycol spacers showed significant stability at buffer solutions with half lives ranging from about 8–25 h, while the underwent a reasonable plasma hydrolysis (49%–88%) in 2 h. Compound 9d with a propylene glycol spacer shows a higher rate of enzymatic hydrolysis than the corresponding ethylene glycol compound 9c. The result of compounds 9a-c indicate that these compounds may be stable during their passage through the GIT until reaching the blood circulation. Full article
Open AccessArticle Intranasal Delivery of Camptothecin-Loaded Tat-Modified Nanomicells for Treatment of Intracranial Brain Tumors
Pharmaceuticals 2012, 5(10), 1092-1102; doi:10.3390/ph5101092
Received: 3 September 2012 / Revised: 27 September 2012 / Accepted: 9 October 2012 / Published: 15 October 2012
Cited by 11 | PDF Full-text (321 KB) | HTML Full-text | XML Full-text
Abstract
The blood-brain barrier is a substantial obstacle for delivering anticancer agents to brain tumors, and new strategies for bypassing it are sorely needed for brain tumor therapy. Intranasal delivery provides a practical, noninvasive method for delivering therapeutic agents to the brain. Intranasal [...] Read more.
The blood-brain barrier is a substantial obstacle for delivering anticancer agents to brain tumors, and new strategies for bypassing it are sorely needed for brain tumor therapy. Intranasal delivery provides a practical, noninvasive method for delivering therapeutic agents to the brain. Intranasal application of nano-sized micelles that have been modified with Tat peptide facilitates brain delivery of fluorescent model materials. In this study, we evaluated a nose-to-brain delivery system for brain tumor therapy. We nasally administered the anti-tumor drug camptothecin (CPT) in solution and in methoxy poly(ethylene glycol) (MPEG)/poly(e-caprolactone) (PCL) amphiphilic block copolymers (MPEG-PCL) and cell penetrating peptide, Tat analog-modified MPEG-PCL (MPEG-PCL-Tat) MPEG-PCL-Tat to rats bearing intracranial glioma tumors and quantified the cytotoxicity against glioma cells, and the therapeutic effects. CPT-loaded MPEG-PCL-Tat micelles showed higher cytotoxicity than CPT-loaded MPEG-PCL. CPT-free MPEG-PCL-Tat didn’t show any cytotoxicity, even at high concentrations (2 mmol/mL). CPT-loaded MPEG-PCL-Tat micelles significantly prolonged the median survival of rats. These results indicate that intranasal delivery of anti-cancer drugs with cell penetrating peptide-modified nanomicelles might be an effective therapy for brain tumors. Full article
(This article belongs to the Special Issue Cell-penetrating Peptides 2012)
Open AccessArticle Norethindrone Acetate in the Medical Management of Adenomyosis
Pharmaceuticals 2012, 5(10), 1120-1127; doi:10.3390/ph5101120
Received: 8 July 2012 / Revised: 4 October 2012 / Accepted: 15 October 2012 / Published: 22 October 2012
Cited by 2 | PDF Full-text (182 KB) | HTML Full-text | XML Full-text
Abstract
The role of norethindrone acetate (NA) in the management of adenomyosis was evaluated with a retrospective chart review of 28 premenopausal women between 27–49 years of age presenting with moderate to severe pelvic pain and bleeding. Bleeding and dysmenorrhea scores were analyzed [...] Read more.
The role of norethindrone acetate (NA) in the management of adenomyosis was evaluated with a retrospective chart review of 28 premenopausal women between 27–49 years of age presenting with moderate to severe pelvic pain and bleeding. Bleeding and dysmenorrhea scores were analyzed using paired T-tests. There was significant improvement of both dysmenorrhea and bleeding after treatment. Age showed no correlation with dysmenorrhea or bleeding. Low dose NA could be considered an effective, well-tolerated and inexpensive medical alternative to surgery for treating symptomatic adenomyosis. Large multicentric studies may help validate our findings. Full article
(This article belongs to the Special Issue Hormone Therapy)
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Review

Jump to: Research

Open AccessReview The Use of California Sagebrush (Artemisia californica) Liniment to Control Pain
Pharmaceuticals 2012, 5(10), 1045-1053; doi:10.3390/ph5101045
Received: 2 July 2012 / Revised: 6 September 2012 / Accepted: 17 September 2012 / Published: 27 September 2012
Cited by 4 | PDF Full-text (209 KB) | HTML Full-text | XML Full-text
Abstract
The incidence of arthritis is increasing every year, as does the need for pain medication. The current work reviews an American Indian liniment that is traditionally used for pain therapy. The chemistry, therapeutic use and safety of the liniment are reviewed. The [...] Read more.
The incidence of arthritis is increasing every year, as does the need for pain medication. The current work reviews an American Indian liniment that is traditionally used for pain therapy. The chemistry, therapeutic use and safety of the liniment are reviewed. The liniment contains monoterpenoids, sesquiterpenes, flavonoids, alkaloids and other compounds. Full article
(This article belongs to the Special Issue Emerging Pain Targets and Therapy)
Open AccessReview Cell-Penetrating Recombinant Peptides for Potential Use in Agricultural Pest Control Applications
Pharmaceuticals 2012, 5(10), 1054-1063; doi:10.3390/ph5101054
Received: 27 August 2012 / Revised: 21 September 2012 / Accepted: 21 September 2012 / Published: 28 September 2012
Cited by 3 | PDF Full-text (214 KB) | HTML Full-text | XML Full-text
Abstract
Several important areas of interest intersect in a class of peptides characterized by their highly cationic and partly hydrophobic structure. These molecules have been called cell-penetrating peptides (CPPs) because they possess the ability to translocate across cell membranes. This ability makes these [...] Read more.
Several important areas of interest intersect in a class of peptides characterized by their highly cationic and partly hydrophobic structure. These molecules have been called cell-penetrating peptides (CPPs) because they possess the ability to translocate across cell membranes. This ability makes these peptides attractive candidates for delivery of therapeutic compounds, especially to the interior of cells. Compounds with characteristics similar to CPPs and that, in addition, have antimicrobial properties are being investigated as antibiotics with a reduced risk of causing resistance. These CPP-like membrane-acting antimicrobial peptides (MAMPs) are α-helical amphipathic peptides that interact with and perturb cell membranes to produce their antimicrobial effects. One source of MAMPs is spider venom. Because these compounds are toxic to insects, they also show promise for development as biological agents for control of insecticide-resistant agricultural pests. Spider venom is a potential source of novel insect-specific peptide toxins. One example is the small amphipathic α-helical peptide lycotoxin-1 (Lyt-1 or LCTX) from the wolf spider (Lycosa carolinensis). One side of the α-helix has mostly hydrophilic and the other mainly hydrophobic amino acid residues. The positive charge of the hydrophilic side interacts with negatively charged prokaryotic membranes and the hydrophobic side associates with the membrane lipid bilayer to permeabilize it. Because the surface of the exoskeleton, or cuticle, of an insect is highly hydrophobic, to repel water and dirt, it would be expected that amphipathic compounds could permeabilize it. Mutagenized lycotoxin 1 peptides were produced and expressed in yeast cultures that were fed to fall armyworm (Spodoptera frugiperda) larvae to identify the most lethal mutants. Transgenic expression of spider venom toxins such as lycotoxin-1 in plants could provide durable insect resistance. Full article
(This article belongs to the Special Issue Cell-penetrating Peptides 2012)
Open AccessReview Mitochondria-Targeted Antioxidant SS31 Prevents Amyloid Beta-Induced Mitochondrial Abnormalities and Synaptic Degeneration in Alzheimer’s Disease
Pharmaceuticals 2012, 5(10), 1103-1119; doi:10.3390/ph5101103
Received: 5 September 2012 / Revised: 4 October 2012 / Accepted: 8 October 2012 / Published: 16 October 2012
Cited by 9 | PDF Full-text (460 KB) | HTML Full-text | XML Full-text
Abstract
In neuronal systems, the health and activity of mitochondria and synapses are tightly coupled. For this reason, it has been postulated that mitochondrial abnormalities may, at least in part, drive neurodegeneration in conditions such as Alzheimer’s disease (AD). Mounting evidence from multiple Alzheimer’s disease cell and mouse models and postmortem brains suggest that loss of mitochondrial integrity may be a key factor that mediates synaptic loss. Therefore, the prevention or rescue of mitochondrial dysfunction may help delay or altogether prevent AD-associated neurodegeneration. Since mitochondrial health is heavily dependent on antioxidant defenses, researchers have begun to explore the use of mitochondria-targeted antioxidants as therapeutic tools to prevent neurodegenerative diseases. This review will highlight advances made using a model mitochondria-targeted antioxidant peptide, SS31, as a potential treatment for AD. Full article
(This article belongs to the Special Issue Mitochondrial Drugs for Neurodegenerative Diseases)
Open AccessReview Advances in Drug Design Based on the Amino Acid Approach: Taurine Analogues for the Treatment of CNS Diseases
Pharmaceuticals 2012, 5(10), 1128-1146; doi:10.3390/ph5101128
Received: 31 July 2012 / Revised: 24 September 2012 / Accepted: 15 October 2012 / Published: 23 October 2012
Cited by 3 | PDF Full-text (337 KB) | HTML Full-text | XML Full-text
Abstract
Amino acids are well known to be an important class of compounds for the maintenance of body homeostasis and their deficit, even for the polar neuroactive aminoacids, can be controlled by supplementation. However, for the amino acid taurine (2-aminoethanesulfonic acid) this is [...] Read more.
Amino acids are well known to be an important class of compounds for the maintenance of body homeostasis and their deficit, even for the polar neuroactive aminoacids, can be controlled by supplementation. However, for the amino acid taurine (2-aminoethanesulfonic acid) this is not true. Due its special physicochemical properties, taurine is unable to cross the blood-brain barrier. In addition of injured taurine transport systems under pathological conditions, CNS supplementation of taurine is almost null. Taurine is a potent antioxidant and anti-inflammatory semi-essential amino acid extensively involved in neurological activities, acting as neurotrophic factor, binding to GABA A/glycine receptors and blocking the excitotoxicity glutamate-induced pathway leading to be a neuroprotective effect and neuromodulation. Taurine deficits have been implicated in several CNS diseases, such as Alzheimer’s, Parkinson’s, epilepsy and in the damage of retinal neurons. This review describes the CNS physiological functions of taurine and the development of new derivatives based on its structure useful in CNS disease treatment. Full article
(This article belongs to the Special Issue Advances in Drug Design)

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