Pharmaceuticals

746 KiB

Open AccessArticle

Pharmacogenomics Implications of Using Herbal Medicinal Plants on African Populations in Health Transition

by Nicholas E. Thomford, Kevin Dzobo, Denis Chopera, Ambroise Wonkam, Michelle Skelton, Dee Blackhurst, Shadreck Chirikure and Collet Dandara

Pharmaceuticals 2015, 8(3), 637-663; https://doi.org/10.3390/ph8030637 - 21 Sep 2015

Cited by 70 | Viewed by 11495

Abstract

The most accessible points of call for most African populations with respect to primary health care are traditional health systems that include spiritual, religious, and herbal medicine. This review focusses only on the use of herbal medicines. Most African people accept herbal medicines [...] Read more.

The most accessible points of call for most African populations with respect to primary health care are traditional health systems that include spiritual, religious, and herbal medicine. This review focusses only on the use of herbal medicines. Most African people accept herbal medicines as generally safe with no serious adverse effects. However, the overlap between conventional medicine and herbal medicine is a reality among countries in health systems transition. Patients often simultaneously seek treatment from both conventional and traditional health systems for the same condition. Commonly encountered conditions/diseases include malaria, HIV/AIDS, hypertension, tuberculosis, and bleeding disorders. It is therefore imperative to understand the modes of interaction between different drugs from conventional and traditional health care systems when used in treatment combinations. Both conventional and traditional drug entities are metabolized by the same enzyme systems in the human body, resulting in both pharmacokinetics and pharmacodynamics interactions, whose properties remain unknown/unquantified. Thus, it is important that profiles of interaction between different herbal and conventional medicines be evaluated. This review evaluates herbal and conventional drugs in a few African countries and their potential interaction at the pharmacogenomics level. Full article

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Open AccessReview

Novel Targeted Agents in Hodgkin and Non-Hodgkin Lymphoma Therapy

by Natalie S. Grover and Steven I. Park

Pharmaceuticals 2015, 8(3), 607-636; https://doi.org/10.3390/ph8030607 - 17 Sep 2015

Cited by 19 | Viewed by 11252

Abstract

There has been a recent emergence of novel targeted agents for treatment of Hodgkin and non-Hodgkin lymphoma. In particular, antibodies and antibody-drug conjugates directed against surface antigens, agents that block immune checkpoint pathways, and small molecule inhibitors directed against cell signaling pathways have [...] Read more.

There has been a recent emergence of novel targeted agents for treatment of Hodgkin and non-Hodgkin lymphoma. In particular, antibodies and antibody-drug conjugates directed against surface antigens, agents that block immune checkpoint pathways, and small molecule inhibitors directed against cell signaling pathways have shown significant promise in patients with relapsed and refractory disease and in the frontline setting. With the development of these new therapies, cytotoxic chemotherapy may be avoided entirely in some clinical settings. This review will present the latest information on these novel treatments in Hodgkin and non-Hodgkin lymphoma and will discuss both recently approved agents as well as drugs currently being studied in clinical trials. Full article

(This article belongs to the Special Issue New Drugs in Hematology)

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Open AccessReview

Potential of Glutamate-Based Drug Discovery for Next Generation Antidepressants

by Shigeyuki Chaki and Kenichi Fukumoto

Pharmaceuticals 2015, 8(3), 590-606; https://doi.org/10.3390/ph8030590 - 17 Sep 2015

Cited by 19 | Viewed by 7910

Abstract

Recently, ketamine has been demonstrated to exert rapid-acting antidepressant effects in patients with depression, including those with treatment-resistant depression, and this discovery has been regarded as the most significant advance in drug development for the treatment of depression in over 50 years. To [...] Read more.

Recently, ketamine has been demonstrated to exert rapid-acting antidepressant effects in patients with depression, including those with treatment-resistant depression, and this discovery has been regarded as the most significant advance in drug development for the treatment of depression in over 50 years. To overcome unwanted side effects of ketamine, numerous approaches targeting glutamatergic systems have been vigorously investigated. For example, among agents targeting the NMDA receptor, the efficacies of selective GluN2B receptor antagonists and a low-trapping antagonist, as well as glycine site modulators such as GLYX-13 and sarcosine have been demonstrated clinically. Moreover, agents acting on metabotropic glutamate receptors, such as mGlu2/3 and mGlu5 receptors, have been proposed as useful approaches to mimicking the antidepressant effects of ketamine. Neural and synaptic mechanisms mediated through the antidepressant effects of ketamine have been being delineated, most of which indicate that ketamine improves abnormalities in synaptic transmission and connectivity observed in depressive states via the AMPA receptor and brain-derived neurotrophic factor-dependent mechanisms. Interestingly, some of the above agents may share some neural and synaptic mechanisms with ketamine. These studies should provide important insights for the development of superior pharmacotherapies for depression with more potent and faster onsets of actions. Full article

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Open AccessReview

Ecology of Anti-Biofilm Agents II: Bacteriophage Exploitation and Biocontrol of Biofilm Bacteria

by Stephen T. Abedon

Pharmaceuticals 2015, 8(3), 559-589; https://doi.org/10.3390/ph8030559 - 9 Sep 2015

Cited by 74 | Viewed by 11301

Abstract

Bacteriophages are the viruses of bacteria. In the guise of phage therapy they have been used for decades to successfully treat what are probable biofilm-containing chronic bacterial infections. More recently, phage treatment or biocontrol of biofilm bacteria has been brought back to the [...] Read more.

Bacteriophages are the viruses of bacteria. In the guise of phage therapy they have been used for decades to successfully treat what are probable biofilm-containing chronic bacterial infections. More recently, phage treatment or biocontrol of biofilm bacteria has been brought back to the laboratory for more rigorous assessment as well as towards the use of phages to combat environmental biofilms, ones other than those directly associated with bacterial infections. Considered in a companion article is the inherent ecological utility of bacteriophages versus antibiotics as anti-biofilm agents. Discussed here is a model for phage ecological interaction with bacteria as they may occur across biofilm-containing ecosystems. Specifically, to the extent that individual bacterial types are not highly abundant within biofilm-containing environments, then phage exploitation of those bacteria may represent a “Feast-or-famine” existence in which infection of highly localized concentrations of phage-sensitive bacteria alternate with treacherous searches by the resulting phage progeny virions for new concentrations of phage-sensitive bacteria to infect. An updated synopsis of the literature concerning laboratory testing of phage use to combat bacterial biofilms is then provided along with tips on how “Ecologically” such phage-mediated biofilm control can be modified to more reliably achieve anti-biofilm efficacy. Full article

(This article belongs to the Special Issue Microbial Biofilms)

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Open AccessReview

Ecology of Anti-Biofilm Agents I: Antibiotics versus Bacteriophages

by Stephen T. Abedon

Pharmaceuticals 2015, 8(3), 525-558; https://doi.org/10.3390/ph8030525 - 9 Sep 2015

Cited by 58 | Viewed by 9719

Abstract

Bacteriophages, the viruses that infect bacteria, have for decades been successfully used to combat antibiotic-resistant, chronic bacterial infections, many of which are likely biofilm associated. Antibiotics as anti-biofilm agents can, by contrast, be inefficacious against even genetically sensitive targets. Such deficiencies in usefulness [...] Read more.

Bacteriophages, the viruses that infect bacteria, have for decades been successfully used to combat antibiotic-resistant, chronic bacterial infections, many of which are likely biofilm associated. Antibiotics as anti-biofilm agents can, by contrast, be inefficacious against even genetically sensitive targets. Such deficiencies in usefulness may result from antibiotics, as naturally occurring compounds, not serving their producers, in nature, as stand-alone disruptors of mature biofilms. Anti-biofilm effectiveness by phages, by contrast, may result from a combination of inherent abilities to concentrate lytic antibacterial activity intracellularly via bacterial infection and extracellularly via localized population growth. Considered here is the anti-biofilm activity of microorganisms, with a case presented for why, ecologically, bacteriophages can be more efficacious than traditional antibiotics as medically or environmentally applied biofilm-disrupting agents. Four criteria, it can be argued, generally must be met, in combination, for microorganisms to eradicate biofilms: (1) Furnishing of sufficiently effective antibacterial factors, (2) intimate interaction with biofilm bacteria over extended periods, (3) associated ability to concentrate antibacterial factors in or around targets, and, ultimately, (4) a means of physically disrupting or displacing target bacteria. In nature, lytic predators of bacteria likely can meet these criteria whereas antibiotic production, in and of itself, largely may not. Full article

(This article belongs to the Special Issue Microbial Biofilms)

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Open AccessArticle

Use of Cyclo-Oxygenase Inhibitors Is Not Associated with Clinical Relapse in Inflammatory Bowel Disease: A Case-Control Study

by Abigail Hensley and Ian L. P. Beales

Pharmaceuticals 2015, 8(3), 512-524; https://doi.org/10.3390/ph8030512 - 7 Sep 2015

Cited by 11 | Viewed by 5326

Abstract

Patients with inflammatory bowel disease (IBD) often have associated conditions, for which anti-inflammatory medication with cyclo-oxygenase (COX) inhibitors may be helpful. The current evidence is conflicting regarding the role of COX-inhibitors in causing relapse in IBD. This case-control study examined the association between [...] Read more.

Patients with inflammatory bowel disease (IBD) often have associated conditions, for which anti-inflammatory medication with cyclo-oxygenase (COX) inhibitors may be helpful. The current evidence is conflicting regarding the role of COX-inhibitors in causing relapse in IBD. This case-control study examined the association between the use of COX inhibitors and relapse of IBD. Logistic regression was used to analyse the relationship between COX-inhibitors and IBD relapse. Overall COX inhibitor use (combined non-steroidal anti-inflammatory drugs (NSAIDs) and selective COX-2 agents) had a negative association with relapse of IBD (adjusted OR 0.26, 95% CI 0.09–0.80). This negative association was confined to ulcerative colitis (UC) (adjusted OR = 0.06, 95% CI 0.01–0.50) and no association was found in Crohn’s disease (CD) patients (adjusted OR 1.25, 95% CI 0.18–7.46). The significant negative association between UC relapse and medication use was also seen with non-specific NSAIDs. Selective COX-2 inhibitor use was rare but non-significantly more common in stable patients. There was no association between low-dose aspirin or paracetamol use and relapse of CD or UC. We conclude that COX-inhibitor use was not associated with an increased risk of relapse in UC or CD, and may be protective in UC. Where indicated, NSAIDs should not be withheld from IBD patients. Full article

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

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Open AccessCommentary

Prospects for Anti-Biofilm Pharmaceuticals

by Philip S. Stewart

Pharmaceuticals 2015, 8(3), 504-511; https://doi.org/10.3390/ph8030504 - 27 Aug 2015

Cited by 32 | Viewed by 7084

Abstract

This commentary highlights several avenues currently being pursued in research labs to the development of new anti-biofilm pharmaceuticals. There is a real need for alternative therapeutic modalities for treating the persistent infections that sometimes form on implanted medical devices or compromised niches within [...] Read more.

This commentary highlights several avenues currently being pursued in research labs to the development of new anti-biofilm pharmaceuticals. There is a real need for alternative therapeutic modalities for treating the persistent infections that sometimes form on implanted medical devices or compromised niches within the body. Strategies being researched include discovering new antimicrobial agents that kill microorganisms in biofilms more effectively than do existing antibiotics, designing drugs that block microbial adhesion or interfere with intercellular communication, developing chemistries to disperse biofilms, and combining agents with different mechanisms of action. Though the need is great, the pathway to commercialization of new drugs is steep. One possible streamlined approach to navigating the regulatory approval process is to repurpose old drugs, a strategy that a few groups have shown can yield agents with anti-biofilm properties. Full article

(This article belongs to the Special Issue Microbial Biofilms)

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Open AccessArticle

Antifungal Activity of 14-Helical β-Peptides against Planktonic Cells and Biofilms of Candida Species

by Namrata Raman, Myung-Ryul Lee, David M. Lynn and Sean P. Palecek

Pharmaceuticals 2015, 8(3), 483-503; https://doi.org/10.3390/ph8030483 - 13 Aug 2015

Cited by 24 | Viewed by 6246

Abstract

Candida albicans is the most prevalent cause of fungal infections and treatment is further complicated by the formation of drug resistant biofilms, often on the surfaces of implanted medical devices. In recent years, the incidence of fungal infections by other pathogenic Candida species [...] Read more.

Candida albicans is the most prevalent cause of fungal infections and treatment is further complicated by the formation of drug resistant biofilms, often on the surfaces of implanted medical devices. In recent years, the incidence of fungal infections by other pathogenic Candida species such as C. glabrata, C. parapsilosis and C. tropicalis has increased. Amphiphilic, helical β-peptide structural mimetics of natural antimicrobial α-peptides have been shown to exhibit specific planktonic antifungal and anti-biofilm formation activity against C. albicans in vitro. Here, we demonstrate that β-peptides are also active against clinically isolated and drug resistant strains of C. albicans and against other opportunistic Candida spp. Different Candida species were susceptible to β-peptides to varying degrees, with C. tropicalis being the most and C. glabrata being the least susceptible. β-peptide hydrophobicity directly correlated with antifungal activity against all the Candida clinical strains and species tested. While β-peptides were largely ineffective at disrupting existing Candida biofilms, hydrophobic β-peptides were able to prevent the formation of C. albicans, C. glabrata, C. parapsilosis and C. tropicalis biofilms. The broad-spectrum antifungal activity of β-peptides against planktonic cells and in preventing biofilm formation suggests the promise of this class of molecules as therapeutics. Full article

(This article belongs to the Special Issue Microbial Biofilms)

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Open AccessArticle

UCP2 Modulates Cardioprotective Effects of Ru360 in Isolated Cardiomyocytes during Ischemia

by Lukas J. Motloch, Sara Reda, Martin Wolny and Uta C. Hoppe

Pharmaceuticals 2015, 8(3), 474-482; https://doi.org/10.3390/ph8030474 - 4 Aug 2015

Cited by 15 | Viewed by 6025

Abstract

Introduction: Ruthenium 360 (Ru360) has been shown to induce cardioprotective mechanisms in perfused hearts. The agent is a specific blocker of the main cardiac mitochondrial uptake mechanism, the mitochondrial calcium uniporter (MCU). UCP2, a mitochondrial membrane protein, which influences cardiac ROS formation [...] Read more.

Introduction: Ruthenium 360 (Ru360) has been shown to induce cardioprotective mechanisms in perfused hearts. The agent is a specific blocker of the main cardiac mitochondrial uptake mechanism, the mitochondrial calcium uniporter (MCU). UCP2, a mitochondrial membrane protein, which influences cardiac ROS formation was reported to interact with the MCU. Methods: To prove whether Ru360 affects ischemic cell injury on the singular cell level, cell viability (CV) in isolated cardiomyocytes from wild type mice (WT) was measured in a model of pelleting hypoxia (PH). To explore a possible influence of UCP2 on cellular survival, as well as on Ru360 function, cardiomyocytes from UCP2^−/− mice were investigated. Results: During PH, Ru360 significantly improved CV in WT cardiomyocytes (Control 26.32% ± 1.58% vs. PH 13.60% ± 1.20% vs. PH+Ru360 19.98% ± 0.98%, n = 6; p < 0.05). No differences in the rate of apoptosis were observed in UCP2^−/− vs. WT. In UCP2^−/− cardiomyocytes, Ru360 reduced the rate of cell death. However, the effect was less pronounced compared to WT cardiomyocytes. Conclusion: Ru360 significantly reduces hypoxic cell injury by preventing single cell apoptosis in WT cardiomyoctes. UCP2 does not affect cell survival in hypoxic cardiomyocytes, but it might modulate cardioprotective effects of Ru360 during ischemia. Full article

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Open AccessReview

On the Quest of Cellular Functions of PEA-15 and the Therapeutic Opportunities

by Yufeng Wei

Pharmaceuticals 2015, 8(3), 455-473; https://doi.org/10.3390/ph8030455 - 31 Jul 2015

Cited by 8 | Viewed by 6566

Abstract

Phosphoprotein enriched in astrocytes, 15 KDa (PEA-15), a ubiquitously expressed small protein in all mammals, is known for decades for its potent interactions with various protein partners along distinct biological pathways. Most notable interacting partners of PEA-15 include extracellular signal-regulated kinase 1 and [...] Read more.

Phosphoprotein enriched in astrocytes, 15 KDa (PEA-15), a ubiquitously expressed small protein in all mammals, is known for decades for its potent interactions with various protein partners along distinct biological pathways. Most notable interacting partners of PEA-15 include extracellular signal-regulated kinase 1 and 2 (ERK1/2) in the mitogen activated protein kinase (MAPK) pathway, the Fas-associated death domain (FADD) protein involving in the formation of the death-inducing signaling complex (DISC), and the phospholipase D1 (PLD1) affecting the insulin sensitivity. However, the actual cellular functions of PEA-15 are still mysterious, and the question why this protein is expressed in almost all cell and tissue types remains unanswered. Here we synthesize the most recent structural, biological, and clinical studies on PEA-15 with emphases on its anti-apoptotic, anti-proliferative, and anti-inflammative properties, and propose a converged protective role of PEA-15 that maintains the balance of death and survival in different cell types. Under conditions that this delicate balance is unsustainable, PEA-15 may become pathological and lead to various diseases, including cancers and diabetes. Targeting PEA-15 interactions, or the use of PEA-15 protein as therapeutics, may provide a wider window of opportunities to treat these diseases. Full article

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Open AccessArticle

Bench to Bedside: Stability Studies of GMP Produced Trastuzumab-TCMC in Support of a Clinical Trial

by Diane E. Milenic, Kwamena E. Baidoo and Martin W. Brechbiel

Pharmaceuticals 2015, 8(3), 435-454; https://doi.org/10.3390/ph8030435 - 29 Jul 2015

Cited by 13 | Viewed by 8383

Abstract

The first-in-human phase 1 clinical radioimmunotherapy (RIT) trial with ²¹²Pb-1,4,7,10-tetraaza-1,4,7,10-tetra-(2-carbamoylmethyl)-cyclododecane-trastuzumab (²¹²Pb-TCMC-trastuzumab) was completed in October 2014 as a joint effort at the University of Alabama (UAB) and the University of California San Diego Moores Cancer Center. The preliminary reports indicate [...] Read more.

The first-in-human phase 1 clinical radioimmunotherapy (RIT) trial with ²¹²Pb-1,4,7,10-tetraaza-1,4,7,10-tetra-(2-carbamoylmethyl)-cyclododecane-trastuzumab (²¹²Pb-TCMC-trastuzumab) was completed in October 2014 as a joint effort at the University of Alabama (UAB) and the University of California San Diego Moores Cancer Center. The preliminary reports indicate that after five dose-levels of intraperitoneally administered ²¹²Pb-TCMC-trastuzumab, patients with carcinomatosis experienced minimal agent-related toxicity. This report presents the data accumulated to date on the stability of the clinical grade, produced according to current good manufacturing practices (cGMP), TCMC-trastuzumab conducted in support of that clinical trial. Of the eleven tests performed with the cGMP TCMC-trastuzumab all but one remained within specifications throughout the 5 year testing period. The protein concentration varied by 0.01 mg/mL at 48 months. Two other assays, ion-exchange high performance liquid chromatography (IEX-HPLC) and a competitive radioimmunoassay (RIA) indicated that the cGMP TCMC-trastuzumab integrity may be changing, although the change thus far is within specifications. Subsequent stability testing will confirm if a trend has truly developed. The cGMP TCMC-trastuzumab was also evaluated for tolerance to higher temperatures and the potential of storage at −80 °C. The immunoconjugate proved stable when subjected to the lower temperatures and to multiple freeze-thaw cycles. The size exclusion (SE) HPLC analysis of the ²⁰³Pb-TCMC-trastuzumab was the only indicator that cGMP TCMC-trastuzumab may be sensitive to storage at 37 °C for 3 months. Full article

(This article belongs to the Special Issue Preparation of Radiopharmaceuticals and Their Use in Drug Development)

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Open AccessArticle

Toxicological Studies of ²¹²Pb Intravenously or Intraperitoneally Injected into Mice for a Phase 1 Trial

by Diane E. Milenic, Alfredo A. Molinolo, María S. Solivella, Eileen Banaga, Julien Torgue, Sarah Besnainou, Martin W. Brechbiel and Kwamena E. Baidoo

Pharmaceuticals 2015, 8(3), 416-434; https://doi.org/10.3390/ph8030416 - 24 Jul 2015

Cited by 17 | Viewed by 6483

Abstract

Faced with the novelty of a ²¹²Pb-labeled monoclonal antibody (mAb) for clinical translation, concerns were expressed by the Food and Drug Administration (FDA) regarding ²¹²Pb prematurely released from the mAb-chelate conjugate. The objective of this study was to simulate the worst [...] Read more.

Faced with the novelty of a ²¹²Pb-labeled monoclonal antibody (mAb) for clinical translation, concerns were expressed by the Food and Drug Administration (FDA) regarding ²¹²Pb prematurely released from the mAb-chelate conjugate. The objective of this study was to simulate the worst case scenario of such a failure. Groups of Balb/c mice (n = 9–20) were administered ²¹²Pb by intraperitoneal (0.0925–1.85 MBq) or intravenous (0.0925–1.11 MBq) injection and then euthanized at 7 or 90 days to assess acute or chronic effects. Weights were recorded prior to injection of the ²¹²Pb and at the end of the observation periods. Blood samples were collected for clinical chemistry and blood cell analysis. Thirty tissues were harvested and formalin fixed for histopathological examination. Treatment related effects of the ²¹²Pb were observed in the bone marrow, spleen, kidneys and the liver. Histological alterations in these organs were considered mild to moderate, indicating low grade toxicity, and not considered severe enough to affect function. This data was presented to the FDA and determined to be acceptable. The clinical trial with ²¹²Pb-TCMC-trastuzumab was approved in January 2011 and the trial opened at the University of Alabama at Birmingham (UAB) in July. Full article

(This article belongs to the Special Issue Preparation of Radiopharmaceuticals and Their Use in Drug Development)

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Open AccessReview

Peptides and Peptidomimetics for Antimicrobial Drug Design

by Biljana Mojsoska and Håvard Jenssen

Pharmaceuticals 2015, 8(3), 366-415; https://doi.org/10.3390/ph8030366 - 13 Jul 2015

Cited by 175 | Viewed by 16774

Abstract

The purpose of this paper is to introduce and highlight a few classes of traditional antimicrobial peptides with a focus on structure-activity relationship studies. After first dissecting the important physiochemical properties that influence the antimicrobial and toxic properties of antimicrobial peptides, the contributions [...] Read more.

The purpose of this paper is to introduce and highlight a few classes of traditional antimicrobial peptides with a focus on structure-activity relationship studies. After first dissecting the important physiochemical properties that influence the antimicrobial and toxic properties of antimicrobial peptides, the contributions of individual amino acids with respect to the peptides antibacterial properties are presented. A brief discussion of the mechanisms of action of different antimicrobials as well as the development of bacterial resistance towards antimicrobial peptides follows. Finally, current efforts on novel design strategies and peptidomimetics are introduced to illustrate the importance of antimicrobial peptide research in the development of future antibiotics. Full article

(This article belongs to the Special Issue Identification and Characterization of Antimicrobial Peptides with Therapeutic Potential)

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Pharmaceuticals, Volume 8, Issue 3 (September 2015) – 13 articles , Pages 366-663

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