Pharmaceuticals2015, 8(4), 696-710; doi:10.3390/ph8040696 (registering DOI) - published 10 October 2015 Show/Hide Abstract
Abstract: Infections caused by multidrug-resistant bacteria have been on the rise. This important issue presents a great challenge to the healthcare system and creates an urgent need for alternative therapeutic agents. As a potential solution to this problem, antimicrobial peptides (AMPs) have attracted increasing attention due to their broad spectrum of targeted microbes. However, most AMPs are expensive to synthesize, have relatively high cytotoxicity to mammalian cells, and are susceptible to proteolytic degradation. In order to overcome these limitations, novel synthetic AMPs are desired. Using 1,3,5-triazine (TN) as a template, several combinatorial libraries with varying cationic charge and lipophilicity were designed and screened by the Kallenbach lab. From this screening, TN-5 was identified as a potent lead. In the present study, this compound was tested for its antimicrobial activities on Escherichia coli and Pseudomonas aeruginosa. In addition to regular planktonic cells, the effects on biofilms and persister cells (metabolically inactive and antibiotic tolerant subpopulation) were also investigated. TN-5 was found to have a minimum inhibitory concentration (MIC) of 12.8 μM for both species and kill regular planktonic cells of both species dose dependently. TN-5 is also effective against persister cells of both E. coli and P. aeruginosa. The killing of biofilm cells of the mucoid P. aeruginosa PDO300 was enhanced by alginate lyase.
Pharmaceuticals2015, 8(4), 675-695; doi:10.3390/ph8040675 - published 30 September 2015 Show/Hide Abstract
Abstract: Continuous energy supply, a necessary condition for life, excites a state far from thermodynamic equilibrium, in particular coherent electric polar vibrations depending on water ordering in the cell. Disturbances in oxidative metabolism and coherence are a central issue in cancer development. Oxidative metabolism may be impaired by decreased pyruvate transfer to the mitochondrial matrix, either by parasitic consumption and/or mitochondrial dysfunction. This can in turn lead to disturbance in water molecules’ ordering, diminished power, and coherence of the electromagnetic field. In tumors with the Warburg (reverse Warburg) effect, mitochondrial dysfunction affects cancer cells (fibroblasts associated with cancer cells), and the electromagnetic field generated by microtubules in cancer cells has low power (high power due to transport of energy-rich metabolites from fibroblasts), disturbed coherence, and a shifted frequency spectrum according to changed power. Therapeutic strategies restoring mitochondrial function may trigger apoptosis in treated cells; yet, before this step is performed, induction (inhibition) of pyruvate dehydrogenase kinases (phosphatases) may restore the cancer state. In tumor tissues with the reverse Warburg effect, Caveolin-1 levels should be restored and the transport of energy-rich metabolites interrupted to cancer cells. In both cancer phenotypes, achieving permanently reversed mitochondrial dysfunction with metabolic-modulating drugs may be an effective, specific anti-cancer strategy.
Pharmaceuticals2015, 8(4), 664-674; doi:10.3390/ph8040664 - published 25 September 2015 Show/Hide Abstract
Abstract: Recently, propranolol was suggested to prevent hyperlactatemia in a child with hypovolemic shock through β-adrenergic blockade. Though it is a known inhibitor of glycolysis, propranolol, outside this observation, has never been reported to fully protect against lactate overproduction. On the other hand, literature evidence exists for a cross-talk between β-adrenergic receptors (protein targets of propranolol) and δ-opioid receptor. In this literature context, it is hypothesized here that anti-diarrheic racecadotril (a pro-drug of thiorphan, an inhibitor of enkephalinases), which, in the cited observation, was co-administered with propranolol, might have facilitated the β-blocker-driven inhibition of glycolysis and resulting lactate production. The opioid-facilitated β-adrenergic blockade would be essentially additivity or even synergism putatively existing between antagonism of β-adrenergic receptors and agonism of δ-opioid receptor in lowering cellular cAMP and dependent functions.
Pharmaceuticals2015, 8(3), 637-663; doi:10.3390/ph8030637 - published 21 September 2015 Show/Hide Abstract
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 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.
Pharmaceuticals2015, 8(3), 607-636; doi:10.3390/ph8030607 - published 17 September 2015 Show/Hide Abstract
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 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.
Pharmaceuticals2015, 8(3), 590-606; doi:10.3390/ph8030590 - published 17 September 2015 Show/Hide Abstract
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 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.