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Keller A.C.,City University of New York | Ma J.,U.S. Food and Drug Administration | Kavalier A.,City University of New York | He K.,Naturex Inc. | And 2 more authors.
Phytomedicine | Year: 2011

The antidiabetic activity of Momordica charantia (L.), Cucurbitaceae, a widely-used treatment for diabetes in a number of traditional medicine systems, was investigated in vitro. Antidiabetic activity has been reported for certain saponins isolated from M. charantia. In this study insulin secretion was measured in MIN6 β-cells incubated with an ethanol extract, saponin-rich fraction, and five purified saponins and cucurbitane triterpenoids from M. charantia, 3β,7β,25-trihydroxycucurbita-5,23(E)-dien-19-al (1), momordicine I (2), momordicine II (3), 3-hydroxycucurbita-5,24-dien-19-al-7,23- di-O-β-glucopyranoside (4), and kuguaglycoside G (5). Treatments were compared to incubation with high glucose (27 mM) and the insulin secretagogue, glipizide (50 μM). At 125 μg/ml, an LC-ToF-MS characterized saponin-rich fraction stimulated insulin secretion significantly more than the DMSO vehicle, p = 0.02. At concentrations 10 and 25 μg/ml, compounds 3 and 5 also significantly stimulated insulin secretion as compared to the vehicle, p ≤ 0.007, and p = 0.002, respectively. This is the first report of a saponin-rich fraction, and isolated compounds from M. charantia, stimulating insulin secretion in an in vitro, static incubation assay. © 2011 Elsevier GmbH. All rights reserved.


PubMed | University of Wisconsin - Madison, University of Cologne, CancerCare Manitoba, Pfizer and 7 more.
Type: | Journal: BMC infectious diseases | Year: 2015

Antifungal prophylaxis is a promising strategy for reducing invasive fungal infections (IFIs) in allogeneic hematopoietic cell transplant (alloHCT) recipients, but the optimum prophylactic agent is unknown. We used mixed treatment comparison (MTC) meta-analysis to compare clinical trials examining the use of oral antifungals for prophylaxis in alloHCT recipients, with the goal of informing medical decision-making.Randomized controlled trials (RCTs) of fluconazole, itraconazole, posaconazole, and voriconazole for primary antifungal prophylaxis were identified through a systematic literature review. Outcomes of interest (incidence of IFI/invasive aspergillosis/invasive candidiasis, all-cause mortality, and use of other antifungals) were extracted from eligible RCTs and incorporated into a Bayesian hierarchical random-effects MTC.Five eligible RCTs, randomizing 2147 patients in total, were included. Relative to fluconazole, prophylaxis with itraconazole (odds ratio [OR]: 0.52; interquartile range [IQR]: 0.35-0.76), posaconazole (OR: 0.56; IQR: 0.32-0.99), and voriconazole (OR: 0.46; IQR: 0.28-0.73) reduced incidence of overall proven/probable IFI. Posaconazole (OR: 0.31; IQR: 0.17-0.58) and voriconazole (OR: 0.33; IQR: 0.17-0.58) prophylaxis reduced proven/probable invasive aspergillosis more than itraconazole (OR: 0.68; IQR: 0.42-1.12). All-cause mortality was similar across all mould-active agents.As expected, mould-active azoles prevented IFIs, particularly invasive aspergillosis, more effectively than fluconazole in alloHCT recipients. The paucity of comparative efficacy data suggests that other factors such as long-term tolerability, availability of intravenous formulations, local IFI epidemiology, and drug costs may need to form the basis for selection among the mould-active azoles.


White H.D.,One Medical Center Drive | White H.D.,York Pharma | Robinson T.D.,York Pharma
International Immunopharmacology | Year: 2015

Abstract Fibromyalgia is a diffuse chronic pain condition that occurs predominantly in women and may be under-reported in men. Symptoms include a loss of feeling of well-being and generalized widespread flu-like muscle aches and pain that fail to resolve due to central sensitization of nociceptive neurons. It has commonalities with a myriad of other chronic pain conditions which include PTSD, "Gulf War Syndrome", and various stress-induced conditions caused, for example, by viral infection, emotional or physical stress, trauma, combat, accident or surgery. It is not understood why some individuals are susceptible to this condition and others are not. White et al., elsewhere in this issue, present a clinical feasibility study designed to test the hypothesis that 1) low or deficient testosterone serum levels are linked to a high risk for an inflamed nociceptive nervous system and resultant chronic pain states, and 2) a testosterone transdermal gel applied once a day by fibromyalgia patients can be an effective therapeutic against chronic pain. Here, a short profile of fibromyalgia is provided along with a brief summary of best practices currently recommended by clinical specialists. The link between testosterone and pain is then discussed, with an overview of scientific studies that lay the foundation for testosterone as a possible important additional therapeutic that has the potential to be safely administered and effective but also avoid the adverse effects of other therapeutics. Finally, novel mechanisms by which testosterone therapy is likely to down-modulate pain signaling are proposed. © 2015 The Authors.


Lehrer S.,York Pharma | Rheinstein P.,Severn Health Solutions
American Journal of Alzheimer's Disease and other Dementias | Year: 2016

The association of soluble tumor necrosis factor receptor type two with poor memory in patients with breast cancer and controls found by Patel et al (2015) may confirm the finding of Holmes et al in 2009 that tumor necrosis factor α is linked to cognitive decline. © SAGE Publications.


Lehrer S.,York Pharma
American Journal of Alzheimer's Disease and other Dementias | Year: 2014

Alzheimer's disease may result from low-grade inflammation of the brain, and the characteristic amyloid β may be a protective response. Epidemiological observation indicates that long-term oral administration of nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen to patients having rheumatoid arthritis results in reduced risk and delayed onset of Alzheimer's disease. However, oral ibuprofen, flurbiprofen, and other NSAIDs are not an effective treatment. The NSAIDs may work as an Alzheimer's preventive but not a treatment because the oral dose to the brain is too small, 1% to 2% of the total plasma concentration. The NSAID brain dose could be significantly increased by delivering the drug intranasally. Flurbiprofen would be preferable to ibuprofen because flurbiprofen has 12 times the potency of ibuprofen. The smaller nasal dose of flurbiprofen than ibuprofen could significantly increase patient compliance. Alzheimer's disease starts in the entorhinal cortex, which is closely connected to the olfactory nerves, and spreads anatomically in a defined pattern. Therefore, a nasal NSAID would readily reach the region of the brain where it is most likely to be therapeutic. © The Author(s) 2014.


Lehrer S.,York Pharma | Rheinstein P.H.,Severn Health Solutions
American Journal of Alzheimer's Disease and other Dementias | Year: 2015

The Alzheimer's Association recently reported that a woman's estimated lifetime risk of developing Alzheimer's at age 65 is 1 in 6, compared to nearly 1 in 11 for a man (ie, female to male ratio 1.8). Based on female to male ratio, Alzheimer's disease could well be an autoimmune disorder. Like Alzheimer's, multiple sclerosis, an autoimmune inflammation of the central nervous system, has a female to male ratio of 2.3. Also based on female to male ratio, Alzheimer's resembles the autoimmune inflammatory disease rheumatoid arthritis, which has a female to male ratio of 2.7. The reasons for the female preponderance in autoimmune disease are unclear, but nonsteroidal anti-inflammatory drugs (NSAIDs) are widely and successfully employed to treat autoimmune anti-inflammatory disease and dramatically relieve symptoms. Moreover, oral NSAIDs consistently reduce the risk of Alzheimer's disease, although they have been totally ineffective as a treatment in multiple failed clinical trials. A basis for this failure might well be that the brain dose after oral administration is too small and not sufficiently early in the pathogenesis of the disorder. But NSAID brain dose could be significantly increased by delivering the NSAIDs intranasally. © The Author(s) 2014.


Krajewska E.,University of Sheffield | Lewis C.,University of Sheffield | Staton C.,University of Sheffield | Macgowan A.,York Pharma | Macneil S.,University of Sheffield
Journal of Tissue Engineering and Regenerative Medicine | Year: 2011

We have previously shown that putrescine induces a psoriatic phenotype in tissue-engineered skin. The initial aim of this study was to further develop this in vitro model by introducing endothelial cells to mimic the increased vascularization found in psoriasis. Human keratinocytes and fibroblasts, which did not express CD34 or CD31 in 2D culture, were added to de-epidermised acellular human dermis and cultured for 4 weeks. For induction of a psoriatic phenotype, putrescine was added during this period. We report that after 4 weeks of culture, and particularly when exposed to putrescine, this model showed expression of vertically organised clusters of CD31 positive cells in the dermis in the absence of any exogenous endothelial cells. Further investigation in 2D cell cultures showed an indirect effect of putrescine on normal keratinocytes causing them to produce soluble factors that increased expression of CD133, CD34 and CD31 in cultured human dermal fibroblasts, previously negative for these antigens. This study reports a new and improved model of psoriasis for in vitro studies and offers a new insight into early stage neovascularization, which is of relevance not only to psoriasis, but to tissue engineering and wound healing in general. © 2010 John Wiley & Sons, Ltd.


PubMed | York Pharma
Type: Journal Article | Journal: American journal of Alzheimer's disease and other dementias | Year: 2016

Alzheimers disease may result from low-grade inflammation of the brain, and the characteristic amyloid may be a protective response. Epidemiological observation indicates that long-term oral administration of nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen to patients having rheumatoid arthritis results in reduced risk and delayed onset of Alzheimers disease. However, oral ibuprofen, flurbiprofen, and other NSAIDs are not an effective treatment. The NSAIDs may work as an Alzheimers preventive but not a treatment because the oral dose to the brain is too small, 1% to 2% of the total plasma concentration. The NSAID brain dose could be significantly increased by delivering the drug intranasally. Flurbiprofen would be preferable to ibuprofen because flurbiprofen has 12 times the potency of ibuprofen. The smaller nasal dose of flurbiprofen than ibuprofen could significantly increase patient compliance. Alzheimers disease starts in the entorhinal cortex, which is closely connected to the olfactory nerves, and spreads anatomically in a defined pattern. Therefore, a nasal NSAID would readily reach the region of the brain where it is most likely to be therapeutic.


PubMed | Severn Health Solutions and York Pharma
Type: Journal Article | Journal: Discovery medicine | Year: 2016

A derangement of brain wound healing may cause some cases of Alzheimers disease. Wound healing, a highly complex process, has four stages: hemostasis, inflammation, repair, and remodeling. Hemostasis and the initial phases of inflammation in brain tissue are typical of all vascularized tissue, such as skin. However, distinct differences arise in brain tissue during the later stages of inflammation, repair, and remodeling, and closely parallel the changes of Alzheimers disease. Our hypothesis -- Alzheimers disease is brain wound healing gone awry at least in some cases -- could be tested by measuring progression with biomarkers for the four stages of wound healing in humans or appropriate animal models. Autopsy studies might be done. Chronic traumatic encephalopathy might also result from the brain wound healing process.


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