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Filippos Kesisoglou - One of the best experts on this subject based on the ideXlab platform.

  • Enabling an HCV Treatment Revolution and the Frontiers of Solid Solution Formulation.
    Journal of pharmaceutical sciences, 2018
    Co-Authors: Craig A. Mckelvey, Filippos Kesisoglou
    Abstract:

    The discovery and development of small molecule direct acting antiviral (DAA) drugs has revolutionized the treatment of Hepatitis C virus infection. Formulations based on solid solution technology have enabled the oral absorption of the majority of commercial DAA products starting with the approval of telaprevir in 2011. A particularly important class of DAA drugs are those targeting nonstructural protein 5A. In addition to simply promoting the oral absorption of nonstructural protein 5A compounds, solid solutions have been used within this class of compounds to mitigate changes in absorption caused by variations in food and Stomach pH. This commentary reviews the formulation and biopHarmaceutical aspects of the solid solutions used to enable the recent revolution in Hepatitis C virus infection treatment.

  • Impaired drug absorption due to high Stomach pH: a review of strategies for mitigation of such effect to enable pHarmaceutical product development.
    Molecular pharmaceutics, 2013
    Co-Authors: Amitava Mitra, Filippos Kesisoglou
    Abstract:

    Published reports have clearly shown that weakly basic drugs which have low solubility at high pH could have impaired absorption in patients with high gastric pH thus leading to reduced and variable bioavailability. Since such reduction in exposure can lead to significant loss of efficacy, it is imperative to (1) understand the behavior of the compound as a function of Stomach pH to inform of any risk of bioavailability loss in clinical studies and (2) develop a robust formulation which can provide adequate exposure in achlorhydric patients. In this review paper, we provide an overview of the factors that can cause high gastric pH in human, discuss clinical and preclinical pHarmacokinetic data for weak bases under conditions of normal and high gastric pH, and give examples of formulation strategies to minimize or mitigate the reduced absorption of weakly basic drugs under high gastric pH conditions. It should be noted that the ability to overcome pH sensitivity issues is highly compound dependent and there are no obvious and general solutions to overcome such effect. Further, we discuss, along with several examples, the use of biopHarmaceutical tools such as in vitro dissolution, absorption modeling, and gastric pH modified animal models to assess absorption risk of weak bases in high gastric pH and also the use of these tools to enable development of formulations to mitigate such effects.

Gareth Trope - One of the best experts on this subject based on the ideXlab platform.

  • pHarmacokinetic and pHarmacodynamic effects of two omeprazole formulations on Stomach pH and gastric ulcer scores
    Equine Veterinary Journal, 2017
    Co-Authors: Sharanne Raidal, Sharon Nielsen, F M Andrews, Gareth Trope
    Abstract:

    SummaryReasons for performing the study Limited data are available on the relative pHarmacokinetics and pHarmacodynamics of different omeprazole formulations. Objectives To compare pHarmacokinetic and pHarmacodynamic effects of a novel omeprazole formulation against a currently registered product. Study design Masked two period, two treatment crossover. Methods Twelve clinically healthy horses were studied over two 6-day treatment periods. Horses were randomly assigned to receive a novel omeprazole paste (ULS) or a currently registered reference omeprazole product (OMO). Gastric pH was measured continuously for 10 hours on the day prior to commencing treatment (Day -1) and after six days of oral treatment (Day 5) using in situ antimony pH probes within an indwelling nasogastric tube. Plasma pHarmacokinetics were determined on Days 0 and 6. Results Treatment significantly (P<0.005) increased gastric pH on Day 5, compared to results obtained prior to treatment (Day -1) and there was no significant difference between products (P = 0.773). Similarly, comparison of median hourly gastric pH (P = 0.593), mean gastric pH (P = 0.154), percentage time pH <4 (P = 0.259) and area under the time-gastric pH response curve (P = 0.734) did not discriminate between products. Both treatments resulted in significantly lower gastric ulcer severity scores (both P = 0.004), with no difference between treatments (P = 0.688). Comparison of mean log area under time-plasma concentration curves demonstrated that, although the lower limit of the 90% confidence interval was within the -20% limit for bioequivalence, the upper limit was exceeded, suggesting the test product could have greater bioavailability than the reference product. Main limitations The small sample size, large inter-horse plasma omeprazole concentrations, and low bioavailability of omeprazole impacted the sensitivity of the bioequivalence analysis. Conclusions ULS matched or slightly exceeded OMO plasma concentrations. Both products resulted in equivalent increases in gastric pH, gastric pH profiles and decrease in gastric ulcer scores. Thus, ULS was pHarmacodynamically equivalent to OMO and was associated with an equivalent beneficial effect on gastric squamous mucosal ulceration. This article is protected by copyright. All rights reserved.

  • pHarmacokinetic and pHarmacodynamic effects of two omeprazole formulations on Stomach pH and gastric ulcer scores.
    Equine veterinary journal, 2017
    Co-Authors: Sharanne Raidal, Frank M. Andrews, Sharon Nielsen, Gareth Trope
    Abstract:

    SummaryReasons for performing the study Limited data are available on the relative pHarmacokinetics and pHarmacodynamics of different omeprazole formulations. Objectives To compare pHarmacokinetic and pHarmacodynamic effects of a novel omeprazole formulation against a currently registered product. Study design Masked two period, two treatment crossover. Methods Twelve clinically healthy horses were studied over two 6-day treatment periods. Horses were randomly assigned to receive a novel omeprazole paste (ULS) or a currently registered reference omeprazole product (OMO). Gastric pH was measured continuously for 10 hours on the day prior to commencing treatment (Day -1) and after six days of oral treatment (Day 5) using in situ antimony pH probes within an indwelling nasogastric tube. Plasma pHarmacokinetics were determined on Days 0 and 6. Results Treatment significantly (P

Benjamin P. Ross - One of the best experts on this subject based on the ideXlab platform.

  • Bifunctional Succinylated ε-Polylysine-Coated Mesoporous Silica Nanoparticles for pH-Responsive and Intracellular Drug Delivery Targeting the Colon
    ACS applied materials & interfaces, 2017
    Co-Authors: Chau T. H. Nguyen, Richard I. Webb, Lynette K. Lambert, Ekaterina Strounina, Edward C. Lee, Marie-odile Parat, Michael A. Mcguckin, Amirali Popat, Peter J. Cabot, Benjamin P. Ross
    Abstract:

    Conventional oral drug formulations for colonic diseases require the administration of high doses of drug to achieve effective drug concentrations at the target site. However, this exposes patients to serious systemic toxicity in order to achieve efficacy. To overcome this problem, an oral drug delivery system was developed by loading a large amount (ca. 34% w/w) of prednisolone into 3-aminopropyl-functionalized mesoporous silica nanoparticles (MCM-NH2) and targeting prednisolone release to the colon by coating the nanoparticle with succinylated e-polylysine (SPL). We demonstrate for the first time the pH-responsive ability of SPL as a “nanogate” to selectively release prednisolone in the pH conditions of the colon (pH 5.5–7.4) but not in the more acidic conditions of the Stomach (pH 1.9) or small intestine (pH 5.0). In addition to targeting drug delivery to the colon, we explored whether the nanoparticles could deliver cargo intracellularly to immune cells (RAW 264.7 macropHages) and intestinal epithelia...

Osmund Mwandemele - One of the best experts on this subject based on the ideXlab platform.

  • Use of Dacid-, Dbile-, zacid-, and zbile-Values in Evaluating Bifidobacteria with Regard to Stomach pH and Bile Salt Sensitivity
    Journal of food science, 2010
    Co-Authors: Li Jia, Nditange Shigwedha, Osmund Mwandemele
    Abstract:

    UNLABELLED The survival of bifidobacteria in simulated conditions of the gastrointestinal (GI) tract was studied based on the D- and z-value concept. Some Bifidobacterium spp. are probiotics that improve microbial balance in the human GI tract. Because they are sensitive to low pH and bile salt concentrations, their viability in the GI tract is limited. The D- and z-value approach was therefore adopted as a result of observing constant log-cell reduction (90%) when Bifidobacterium spp. were exposed to these 2 different stressing factors. Survivals of one strain each or 4 species of Bifidobacterium was studied at pH between 3.0 and 4.5 and in ox-bile between 0.15% and 0.60% for times up to 41 h. From the D(acid)- and D(bile)-values, the order of resistance to acid and bile was B. bifidum > B. infantis > B. longum > B. adolescentis. While the former 3 strains retained high cell viability at pH 3.5 (>5.5 log CFU/mL after 5 h) and at elevated bile salt concentration of 0.6% (>4.5 log CFU/mL after 3 h), B. adolescentis was less resistant (

  • use of dacid dbile zacid and zbile values in evaluating bifidobacteria with regard to Stomach pH and bile salt sensitivity
    Journal of Food Science, 2010
    Co-Authors: Li Jia, Nditange Shigwedha, Osmund Mwandemele
    Abstract:

    UNLABELLED The survival of bifidobacteria in simulated conditions of the gastrointestinal (GI) tract was studied based on the D- and z-value concept. Some Bifidobacterium spp. are probiotics that improve microbial balance in the human GI tract. Because they are sensitive to low pH and bile salt concentrations, their viability in the GI tract is limited. The D- and z-value approach was therefore adopted as a result of observing constant log-cell reduction (90%) when Bifidobacterium spp. were exposed to these 2 different stressing factors. Survivals of one strain each or 4 species of Bifidobacterium was studied at pH between 3.0 and 4.5 and in ox-bile between 0.15% and 0.60% for times up to 41 h. From the D(acid)- and D(bile)-values, the order of resistance to acid and bile was B. bifidum > B. infantis > B. longum > B. adolescentis. While the former 3 strains retained high cell viability at pH 3.5 (>5.5 log CFU/mL after 5 h) and at elevated bile salt concentration of 0.6% (>4.5 log CFU/mL after 3 h), B. adolescentis was less resistant (<3.4 log CFU/mL). The z(acid)- and z(bile)-values calculated from the D(acid)- and D(bile)-values ranged from 1.11 to 1.55 pH units and 0.40% to 0.49%, respectively. The results suggest that the D(acid)-, D(bile)-, z(acid)-, and z(bile)-value approach could be more appropriate than the screening and selection method in evaluating survival of probiotic bacteria, and in measuring their tolerance or resistance to gastric acidity and the associated bile salt concentration in the small intestine. PRACTICAL APPLICATION The evaluation of the tolerance of bifidobacteria to bile salts and low pH has been made possible by use of D- and z-value concept. The calculated z(acid)- and z(bile)-values were all fairly similar for the strains used and suggest the effect of increasing the bile salt concentration or decreasing the pH on the D(acid)- and D(bile)-values. This approach would be useful for predicting the suitability of bifidobacteria and other lactic acid bacteria (LAB) as probiotics for use in real-life situations.

Frank M. Andrews - One of the best experts on this subject based on the ideXlab platform.

  • pHarmacokinetic and pHarmacodynamic effects of two omeprazole formulations on Stomach pH and gastric ulcer scores.
    Equine veterinary journal, 2017
    Co-Authors: Sharanne Raidal, Frank M. Andrews, Sharon Nielsen, Gareth Trope
    Abstract:

    SummaryReasons for performing the study Limited data are available on the relative pHarmacokinetics and pHarmacodynamics of different omeprazole formulations. Objectives To compare pHarmacokinetic and pHarmacodynamic effects of a novel omeprazole formulation against a currently registered product. Study design Masked two period, two treatment crossover. Methods Twelve clinically healthy horses were studied over two 6-day treatment periods. Horses were randomly assigned to receive a novel omeprazole paste (ULS) or a currently registered reference omeprazole product (OMO). Gastric pH was measured continuously for 10 hours on the day prior to commencing treatment (Day -1) and after six days of oral treatment (Day 5) using in situ antimony pH probes within an indwelling nasogastric tube. Plasma pHarmacokinetics were determined on Days 0 and 6. Results Treatment significantly (P

  • Gastric juice pH measurement in horses: Three‐quarters of a century of history!
    Equine Veterinary Education, 2015
    Co-Authors: Frank M. Andrews
    Abstract:

    Summary Inhibition of gastric acid and increased Stomach pH>4.0 is currently accepted as the mainstay of treatment for gastric ulcers in horses. Measurement of gastric pH is complicated and requires placement of a cannula and collection of gastric juice or placement of pH electrodes in the Stomach. Since the distance from the nares to the Stomach is approximately 200 cm, finding a system with a pH electrode with this length is difficult, not to mention difficult to maintain. There has been a fascination with the measurement of gastric juice pH in horses that has covered three-quarters of a century starting with a fistula model in 1933 and culminating in a recent technique described in this issue. Placement of gastric cannulas and various pH electrodes have been used to measure gastric juice pH in horses in the past and present, but the future may require more sopHisticated methods as we look at the efficacy of different formulations of acid suppressive drugs for treatment of equine gastric ulcer syndrome.

  • OVERVIEW OF GASTRIC AND COLONIC ULCERS
    2015
    Co-Authors: Frank M. Andrews
    Abstract:

    Equine gastric ulcer syndrome (EGUS) and right dorsal colitis (RDC) are common in performance horses. Diagnoses are based on history, clinical signs, laboratory findings, gastroscopic examination, and response to altered diet and medical therapy. Effective treatment strategies for EGUS focus on increasing Stomach pH by inhibitin

  • Take Home Message
    2015
    Co-Authors: Frank M. Andrews
    Abstract:

    Equine Gastric Ulcer Syndrome (EGUS) and Right Dorsal Colitis (RDC) are common in performance horses. Diagnoses are based on history, clinical signs, laboratory findings, gastroscopic examination, and response to altered diet and medical therapy. Effective treatment strategies for EGUS focus on increasing Stomach pH by inhibiting or buffering gastric acid, which allows a permissive environment for ulcer healing, and environmental and dietary management. Effective treatment strategies for RDC focus on removing non-steroidal anti-inflammatory drugs (NSAIDs), decreasing the bulk in the diet, reducing inflammation, coating and lubricating the colon and decreasing environmental stress. Prevention of these conditions requires long-term dietary and environmental management. Equine Gastric Ulcer Syndrome Gastric ulcers are common in performance horses. The term Equine Gastric Ulcer Syndrome (EGUS) was coined to describe the condition of erosions and ulcerations occurring in the distal esopHagus, non-glandular and glandular Stomach, and proximal duodenum of horses.1 EGUS is caused by many factors including anatomy of the Stomach, exercise, restricted feed intake, diet, environmental stress (stall or transport), and the use of non-steroidal anti-inflammatory agents.2 Diagnosis of EGUS is based on history, clinical signs, endoscopic examination, and response to treatment. All ages and breeds of horses are susceptible to EGUS and current therapeutic strategies focus on blocking gastric acid secretion and raising Stomach pH to ≥ 4.0. To date there is only one Federal Drug Administration (FDA) approved pHarmacologic agent for treatment of EGUS; GastroGard ® (Merial Limited, Duluth, GA). However, a more comprehensive approach to EGUS diagnosis and treatment includes determining and correcting of the underlying cause, environmental management, dietary manipulation, and pHarmacologic intervention

  • OVERVIEW OF GASTRIC AND COLONIC ULCERS
    2009
    Co-Authors: Frank M. Andrews
    Abstract:

    Equine gastric ulcer syndrome (EGUS) and right dorsal colitis (RDC) are common in performance horses. Diagnoses are based on history, clinical signs, laboratory findings, gastroscopic examination, and response to altered diet and medical therapy. Effective treatment strategies for EGUS focus on increasing Stomach pH by inhibiting or buffering gastric acid, which allows a permissive environment for ulcer healing, and environmental and dietary management. Effective treatment strategies for RDC focus on removing nonsteroidal anti-inflammatory drugs (NSAIDs), decreasing the bulk in the diet, reducing inflammation, coating and lubricating the colon, and decreasing environmental stress. Prevention of these conditions requires long-term dietary and environmental management.