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Lichtenberger LM. Development of the PC-NSAID technology: From contact angle to Vazalore®. Drug Discov Today 2023; 28:103411. [PMID: 36270473 DOI: 10.1016/j.drudis.2022.103411] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2022] [Revised: 08/10/2022] [Accepted: 10/13/2022] [Indexed: 11/07/2022]
Abstract
We describe strategies in drug development to reduce the gastrointestinal (GI) toxicity of nonsteroidal anti-inflammatory drugs (NSAIDs). We then provide an overview of the experiments that led to the development of PC-NSAIDs, a novel family of NSAIDs associated with phosphatidylcholine (PC) that have reduced GI toxicity and full therapeutic activity. Furthermore, we describe the evidence showing: that the stomach possesses hydrophobic properties that are attributable to phospholipids lining the mucus gel layer; and that NSAIDs chemically associate with intrinsic PC, thereby attenuating the tissue's hydrophobic properties. Further, pre-associating NSAIDs with PC reduces the GI toxicity of these drugs, both in rodent ulcer models and in human subjects, without affecting the drugs' therapeutic activity. Finally, we discuss the commercialization and launch of Aspirin-PC, an over-the-counter (OTC) drug with the brand name Vazalore®.
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Affiliation(s)
- Lenard M Lichtenberger
- Department of Integrative Biology & Pharmacology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA.
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Ontogeny and caudal autotomy fracture planes in a large scincid lizard, Egernia kingii. Sci Rep 2022; 12:7051. [PMID: 35488011 PMCID: PMC9054770 DOI: 10.1038/s41598-022-10962-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Accepted: 04/14/2022] [Indexed: 11/09/2022] Open
Abstract
Many lizard species use caudal autotomy, the ability to self-amputate a portion of the tail, as an effective but costly survival strategy. However, as a lizard grows, its increased size may reduce predation risk allowing for less costly strategies (e.g., biting and clawing) to be used as the primary defence. The King's skink (Egernia kingii) is a large scincid up to approximately 244 mm snout to vent length (SVL) in size when adult. Adults rely less on caudal autotomy than do juveniles due to their size and strength increase during maturation. It has been hypothesised that lower behavioural reliance on autotomy in adults is reflected in loss or restriction of caudal vertebrae fracture planes through ossification as caudal intra-vertebral fracture planes in some species ossify during ontogenetic growth. To test this, we used micro-CT to image the tails of a growth series of seven individuals of E. kingii. We show that fracture planes are not lost or restricted ontogenetically within E. kingii, with adults retaining between 39-44 autotomisable vertebrae following 5-6 non-autotomisable vertebrae. Even though mature E. kingii rely less on caudal autotomy than do juveniles, this research shows that they retain the maximum ability to autotomise their tails, providing a last resort option to avoid threats. The potential costs associated with retaining caudal autotomy are most likely mitigated through neurological control of autotomy and E. kingii's longevity.
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Hoogevest P, Tiemessen H, Metselaar JM, Drescher S, Fahr A. The Use of Phospholipids to Make Pharmaceutical Form Line Extensions. EUR J LIPID SCI TECH 2021. [DOI: 10.1002/ejlt.202000297] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Affiliation(s)
- Peter Hoogevest
- Phospholipid Research Center Im Neuenheimer Feld 515 Heidelberg 69120D‐69120 Germany
| | - Harry Tiemessen
- Technical & Research Development PHAD PDU Specialty Novartis Campus Physical Garden (WSJ 177) 2.14 Basel CH‐4002 Switzerland
| | - Josbert M. Metselaar
- Institute for Experimental Molecular Imaging, RWTH Aachen University Clinic Aachen D‐52074 Germany
- Institute for Biomedical Engineering, Faculty of Medicine RWTH Aachen University Aachen D‐52074 Germany
| | - Simon Drescher
- Phospholipid Research Center Im Neuenheimer Feld 515 Heidelberg D‐69120 Germany
| | - Alfred Fahr
- Professor Emeritus, Pharmaceutical Technology Friedrich‐Schiller‐University Jena Jena Germany
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Davis JS, Kanikarla-Marie P, Gagea M, Yu PL, Fang D, Sebastian M, Yang P, Hawk E, Dashwood R, Lichtenberger LM, Menter D, Kopetz S. Sulindac plus a phospholipid is effective for polyp reduction and safer than sulindac alone in a mouse model of colorectal cancer development. BMC Cancer 2020; 20:871. [PMID: 32912193 PMCID: PMC7488444 DOI: 10.1186/s12885-020-07311-4] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Accepted: 08/17/2020] [Indexed: 02/06/2023] Open
Abstract
Background Non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin and sulindac are effective for colorectal cancer prevention in humans and some animal models, but concerns over gastro-intestinal (GI) ulceration and bleeding limit their potential for chemopreventive use in broader populations. Recently, the combination of aspirin with a phospholipid, packaged as PL-ASA, was shown to reduce GI toxicity in a small clinical trial. However, these studies were done for relatively short periods of time. Since prolonged, regular use is needed for chemopreventive benefit, it is important to know whether GI safety is maintained over longer use periods and whether cancer prevention efficacy is preserved when an NSAID is combined with a phospholipid. Methods As a first step to answering these questions, we treated seven to eight-week-old, male and female C57B/6 Apcmin/+ mice with the NSAID sulindac, with and without phosphatidylcholine (PC) for 3-weeks. At the end of the treatment period, we evaluated polyp burden, gastric toxicity, urinary prostaglandins (as a marker of sulindac target engagement), and blood chemistries. Results Both sulindac and sulindac-PC treatments resulted in significantly reduced polyp burden, and decreased urinary prostaglandins, but sulindac-PC treatment also resulted in the reduction of gastric lesions compared to sulindac alone. Conclusions Together these data provide pre-clinical support for combining NSAIDs with a phospholipid, such as phosphatidylcholine to reduce GI toxicity while maintaining chemopreventive efficacy.
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Affiliation(s)
- Jennifer S Davis
- Departments of Epidemiology, The University of Texas, MD Anderson Cancer Center, PO Box 301439, Houston, TX, 77230-1439, USA.
| | - Preeti Kanikarla-Marie
- Departments of Gastrointestinal Medical Oncology, University of Texas, MD Anderson Cancer Center, Houston, TX, USA
| | - Mihai Gagea
- Departments of Veterinary Medicine and Surgery, University of Texas, MD Anderson Cancer Center, Houston, TX, USA
| | - Patrick L Yu
- McGovern Medical School, University of Texas Health Science Center, Houston, TX, USA
| | - Dexing Fang
- McGovern Medical School, University of Texas Health Science Center, Houston, TX, USA
| | - Manu Sebastian
- Departments of Epigenetics & Molecular Carcinogenesis, University of Texas, MD Anderson Cancer Center, Houston, TX, USA
| | - Peiying Yang
- Departments of Palliative, Rehabilitation and Integrative Medicine, University of Texas, MD Anderson Cancer Center, Houston, TX, USA
| | - Ernest Hawk
- Division of Cancer Prevention and Population Sciences, University of Texas, MD Anderson Cancer Center, Houston, TX, USA
| | - Roderick Dashwood
- Center for Epigenetics & Disease Prevention, Institute of Biosciences and Technology, Texas A&M University, Houston, TX, USA
| | | | - David Menter
- Departments of Gastrointestinal Medical Oncology, University of Texas, MD Anderson Cancer Center, Houston, TX, USA
| | - Scott Kopetz
- Departments of Gastrointestinal Medical Oncology, University of Texas, MD Anderson Cancer Center, Houston, TX, USA
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Hoogevest P. Non‐Aqueous Phospholipid Concentrates for Increasing the Bioavailability of Poorly Soluble Compounds. EUR J LIPID SCI TECH 2020. [DOI: 10.1002/ejlt.201900411] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Affiliation(s)
- Peter Hoogevest
- Phospholipid Research Center Im Neuenheimer Feld 515 Heidelberg D‐69120 Germany
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Pereira-Leite C, Jamal SK, Almeida JP, Coutinho A, Prieto M, Cuccovia IM, Nunes C, Reis S. Neutral Diclofenac Causes Remarkable Changes in Phosphatidylcholine Bilayers: Relevance for Gastric Toxicity Mechanisms. Mol Pharmacol 2020; 97:295-303. [PMID: 32102968 DOI: 10.1124/mol.119.118299] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2019] [Accepted: 01/24/2020] [Indexed: 02/14/2025] Open
Abstract
The main objective of this study was to clarify the topical mechanisms underlying diclofenac-induced gastric toxicity by considering for the first time both ionization states of this nonsteroidal anti-inflammatory drug. 1,2-Dimyristoyl-sn-glycero-3-phosphocholine (DMPC) liposomes were the model system chosen to mimic the protective phospholipid layers of the gastric mucosa and to describe the interactions with diclofenac, considering the pH gradient found in the gastric mucosa (3 < pH < 7.4). Complementary experimental techniques were combined to evaluate the drug's affinity for DMPC bilayers, as well as to assess the drug's effects on the structural properties of the phospholipid bilayer. The diclofenac-DMPC interactions were clearly dependent on the drug's ionization state. Neutral diclofenac displayed greater affinity for DMPC bilayers than anionic diclofenac. Moreover, the protonated/neutral form of the drug induced more pronounced and/or distinct alterations in the structure of the DMPC bilayer than the deprotonated/ionized form, considering similar membrane concentrations. Therefore, neutral diclofenac-induced changes in the structural properties of the external phospholipid layers of the gastric mucosa may constitute an additional toxicity mechanism of this worldwide-used drug, which shall be considered for the development of safer therapeutic strategies. SIGNIFICANCE STATEMENT: Neutral or anionic diclofenac exerted distinct alterations in phosphatidylcholine bilayers, which are used in this work as models for the protective phospholipid layers of the gastric mucosa. Remarkable changes were induced by neutral diclofenac in the structural properties of the phospholipid bilayer, suggesting that both ionized and neutral states of nonsteroidal anti-inflammatory drugs must be considered to clarify their mechanisms of toxicity and to ultimately develop safer anti-inflammatory drugs.
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Affiliation(s)
- Catarina Pereira-Leite
- LAQV, REQUIMTE, Departamento de Ciências Químicas, Faculdade de Farmácia, Universidade do Porto, Porto, Portugal (C.P.-L., S.K.J., J.P.A., C.N., S.R.); Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, Brazil (C.P.-L., I.M.C.); IBB-Institute for Bioengineering and Biosciences, Instituto Superior Técnico (A.C., M.P.) and Departamento de Química e Bioquímica, Faculdade de Ciências (A.C.), Universidade de Lisboa, Lisboa, Portugal
| | - Sarah K Jamal
- LAQV, REQUIMTE, Departamento de Ciências Químicas, Faculdade de Farmácia, Universidade do Porto, Porto, Portugal (C.P.-L., S.K.J., J.P.A., C.N., S.R.); Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, Brazil (C.P.-L., I.M.C.); IBB-Institute for Bioengineering and Biosciences, Instituto Superior Técnico (A.C., M.P.) and Departamento de Química e Bioquímica, Faculdade de Ciências (A.C.), Universidade de Lisboa, Lisboa, Portugal
| | - João P Almeida
- LAQV, REQUIMTE, Departamento de Ciências Químicas, Faculdade de Farmácia, Universidade do Porto, Porto, Portugal (C.P.-L., S.K.J., J.P.A., C.N., S.R.); Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, Brazil (C.P.-L., I.M.C.); IBB-Institute for Bioengineering and Biosciences, Instituto Superior Técnico (A.C., M.P.) and Departamento de Química e Bioquímica, Faculdade de Ciências (A.C.), Universidade de Lisboa, Lisboa, Portugal
| | - Ana Coutinho
- LAQV, REQUIMTE, Departamento de Ciências Químicas, Faculdade de Farmácia, Universidade do Porto, Porto, Portugal (C.P.-L., S.K.J., J.P.A., C.N., S.R.); Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, Brazil (C.P.-L., I.M.C.); IBB-Institute for Bioengineering and Biosciences, Instituto Superior Técnico (A.C., M.P.) and Departamento de Química e Bioquímica, Faculdade de Ciências (A.C.), Universidade de Lisboa, Lisboa, Portugal
| | - Manuel Prieto
- LAQV, REQUIMTE, Departamento de Ciências Químicas, Faculdade de Farmácia, Universidade do Porto, Porto, Portugal (C.P.-L., S.K.J., J.P.A., C.N., S.R.); Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, Brazil (C.P.-L., I.M.C.); IBB-Institute for Bioengineering and Biosciences, Instituto Superior Técnico (A.C., M.P.) and Departamento de Química e Bioquímica, Faculdade de Ciências (A.C.), Universidade de Lisboa, Lisboa, Portugal
| | - Iolanda M Cuccovia
- LAQV, REQUIMTE, Departamento de Ciências Químicas, Faculdade de Farmácia, Universidade do Porto, Porto, Portugal (C.P.-L., S.K.J., J.P.A., C.N., S.R.); Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, Brazil (C.P.-L., I.M.C.); IBB-Institute for Bioengineering and Biosciences, Instituto Superior Técnico (A.C., M.P.) and Departamento de Química e Bioquímica, Faculdade de Ciências (A.C.), Universidade de Lisboa, Lisboa, Portugal
| | - Cláudia Nunes
- LAQV, REQUIMTE, Departamento de Ciências Químicas, Faculdade de Farmácia, Universidade do Porto, Porto, Portugal (C.P.-L., S.K.J., J.P.A., C.N., S.R.); Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, Brazil (C.P.-L., I.M.C.); IBB-Institute for Bioengineering and Biosciences, Instituto Superior Técnico (A.C., M.P.) and Departamento de Química e Bioquímica, Faculdade de Ciências (A.C.), Universidade de Lisboa, Lisboa, Portugal
| | - Salette Reis
- LAQV, REQUIMTE, Departamento de Ciências Químicas, Faculdade de Farmácia, Universidade do Porto, Porto, Portugal (C.P.-L., S.K.J., J.P.A., C.N., S.R.); Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, Brazil (C.P.-L., I.M.C.); IBB-Institute for Bioengineering and Biosciences, Instituto Superior Técnico (A.C., M.P.) and Departamento de Química e Bioquímica, Faculdade de Ciências (A.C.), Universidade de Lisboa, Lisboa, Portugal
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Methylisothiazolinone induces apoptotic cell death via matrix metalloproteinase activation in human bronchial epithelial cells. Toxicol In Vitro 2020; 62:104661. [DOI: 10.1016/j.tiv.2019.104661] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2019] [Revised: 09/16/2019] [Accepted: 09/19/2019] [Indexed: 12/16/2022]
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Macierzanka A, Torcello-Gómez A, Jungnickel C, Maldonado-Valderrama J. Bile salts in digestion and transport of lipids. Adv Colloid Interface Sci 2019; 274:102045. [PMID: 31689682 DOI: 10.1016/j.cis.2019.102045] [Citation(s) in RCA: 112] [Impact Index Per Article: 18.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2019] [Accepted: 10/05/2019] [Indexed: 12/11/2022]
Abstract
Because of their unusual chemical structure, bile salts (BS) play a fundamental role in intestinal lipid digestion and transport. BS have a planar arrangement of hydrophobic and hydrophilic moieties, which enables the BS molecules to form peculiar self-assembled structures in aqueous solutions. This molecular arrangement also has an influence on specific interactions of BS with lipid molecules and other compounds of ingested food and digestive media. Those comprise the complex scenario in which lipolysis occurs. In this review, we discuss the BS synthesis, composition, bulk interactions and mode of action during lipid digestion and transport. We look specifically into surfactant-related functions of BS that affect lipolysis, such as interactions with dietary fibre and emulsifiers, the interfacial activity in facilitating lipase and colipase anchoring to the lipid substrate interface, and finally the role of BS in the intestinal transport of lipids. Unravelling the roles of BS in the processing of lipids in the gastrointestinal tract requires a detailed analysis of their interactions with different compounds. We provide an update on the most recent findings concerning two areas of BS involvement: lipolysis and intestinal transport. We first explore the interactions of BS with various dietary fibres and food emulsifiers in bulk and at interfaces, as these appear to be key aspects for understanding interactions with digestive media. Next, we explore the interactions of BS with components of the intestinal digestion environment, and the role of BS in displacing material from the oil-water interface and facilitating adsorption of lipase. We look into the process of desorption, solubilisation of lipolysis, products and formation of mixed micelles. Finally, the BS-driven interactions of colloidal particles with the small intestinal mucus layer are considered, providing new findings for the overall assessment of the role of BS in lipid digestion and intestinal transport. This review offers a unique compilation of well-established and most recent studies dealing with the interactions of BS with food emulsifiers, nanoparticles and dietary fibre, as well as with the luminal compounds of the gut, such as lipase-colipase, triglycerides and intestinal mucus. The combined analysis of these complex interactions may provide crucial information on the pattern and extent of lipid digestion. Such knowledge is important for controlling the uptake of dietary lipids or lipophilic pharmaceuticals in the gastrointestinal tract through the engineering of novel food structures or colloidal drug-delivery systems.
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Bhatt P, Lalani R, Vhora I, Patil S, Amrutiya J, Misra A, Mashru R. Liposomes encapsulating native and cyclodextrin enclosed paclitaxel: Enhanced loading efficiency and its pharmacokinetic evaluation. Int J Pharm 2018; 536:95-107. [DOI: 10.1016/j.ijpharm.2017.11.048] [Citation(s) in RCA: 98] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2017] [Revised: 11/02/2017] [Accepted: 11/21/2017] [Indexed: 01/06/2023]
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Schwingshackl A, Lopez B, Teng B, Luellen C, Lesage F, Belperio J, Olcese R, Waters CM. Hyperoxia treatment of TREK-1/TREK-2/TRAAK-deficient mice is associated with a reduction in surfactant proteins. Am J Physiol Lung Cell Mol Physiol 2017; 313:L1030-L1046. [PMID: 28839101 DOI: 10.1152/ajplung.00121.2017] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2017] [Revised: 08/15/2017] [Accepted: 08/16/2017] [Indexed: 12/29/2022] Open
Abstract
We previously proposed a role for the two-pore domain potassium (K2P) channel TREK-1 in hyperoxia (HO)-induced lung injury. To determine whether redundancy among the three TREK isoforms (TREK-1, TREK-2, and TRAAK) could protect from HO-induced injury, we now examined the effect of deletion of all three TREK isoforms in a clinically relevant scenario of prolonged HO exposure and mechanical ventilation (MV). We exposed WT and TREK-1/TREK-2/TRAAK-deficient [triple knockout (KO)] mice to either room air, 72-h HO, MV [high and low tidal volume (TV)], or a combination of HO + MV and measured quasistatic lung compliance, bronchoalveolar lavage (BAL) protein concentration, histologic lung injury scores (LIS), cellular apoptosis, and cytokine levels. We determined surfactant gene and protein expression and attempted to prevent HO-induced lung injury by prophylactically administering an exogenous surfactant (Curosurf). HO treatment increased lung injury in triple KO but not WT mice, including an elevated LIS, BAL protein concentration, and markers of apoptosis, decreased lung compliance, and a more proinflammatory cytokine phenotype. MV alone had no effect on lung injury markers. Exposure to HO + MV (low TV) further decreased lung compliance in triple KO but not WT mice, and HO + MV (high TV) was lethal for triple KO mice. In triple KO mice, the HO-induced lung injury was associated with decreased surfactant protein (SP) A and SPC but not SPB and SPD expression. However, these changes could not be explained by alterations in the transcription factors nuclear factor-1 (NF-1), NKX2.1/thyroid transcription factor-1 (TTF-1) or c-jun, or lamellar body levels. Prophylactic Curosurf administration did not improve lung injury scores or compliance in triple KO mice.
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Affiliation(s)
| | - Benjamin Lopez
- Department of Pediatrics, University of California, Los Angeles, California
| | - Bin Teng
- Department of Physiology, University of Tennessee Health Science Center, Memphis, Tennessee; and
| | - Charlean Luellen
- Department of Physiology, University of Tennessee Health Science Center, Memphis, Tennessee; and
| | - Florian Lesage
- Université Côte d'Azur, Institut de Pharmacologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique, Laboratory of Excellence "Ion Channel Science and Therapeutics," Valbonne, France
| | - John Belperio
- Department of Pulmonary and Critical Care, University of California, Los Angeles, California
| | - Riccardo Olcese
- Department of Anesthesiology and Perioperative Medicine, University of California, Los Angeles, California
| | - Christopher M Waters
- Department of Physiology, University of Tennessee Health Science Center, Memphis, Tennessee; and
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Abstract
Although Andre Robert's historic article on "gastric cytoprotection" in 1979 introduced this new name and concept, gastroprotective drugs (e.g. sofalcone, sucralfate), which prevent and/or accelerate healing of gastric ulcers without inhibiting acid secretion, were known in Japan before or around that time. But since Robert's studies were solely focused on prostaglandins (PG), they became the center of gastrointestinal research for more than 30 years. As endogenous products, PG were implicated in mediating the gastroprotective effect of other drugs such as sofalcone and sucralfate, despite that the cyclooxygenase inhibitor indomethacin diminished but never abolished gastroprotection by other drugs. Another group of endogenous substances, that is, sulfhydryls (SH), investigated in parallel with PG, also seem to play a mechanistic role in gastroprotection, especially since SH alkylators like N-ethylmaleimide counteract virtually any form of gastroprotection. In Robert's terms of "prevention of chemically induced acute mucosal lesions," so far no single mechanism could explain the beneficial effects of diverse protective agents, but I argue that these two endogenous substances (i.e. PG, SH), in addition to histamine, are the main mechanistic mediators of acute gastroprotection: PG and histamine, because as mediators of acute inflammation, they increase vascular permeability (VP), and SH scavenge free radicals. This is contrary to the search for a single mechanism of action, long focused on enhanced secretion of mucus and/or bicarbonate that may contribute but cannot explain all forms of gastroprotection. Nevertheless, based on research work of the last 30 years, in part from our lab, a new mechanistic explanation of gastroprotection may be formulated: it's a complex but orderly and evolution-based physiologic response of the gastric mucosa under pathologic conditions. Namely, one of the first physiologic defense responses of any organ is inflammation that starts with rapid vascular changes (e.g. increased VP and blood flow), followed by cellular events (e.g. infiltration by acute and chronic inflammatory cells). Thus, PG and histamine, by increasing VP create a perivascular edema that dilutes and delays toxic agents reaching the subepithelial capillaries. Otherwise, damaging chemicals may induce severe early vascular injury resulting in blood flow stasis, hypoxia, and necrosis of surrounding epithelial and mesenchymal cells. In this complex response, increased mucus and/or bicarbonate secretion seem to cause luminal dilution of gastrotoxic chemicals that is further reinforced by a perivascular, histodilutional component. This mechanistic explanation would encompass the protective actions of diverse agents as PG, small doses of histamine, motility stimulants, and dilute irritants (i.e. "adaptive cytoprotection"). Thus, although markedly increased VP is pathologic, slight increase in VP seems to be protective, that is, a key element in the complex pathophysiologic response during acute gastroprotection. Over the years, "gastroprotection" was also applied to accelerated healing of chronic gastroduodenal ulcers without reduction of acid secretion. The likely main mechanism here is the binding of angiogenic growth factors (e.g. basic fibroblast growth factor, vascular endothelial growth factor) to the heparin-like structures of sucralfate and sofalcone. Thus, despite intensive research of the last 30 years, gastroprotection is incompletely understood, and we are still far away from effectively treating Helicobacter pylori-negative ulcers and preventing nonsteroidal anti-inflammatory drugs-caused erosions and ulcers in the upper and lower gastrointestinal tract; hence "gastric cytoprotection" research is still relevant.
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Affiliation(s)
- Sandor Szabo
- Departments of Pathology and Pharmacology, University of California-Irvine and VA Medical Center, Long Beach, California, USA
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Woodward MC, Huff NK, Garza F, Keowen ML, Kearney MT, Andrews FM. Effect of pectin, lecithin, and antacid feed supplements (Egusin®) on gastric ulcer scores, gastric fluid pH and blood gas values in horses. BMC Vet Res 2014; 10 Suppl 1:S4. [PMID: 25238454 PMCID: PMC4123152 DOI: 10.1186/1746-6148-10-s1-s4] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/03/2022] Open
Abstract
Background The objectives of this study were to evaluate the effects of two commercial feed supplements, Egusin 250® [E-250] and Egusin SLH® [E-SLH], on gastric ulcer scores, gastric fluid pH, and blood gas values in stall-confined horses undergoing feed-deprivation. Methods Nine Thoroughbred horses were used in a three-period crossover study. For the three treatment groups, sweet feed was mixed with E-250, E-SLH, or nothing (control group) and fed twice daily. Horses were treated for 21 days, then an additional 7 days while on an alternating feed-deprivation model to induce or worsen ulcers (period one). In periods two and three, horses (n=6) were treated for an additional 7 days after feed-deprivation. Gastroscopies were performed on day -1 (n=9), day 21 (n=9), day 28 (n=9) and day 35 (n=6). Gastric juice pH was measured and gastric ulcer scores were assigned. Venous blood gas values were also measured. Results Gastric ulcers in control horses significantly decreased after 21 days, but there was no difference in ulcer scores when compared to the Egusin® treated horses. NG gastric ulcer scores significantly increased in E-250 and control horses on day 28 compared to day 21 as a result of intermittent feed-deprivation, but no treatment effect was observed. NG ulcer scores remained high in the control group but significantly decreased in the E-SLH- and E-250-treated horses by day 35. Gastric juice pH values were low and variable and no treatment effect was observed. Mean blood pCO2 values were significantly increased two hours after feeding in treated horses compared to controls, whereas mean blood TCO2 values increased in the 24 hour sample, but did not exceed 38 mmol/l. Conclusions The feed-deprivation model increased NG gastric ulcer severity in the horses. However, by day 35, Egusin® treated horses had less severe NG gastric ulcers compared to untreated control horses. After 35 days, Egusin® products tested here ameliorate the severity of gastric ulcers in stall-confined horses after feed stress.
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Du CYQ, Choi RCY, Dong TTX, Lau DTW, Tsim KWK. Yu Ping Feng San, an ancient Chinese herbal decoction, regulates the expression of inducible nitric oxide synthase and cyclooxygenase-2 and the activity of intestinal alkaline phosphatase in cultures. PLoS One 2014; 9:e100382. [PMID: 24967898 PMCID: PMC4072625 DOI: 10.1371/journal.pone.0100382] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2014] [Accepted: 05/27/2014] [Indexed: 01/29/2023] Open
Abstract
Yu Ping Feng San (YPFS), a Chinese herbal decoction comprising Astragali Radix (AR; Huangqi), Atractylodis Macrocephalae Rhizoma (AMR; Baizhu), and Saposhnikoviae Radix (SR; Fangfeng), has been used clinically to treat inflammatory bowel diseases (IBD). Previously, we demonstrated a dual role of YPFS in regulating cytokine release in cultured macrophages. In this study, we elucidated the anti-inflammatory effect of YPFS that is mediated through modulating the expression of three key enzymes involved in IBD: inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and intestinal alkaline phosphatase (IALP). In a lipopolysaccharide (LPS)-induced chronic-inflammation model of cultured murine macrophages, YPFS treatment suppressed the activation of iNOS and COX-2 expression in a dose-dependent manner. Conversely, application of YPFS in cultured small intestinal enterocytes markedly induced the expression of IALP in a time-dependent manner, which might strengthen the intestinal detoxification system. A duality of YPFS in modulating the expression of iNOS and COX-2 was determined here. The expression of iNOS and COX-2 in macrophages was induced by YPFS, and this activation was partially blocked by the NF-κB-specific inhibitor BAY 11-7082, indicating a role of NF-κB signaling. These YPFS-induced changes in gene regulation strongly suggest that the anti-inflammatory effects of YPFS are mediated through the regulation of inflammatory enzymes.
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Affiliation(s)
- Crystal Y. Q. Du
- Division of Life Science and Centre for Chinese Medicine, The Hong Kong University of Science and Technology, Hong Kong SAR, China
| | - Roy C. Y. Choi
- Division of Life Science and Centre for Chinese Medicine, The Hong Kong University of Science and Technology, Hong Kong SAR, China
| | - Tina T. X. Dong
- Division of Life Science and Centre for Chinese Medicine, The Hong Kong University of Science and Technology, Hong Kong SAR, China
| | - David T. W. Lau
- Division of Life Science and Centre for Chinese Medicine, The Hong Kong University of Science and Technology, Hong Kong SAR, China
| | - Karl W. K. Tsim
- Division of Life Science and Centre for Chinese Medicine, The Hong Kong University of Science and Technology, Hong Kong SAR, China
- * E-mail:
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Bothiraja C, Yojana BD, Pawar AP, Shaikh KS, Thorat UH. Fisetin-loaded nanocochleates: formulation, characterisation,in vitroanticancer testing, bioavailability and biodistribution study. Expert Opin Drug Deliv 2013; 11:17-29. [DOI: 10.1517/17425247.2013.860131] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
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15
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Development of plumbagin-loaded phospholipid–Tween® 80 mixed micelles: formulation, optimization, effect on breast cancer cells and human blood/serum compatibility testing. Ther Deliv 2013; 4:1247-59. [DOI: 10.4155/tde.13.92] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Background: Phospholipid and Tween® 80 mixed micelles were investigated as injectable nanocarriers for the natural anticancer compound, plumbagin (PBG), with the aim to improve anticancer efficiency. PBG-loaded mixed micelles were fabricated by self-assembly; composition being optimized using 32 factorial design. Results & discussion: Optimized mixed micelles were spherical and 46 nm in size. Zeta potential, drug loading and encapsulation efficiency were 5.04 mV, 91.21 and 98.38% respectively. Micelles demonstrated sustained release of PBG. Micelles caused a 2.1-fold enhancement in vitro antitumor activity of PBG towards MCF-7 cells. Micelles proved safe for intravenous injection as PBG was stable at high pH; micelle size and encapsulation efficiency were retained upon dilution. Conclusion: Developed mixed micelles proved potential nanocarriers for PBG in cancer chemotherapy.
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16
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Semalty A, Tanwar YS. Nimesulide-phosphatidylcholine Complex for Improvement of Solubility and
Dissolution. ACTA ACUST UNITED AC 2013. [DOI: 10.3923/ajdd.2013.225.234] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
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17
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Tovey FI, Bardhan KD, Hobsley M. Dietary phosphilipids and sterols protective against peptic ulceration. Phytother Res 2013; 27:1265-1269. [PMID: 23097339 DOI: 10.1002/ptr.4865] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2012] [Revised: 09/23/2012] [Accepted: 09/27/2012] [Indexed: 12/16/2022]
Abstract
The prevalence of duodenal ulceration in regions of developing countries with a stable diet is related to the staple food(s) in that diet. A higher prevalence occurs in areas where the diet is principally milled rice, refined wheat or maize, yams, cassava, sweet potato or green bananas, and a lower prevalence in areas where the staple diet is based on unrefined wheat or maize, soya, certain millets or certain pulses. Experiments using animal peptic ulcer models showed that the lipid fraction in foods from the staple diets of low prevalence areas gave protection against both gastric and duodenal ulceration, including ulceration due to non-steroidal anti-inflammatory drugs (NSAIDs), and also promoted healing of ulceration. The protective activity was found to lie in the phospholipid, sterol and sterol ester fractions of the lipid. Amongst individual phospholipids present in the phospholipid fraction, phosphatidyl ethanolamine (cephalin) and phosphatidyl choline (Lecithin) predominated. The sterol fraction showing activity contained β-sitosterol, stigmasterol and an unidentified isomer of β-sitosterol. The evidence shows that dietary phytosterols and phospholipids, both individually and in combination, have a protective effect on gastroduodenal mucosa. These findings may prove to be important in the prevention and management of duodenal and gastric ulceration including ulceration due to NSAIDs.
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Affiliation(s)
- F I Tovey
- Division of Surgery and Interventional Science, University College, London, UK.
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18
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Pereira-Leite C, Nunes C, Reis S. Interaction of nonsteroidal anti-inflammatory drugs with membranes: in vitro assessment and relevance for their biological actions. Prog Lipid Res 2013; 52:571-84. [PMID: 23981364 DOI: 10.1016/j.plipres.2013.08.003] [Citation(s) in RCA: 71] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2013] [Revised: 08/01/2013] [Accepted: 08/16/2013] [Indexed: 12/12/2022]
Abstract
Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most commonly used drugs in the world due to their anti-inflammatory, analgesic and antipyretic properties. Nevertheless, the consumption of these drugs is still associated with the occurrence of a wide spectrum of adverse effects. Regarding the major role of membranes in cellular events, the hypothesis that the biological actions of NSAIDs may be related to their effect at the membrane level has triggered the in vitro assessment of NSAIDs-membrane interactions. The use of membrane mimetic models, cell cultures, a wide range of experimental techniques and molecular dynamics simulations has been providing significant information about drugs partition and location within membranes and also about their effect on diverse membrane properties. These studies have indeed been providing evidences that the effect of NSAIDs at membrane level may be an additional mechanism of action and toxicity of NSAIDs. In fact, the pharmacokinetic properties of NSAIDs are closely related to the ability of these drugs to interact and overcome biological membranes. Moreover, the therapeutic actions of NSAIDs may also result from the indirect inhibition of cyclooxygenase due to the disturbing effect of NSAIDs on membrane properties. Furthermore, increasing evidences suggest that the disordering effects of these drugs on membranes may be in the basis of the NSAIDs-induced toxicity in diverse organ systems. Overall, the study of NSAIDs-membrane interactions has proved to be not only important for the better understanding of their pharmacological actions, but also for the rational development of new approaches to overcome NSAIDs adverse effects.
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Affiliation(s)
- Catarina Pereira-Leite
- REQUIMTE, Laboratório de Química Aplicada, Departamento de Ciências Químicas, Faculdade de Farmácia da Universidade do Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal
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19
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Nunes C, Lopes D, Pinheiro M, Pereira-Leite C, Reis S. In vitro assessment of NSAIDs-membrane interactions: significance for pharmacological actions. Pharm Res 2013; 30:2097-2107. [PMID: 23703372 DOI: 10.1007/s11095-013-1066-8] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2013] [Accepted: 04/19/2013] [Indexed: 10/26/2022]
Abstract
PURPOSE To study interactions between nonsteroidal anti-inflammatory drugs (NSAIDs) and membrane mimetic models. METHODS The interactions of indomethacin and nimesulide with liposomes of dipalmitoylphosphatidylcholine (DPPC) at two physiological pH conditions (pH 7.4 and 5.0) were investigated by time-resolved and steady-state fluorescence techniques and derivative ultraviolet/visible absorption spectrophotometry. Fluorescence quenching studies that assess the location of the drugs interacting with the membrane were carried out using labeled liposomes with trimethylammonium-diphenylhexatriene (TMA-DPH), a fluorescent probe with well-known membrane localization. Partition of the drugs within membranes was determined by calculating their partition coefficients (K p ) between liposomes and water using derivative ultraviolet/visible absorption spectrophotometry in a temperature range of 37-50°C. The Van't Hoff analysis of the temperature dependence of K p values allowed calculating the membrane-water variation of enthalpy (ΔH w→m) and entropy (ΔS w→m) and consequently the Gibbs free energy (ΔG w→m). RESULTS Results indicate that quenching, partitioning and thermodynamic parameters inherent to the interaction of the studied drugs with the membrane mimetic model are deeply dependent on the initial organization of the membrane, on the pH medium and on the physical properties of the drug. CONCLUSIONS The interactions between NSAIDs and membranes are manifested as changes in the physical and thermodynamic properties of the bilayers. Depending on the composition and physical state of the membrane and the chemical structure of the NSAID, the interaction can support or prevent drug activity or toxicity.
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Affiliation(s)
- Cláudia Nunes
- REQUIMTE, Departamento de Ciências Químicas, Faculdade de Farmácia, Universidade do Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal.
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20
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Ma WC, Zhang Q, Li H, Larregieu CA, Zhang N, Chu T, Jin H, Mao SJ. Development of intravenous lipid emulsion of α-asarone with significantly improved safety and enhanced efficacy. Int J Pharm 2013; 450:21-30. [PMID: 23608202 DOI: 10.1016/j.ijpharm.2013.04.023] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2012] [Revised: 02/24/2013] [Accepted: 04/08/2013] [Indexed: 10/26/2022]
Abstract
Severe adverse events have been frequently associated with taking the commercially available formulation of α-asarone injection (α-asarone-I). Hence, we sought to develop an intravenous lipid emulsion of α-asarone (α-asarone-LE), where we hypothesized that these adverse events could be prevented. Using a central composite design-response surface methodology, we developed and optimized an emulsion formulation of α-asarone-LE that composed of 10.0% (w/v) soybean oil, 0.4% (w/v) α-asarone, 1.2% (w/v) soybean lecithin, 0.3% (w/v) F68, and 2.2% (w/v) glycerol. The mean particle size of α-asarone-LE was 226±11 nm, the ζ-potential was -25.6±1.2 mV, the encapsulation efficiency was 99.2±0.1% and the drug loading efficiency was 3.45%. Stability, safety, and efficacy studies of α-asarone-LE were systematically investigated and compared to those of α-asarone-I. The α-asarone-LE not only showed a desired stability, but also exhibited excellent safety and improved efficacy in vivo, indicating its great potential for clinical application in the future.
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Affiliation(s)
- Wei-Cong Ma
- Key Laboratory of Drug Targeting and Drug Delivery System, Ministry of Education & West China School of Pharmacy, Sichuan University, No. 17, Section 3, Southern Renmin Road, Chengdu 610041, PR China
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21
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Macierzanka A, Böttger F, Rigby NM, Lille M, Poutanen K, Mills ENC, Mackie AR. Enzymatically structured emulsions in simulated gastrointestinal environment: impact on interfacial proteolysis and diffusion in intestinal mucus. LANGMUIR : THE ACS JOURNAL OF SURFACES AND COLLOIDS 2012; 28:17349-17362. [PMID: 23171215 DOI: 10.1021/la302194q] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/01/2023]
Abstract
Fundamental knowledge of physicochemical interactions in the gastrointestinal environment is required in order to support rational designing of protein-stabilized colloidal food and pharmaceutical delivery systems with controlled behavior. In this paper, we report on the colloidal behavior of emulsions stabilized with the milk protein sodium caseinate (Na-Cas), and exposed to conditions simulating the human upper gastrointestinal tract. In particular, we looked at how the kinetics of proteolysis was affected by adsorption to an oil-water interface in emulsion and whether the proteolysis and the emulsion stability could be manipulated by enzymatic structuring of the interface. After cross-linking with the enzyme transglutaminase, the protein was digested with use of an in vitro model of gastro-duodenal proteolysis in the presence or absence of physiologically relevant surfactants (phosphatidylcholine, PC; bile salts, BS). Significant differences were found between the rates of digestion of Na-Cas cross-linked in emulsion (adsorbed protein) and in solution. In emulsion, the digestion of a population of polypeptides of M(r) ca. 50-100 kDa was significantly retarded through the gastric digestion. The persistent interfacial polypeptides maintained the original emulsion droplet size and prevented the system from phase separating. Rapid pepsinolysis of adsorbed, non-cross-linked Na-Cas and its displacement by PC led to emulsion destabilization. These results suggest that structuring of emulsions by enzymatic cross-linking of the interfacial protein may affect the phase behavior of emulsion in the stomach and the gastric digestion rate in vivo. Measurements of ζ-potential revealed that BS displaced the remaining protein from the oil droplets during the simulated duodenal phase of digestion. Diffusion of the postdigestion emulsion droplets through ex vivo porcine intestinal mucus was only significant in the presence of BS due to the high negative charge these biosurfactants imparted to the droplets. This implies that the electrostatic repulsion produced can prevent the droplets from being trapped by the mucus matrix and facilitate their transport across the small intestine mucosal barrier.
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Affiliation(s)
- Adam Macierzanka
- Institute of Food Research, Norwich Research Park, Colney Lane, Norwich NR4 7UA, United Kingdom.
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Ceserani R, Casciarri I, Cavalletti E, Cazzulani P. Action of Nimesulide on Rat Gastric Prostaglandins and Renal Function. ACTA ACUST UNITED AC 2012. [DOI: 10.1007/bf03258312] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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Nayak A, Dodagatta-Marri E, Tsolaki AG, Kishore U. An Insight into the Diverse Roles of Surfactant Proteins, SP-A and SP-D in Innate and Adaptive Immunity. Front Immunol 2012; 3:131. [PMID: 22701116 PMCID: PMC3369187 DOI: 10.3389/fimmu.2012.00131] [Citation(s) in RCA: 123] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2011] [Accepted: 05/07/2012] [Indexed: 01/20/2023] Open
Abstract
Surfactant proteins SP-A and SP-D are hydrophilic, collagen-containing calcium-dependent lectins, which appear to have a range of innate immune functions at pulmonary as well as extrapulmonary sites. These proteins bind to target ligands on pathogens, allergens, and apoptotic cells, via C-terminal homotrimeric carbohydrate recognition domains, while the collagen region brings about the effector functions via its interaction with cell surface receptors. SP-A and SP-D deal with various pathogens, using a range of innate immune mechanisms such as agglutination/aggregation, enhancement of phagocytosis, and killing mechanisms by phagocytic cells and direct growth inhibition. SP-A and SP-D have also been shown to be involved in the control of pulmonary inflammation including allergy and asthma. Emerging evidence suggest that SP-A and SP-D are capable of linking innate immunity with adaptive immunity that includes modulation of dendritic cell function and helper T cell polarization. This review enumerates immunological properties of SP-A and SP-D inside and outside lungs and discusses their importance in human health and disease.
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Affiliation(s)
- Annapurna Nayak
- Centre for Infection, Immunity and Disease Mechanisms, School of Health Sciences and Social Care, Brunel University London, UK
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24
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Ruan YC, Zhou W, Chan HC. Regulation of smooth muscle contraction by the epithelium: role of prostaglandins. Physiology (Bethesda) 2011; 26:156-70. [PMID: 21670162 DOI: 10.1152/physiol.00036.2010] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
As an analog to the endothelium situated next to the vascular smooth muscle, the epithelium is emerging as an important regulator of smooth muscle contraction in many vital organs/tissues by interacting with other cell types and releasing epithelium-derived factors, among which prostaglandins have been demonstrated to play a versatile role in governing smooth muscle contraction essential to the physiological and pathophysiological processes in a wide range of organ systems.
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Affiliation(s)
- Ye Chun Ruan
- School of Life Science, Sun Yat-sen University, China
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25
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Nunes C, Brezesinski G, Pereira-Leite C, Lima JLFC, Reis S, Lúcio M. NSAIDs interactions with membranes: a biophysical approach. LANGMUIR : THE ACS JOURNAL OF SURFACES AND COLLOIDS 2011; 27:10847-58. [PMID: 21790169 DOI: 10.1021/la201600y] [Citation(s) in RCA: 76] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/08/2023]
Abstract
This work focuses on the interaction of four representative NSAIDs (nimesulide, indomethacin, meloxicam, and piroxicam) with different membrane models (liposomes, monolayers, and supported lipid bilayers), at different pH values, that mimic the pH conditions of normal (pH 7.4) and inflamed cells (pH 5.0). All models are composed of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) which is a representative phospholipid of most cellular membranes. Several biophysical techniques were employed: Fluorescence steady-state anisotropy to study the effects of NSAIDs in membrane microviscosity and thus to assess the main phase transition of DPPC, surface pressure-area isotherms to evaluate the adsorption and penetration of NSAIDs into the membrane, IRRAS to acquire structural information of DPPC monolayers upon interaction with the drugs, and AFM to study the changes in surface topography of the lipid bilayers caused by the interaction with NSAIDs. The NSAIDs show pronounced interactions with the lipid membranes at both physiological and inflammatory conditions. Liposomes, monolayers, and supported lipid bilayers experiments allow the conclusion that the pH of the medium is an essential parameter when evaluating drug-membrane interactions, because it conditions the structure of the membrane and the ionization state of NSAIDs, thereby influencing the interactions between these drugs and the lipid membranes. The applied models and techniques provided detailed information about different aspects of the drug-membrane interaction offering valuable information to understand the effect of these drugs on their target membrane-associated enzymes and their side effects at the gastrointestinal level.
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Affiliation(s)
- Cláudia Nunes
- REQUIMTE, Departamento de Química, Faculdade de Farmácia, Universidade do Porto, Rua Aníbal Cunha, Porto, Portugal
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26
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Structural properties of so-called NSAID–phospholipid-complexes. Eur J Pharm Sci 2011; 44:103-16. [DOI: 10.1016/j.ejps.2011.06.010] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2011] [Revised: 06/17/2011] [Accepted: 06/20/2011] [Indexed: 11/23/2022]
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27
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Tovey FI, Capanoglu D, Langley GJ, Herniman JM, Bor S, Ozutemiz O, Hobsley M, Bardhan KD, Linclau B. Dietary Phytosterols Protective Against Peptic Ulceration. Gastroenterology Res 2011; 4:149-156. [PMID: 27942332 PMCID: PMC5139726 DOI: 10.4021/gr328w] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/04/2011] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND In developing countries the prevalence of duodenal ulceration is related to the staple diet and not to the prevalence of Helicobacter pylori. Experiments using animal peptic ulcer models show that the lipid fraction in foods from the staple diets of low prevalence areas gives protection against ulceration, including ulceration due to non-steroidal anti-inflammatory drugs (NSAIDs), and also promotes healing of ulceration. The lipid from the pulse Dolichos biflorus (Horse gram) was highly active and used for further investigations. Further experiments showed the phospholipids, sterol esters and sterols present in Horse gram lipid were gastroprotective. Dietary phospholipids are known to be protective, but the nature of protective sterols in staple diets is not known. The present research investigates the nature of the protective phytosterols. METHODS Sterol fractions were extracted from the lipid in Dolichos biflorus and tested for gastroprotection using the rat ethanol model. The fractions showing protective activity were isolated and identification of the components was investigated by Gas Chromatography-Mass Spectrometry (GC-MS). RESULTS The protective phytosterol fraction was shown to consist of stigmasterol, β-sitosterol and a third as yet unidentified sterol, isomeric with β-sitosterol. CONCLUSIONS Dietary changes, affecting the intake of protective phospholipids and phytosterols, may reduce the prevalence of duodenal ulceration in areas of high prevalence and may reduce the incidence of recurrent duodenal ulceration after healing and elimination of Helicobacter pylori infection. A combination of phospholipids and phytosterols, such as found in the lipid fraction of ulceroprotecive foods, may be of value in giving protection against the ulcerogenic effect of NSAIDs.
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Affiliation(s)
- Frank I Tovey
- Division of Surgery and Interventional Science, University College, London, UK
| | - Doga Capanoglu
- Department of Gastroenterology, Ege University, Bornova, Turkey
| | | | | | - Serhat Bor
- Department of Gastroenterology, Ege University, Bornova, Turkey
| | - Omer Ozutemiz
- Department of Gastroenterology, Ege University, Bornova, Turkey
| | - Michael Hobsley
- Division of Surgery and Interventional Science, University College, London, UK
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Semalty A, Semalty M, Rawat BS, Singh D, Rawat MSM. Development and evaluation of pharmacosomes of aceclofenac. Indian J Pharm Sci 2011; 72:576-81. [PMID: 21694988 PMCID: PMC3116301 DOI: 10.4103/0250-474x.78523] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2009] [Revised: 08/18/2010] [Accepted: 09/12/2010] [Indexed: 11/11/2022] Open
Abstract
Pharmacosomes are amphiphilic lipid vesicular systems containing phospholipid complexes with a potential to improve bioavailability of poorly water soluble as well as poorly lipophilic drugs. To improve the water solubility, bioavailability and minimize the gastrointestinal toxicity of aceclofenac, its pharmacosomes were prepared. Aceclofenac was complexed with phosphatidylcholine (80%) in two different ratios (1:1 and 2:1) using conventional solvent evaporation technique. Pharmacosomes thus prepared were subjected to solubility and drug content evaluation, scanning electron microscopy, differential scanning calorimetry, X ray powder diffraction and in vitro dissolution study. Pharmacosomes of aceclofenac were found to be disc shaped with rough surface in scanning electron microscopy. Drug content was found to be 91.88% (w/w) for aceclofenac phospholipid complex (1:1) and 89.03% (w/w) aceclofenac-phospholipid complex (2:1). Differential scanning calorimetric thermograms and X ray powder diffraction datas confirmed the formation of phospholipid complex. Solubility and dissolution profile of the prepared complex was found to be much better than aceclofenac.
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Affiliation(s)
- A Semalty
- Departments of Pharmaceutical Sciences H. N. B. Garhwal University, Srinagar (Garhwal)-246 174, India
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Nunes C, Brezesinski G, Lima JLFC, Reis S, Lúcio M. Synchrotron SAXS and WAXS Study of the Interactions of NSAIDs with Lipid Membranes. J Phys Chem B 2011; 115:8024-32. [DOI: 10.1021/jp2025158] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Affiliation(s)
- Cláudia Nunes
- REQUIMTE, Departamento de Química, Faculdade de Farmácia, Universidade do Porto, Rua Aníbal Cunha, Porto, Portugal
| | - Gerald Brezesinski
- Max Planck Institute of Colloids and Interfaces, Science Park Golm, Am Mühlenberg 1, 14476 Potsdam, Germany
| | - José L. F. C. Lima
- REQUIMTE, Departamento de Química, Faculdade de Farmácia, Universidade do Porto, Rua Aníbal Cunha, Porto, Portugal
| | - Salette Reis
- REQUIMTE, Departamento de Química, Faculdade de Farmácia, Universidade do Porto, Rua Aníbal Cunha, Porto, Portugal
| | - Marlene Lúcio
- REQUIMTE, Departamento de Química, Faculdade de Farmácia, Universidade do Porto, Rua Aníbal Cunha, Porto, Portugal
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30
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Shiraki M, Yamazaki Y, Kuroda T, Tanaka S, Miyata K. Serum level of pepsinogen significantly associated with gastric distress induced by amino-bisphosphonates. Osteoporos Int 2011; 22:1717-23. [PMID: 21069296 DOI: 10.1007/s00198-010-1374-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2010] [Accepted: 08/11/2010] [Indexed: 10/19/2022]
Abstract
UNLABELLED To elucidate whether serum levels of pepsinogens are associated with the occurrence of gastrointestinal adverse events induced by amino-bisphosphonates (amino-BP), the serum levels of pepsinogen were measured in amino-BP users. Our results indicate that measurement of pepsinogen I is useful in predicting gastric distress induced by amino-BP in osteoporosis. INTRODUCTION To elucidate whether serum levels of pepsinogens are associated with the occurrence of gastrointestinal adverse events induced by amino-BP, the serum levels of pepsinogen I and II were measured in amino-BP users. METHODS When the patients complained of gastric distress symptoms during the first 6 months after amino-BP use resulting in discontinuation of the drug, endoscopical examinations were performed to assess whether gastric lesions were present. A total of 223 amino-BP users were enrolled in the study, of which 47 patients refused to take the drug due to gastric distress symptoms. The remaining 176 patients did not complain of any gastric distress. RESULTS Among 47 patients, eight patients showed obvious gastric lesions such as gastric or duodenal ulcers and acute gastric mucosal lesions in the endoscopical examination. The remaining 39 patients did not show any gastric lesions. The possible confounding factors, such as a Helicobactor pylori infection or concurrent use of ulcerogenic agents, did cause not affect gastric distress in amino-BP users. The serum pepsinogen I level was significantly associated with severity of the gastric lesion 46.8 ± 27.7, 60.8 ± 32.4, and 103.4 ± 49.2 ng/ml for patients without any gastric distress, with gastric distress accompanied no gastric lesions, and with gastric distress accompanied gastric lesions, respectively. CONCLUSIONS ROC analysis revealed that the cutoff value of pepsinogen I for expectation of gastric regions was 76.8 ng/ml. The results clearly indicate that measurement of pepsinogen I may be useful in predicting gastric distress induced by amino-BP in osteoporosis.
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Affiliation(s)
- M Shiraki
- Research Institute and Practice for Involutional Diseases, Nagano, Japan.
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Liang H, Yang Q, Deng L, Lu J, Chen J. Phospholipid–Tween 80 mixed micelles as an intravenous delivery carrier for paclitaxel. Drug Dev Ind Pharm 2011; 37:597-605. [DOI: 10.3109/03639045.2010.533276] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
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Lipid based therapy for ulcerative colitis-modulation of intestinal mucus membrane phospholipids as a tool to influence inflammation. Int J Mol Sci 2010; 11:4149-64. [PMID: 21152327 PMCID: PMC2996791 DOI: 10.3390/ijms11104149] [Citation(s) in RCA: 53] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2010] [Revised: 10/15/2010] [Accepted: 10/16/2010] [Indexed: 02/06/2023] Open
Abstract
Ulcerative colitis (UC) is the result of an inappropriate colonic inflammatory response triggered by environmental and genetic factors. We have recently shown that mucus from UC patients has a decreased phosphatidylcholine (PC) content, while clinical trials revealed that therapeutic addition of PC to the colonic mucus alleviated the inflammatory activity. The mechanisms behind this are still unclear. We hypothesized that PC has at least two possible functions in the intestine: First, it establishes the surface hydrophobicity of the mucus and therefore protects the underlying tissue against intraluminal aggressors; recent experiments on surgical specimens revealed reduced surface tension and hydrophobicity in UC patients. Second, mucus phospholipids might also be integrated into the plasma membranes of enterocytes and thereby influence the signaling state of the mucosa. PC has been shown to inhibit TNF-α induced pro-inflammatory responses including: (1) assembly of plasma membrane actin; (2) activation of MAP kinases ERK and p38; and (3) activation of NF-κB and synthesis of pro-inflammatory gene products. Other phospholipids like phosphatidylethanolamine or sphingomyelin had no effect. PC also inhibited latex bead phagosome actin assembly, killing of M. tuberculosis in macrophages, and sphingosine-1-phosphate induced actin assembly in macrophages. Collectively, these results provide a molecular foundation that shows PC, firstly, as an anti-inflammatory, and secondly, as a surface hydrophobicity increasing compound with promising therapeutic potential in the treatment of inflammatory bowel disease.
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Chen J, Green-Church KB, Nichols KK. Shotgun lipidomic analysis of human meibomian gland secretions with electrospray ionization tandem mass spectrometry. Invest Ophthalmol Vis Sci 2010; 51:6220-31. [PMID: 20671273 DOI: 10.1167/iovs.10-5687] [Citation(s) in RCA: 99] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
PURPOSE The purpose of this investigation was to determine the major molecular components of the lipids in normal human meibomian gland secretions (meibum). METHODS The meibum samples were studied by direct infusion electrospray ionization (ESI), quadrupole time-of-flight mass spectrometry, and tandem mass spectrometry (MS/MS) analysis, in both positive and negative detection modes. RESULTS Hundreds of peaks were detected, among which the molecular compositions and subclasses of approximately 160 major peaks were confidently identified. The compositions and subclasses of these peaks were determined from collision-induced dissociation fragmentation patterns, high-resolution and high-mass-accuracy spectra, and references of literature reports. The major peaks detected in positive mode were those of nonpolar lipids, including wax esters, cholesteryl esters, triacylglycerols, and diesters, whereas in negative mode, the major peaks detected were those of polar lipids, including free fatty acids and (O-acyl)-ω-hydroxy fatty acids. CONCLUSIONS The analysis of intact lipids in meibum with direct infusion ESI-MS/MS analysis has the advantages of minimal sample preparation (no chromatography or pre-separation needed), mild experimental conditions, high throughput, and high sensitivity.
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Affiliation(s)
- Jianzhong Chen
- Applied Biotechnology Branch, Air Force Research Laboratory, Dayton, Ohio, USA
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van Rozendaal BAWM, van Golde LMG, Haagsman HP. Localization and Functions of SP-A and SP-D at Mucosal Surfaces. ACTA ACUST UNITED AC 2010. [DOI: 10.1080/15513810109168824] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
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Lane ME, Kim MJ. Assessment and prevention of gastrointestinal toxicity of non-steroidal anti-inflammatory drugs. J Pharm Pharmacol 2010. [DOI: 10.1111/j.2042-7158.2006.tb01645.x] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Abstract
Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used for analgesic, anti-inflammatory and, in the case of aspirin, for anti-thrombotic actions. The serious gastrointestinal side-effects associated with these drugs are of concern and pose a significant obstacle to their use. This review discusses the pathogenic mechanisms by which the conventional acidic NSAIDs induce gastrointestinal toxicity, with particular emphasis on non-prostaglandin effects. Methods of assessment of NSAID-induced enteropathy are reviewed, with particular emphasis on the use of functional measurement of NSAID-induced changes in the gastrointestinal tract. The advances in our knowledge of the pathogenesis of these effects have resulted in the development of a range of novel NSAIDs. Where functional assessment of the effects of NSAIDs has been employed, it appears to be more useful as an indicator of early-stage changes rather than a predictor of the effects of long-term NSAID exposure. Successful pharmaceutical strategies now offer considerable promise for reducing the severity of NSAID damage to the gastrointestinal tract. The utility of intestinal permeability measurements for selection and assessment of these strategies is discussed.
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Affiliation(s)
- Majella E Lane
- Department of Pharmaceutics, School of Pharmacy, 29-39 Brunswick Square, London, WC1N 1AX, UK
| | - Mi-Jeong Kim
- Gastrointestinal, Pulmonary and Metabolic Drug Division, Department of Drug Evaluation, Korea Food and Drug Administration, 5 Nokbun-dong, Eunpyung-Ku, Seoul 122-704, South Korea
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Jain P, Jain S, Prasad KN, Jain SK, Vyas SP. Polyelectrolyte coated multilayered liposomes (nanocapsules) for the treatment of Helicobacter pylori infection. Mol Pharm 2009; 6:593-603. [PMID: 19718807 DOI: 10.1021/mp8002539] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Helicobacter pylori infection is one of the major causes of gastric cancers. A number of systems have already been reported, but 100% eradication has never been achieved. The present invention designs a gastro-retentive drug delivery system incorporated with amoxicillin and metronidazole, specifically suited for the eradication of Helicobacter pylori infections due to its mucoadhesiveness in the presence of polyelectrolyte polymers. The system possesses the advantages of both vesicular and particulate carriers, and it was prepared by alternative coating of polyanion (poly(acrylic acid), PAA) and polycation (poly(allylamine hydrochloride), PAH) using liposomes as the core. Compared with the conventional liposomes, the polyelectrolyte based multilayered system (nanocapsules) gave prolonged drug release in simulated gastric fluid, which is well suited for drug delivery against H. pylori infection in the stomach. In vitro growth inhibition study, agglutination assay, and in situ adherence assay in cultured H. pylori suggested the successful in vitro activity and binding propensity of the system. In vivo bacterial clearance study carried out in a H. pylori infected mouse model finally confirmed the success of the developed novel nanocapsule system. Thus, the newly developed composite nanocapsules along with the use of combination therapy proved to have commendable potential in Helicobacter pylori eradication as compared to already existing conventional and novel drug delivery systems.
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Affiliation(s)
- Parul Jain
- Department of Pharmaceutical Sciences, Dr. Hari Singh Gour University, Sagar (M.P.) 470003, India
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Semalty A, Semalty M, Rawat BS, Singh D, Rawat MSM. Pharmacosomes: the lipid-based new drug delivery system. Expert Opin Drug Deliv 2009; 6:599-612. [DOI: 10.1517/17425240902967607] [Citation(s) in RCA: 96] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
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Lichtenberger LM, Romero JJ, Dial EJ. Gastrointestinal safety and therapeutic efficacy of parenterally administered phosphatidylcholine-associated indomethacin in rodent model systems. Br J Pharmacol 2009; 157:252-7. [PMID: 19366347 DOI: 10.1111/j.1476-5381.2009.00159.x] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022] Open
Abstract
BACKGROUND AND PURPOSE Indomethacin is a non-steroidal anti-inflammatory drug (NSAID) that is limited in its enteral or parenteral use by side effects of gastroduodenal bleeding and ulceration. We have investigated the ability of phosphatidylcholine associated with indomethacin to form a therapeutically effective drug (INDO-PC) with reduced gastrointestinal (GI) toxicity for parenteral use. EXPERIMENTAL APPROACH Rats were treated acutely by intravenous or chronically with subcutaneous injection of vehicle, indomethacin or INDO-PC using three related protocols. We then evaluated the following properties of these parenterally administered test drugs: (i) GI toxicity (luminal and faecal haemoglobin; intestinal perforations and adhesions; and haematocrit); (ii) bioavailability (plasma indomethacin); and (iii) therapeutic efficacy (analgesia from sensitivity to pressure; anti-inflammatory from ankle thickness; cyclo-oxygenase (COX) inhibition from synovial fluid prostaglandin E(2) concentration) in rats with adjuvant-induced joint inflammation. KEY RESULTS Acute and chronic dosing with INDO-PC produced less GI bleeding and intestinal injury than indomethacin alone, whereas the bioavailability, analgesic, anti-inflammatory and COX inhibitory activity of INDO-PC were comparable to indomethacin. CONCLUSIONS AND IMPLICATIONS The chemical association of phosphatidylcholine with indomethacin appears to markedly reduce the GI toxicity of the NSAID while providing equivalent therapeutic efficacy in a parenteral INDO-PC formulation.
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Affiliation(s)
- L M Lichtenberger
- The University of Texas Health Science Center at Houston, Medical School, Houston, Texas 77030, USA
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Intestinal permeability in the pathogenesis of NSAID-induced enteropathy. J Gastroenterol 2009; 44 Suppl 19:23-9. [PMID: 19148789 DOI: 10.1007/s00535-008-2266-6] [Citation(s) in RCA: 100] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2008] [Accepted: 07/22/2008] [Indexed: 02/06/2023]
Abstract
BACKGROUND The pathogenesis of nonsteroidal antiinflammatory drug (NSAID)-induced small bowel disease suggests that increased intestinal permeability is the central mechanism that translates biochemical damage to tissue damage. The purpose of this review is to summarize studies on the effect of NSAIDs to increase intestinal permeability in humans and methods for limiting this effect. METHODS A Medline search was made for papers that described measurements of increased intestinal permeability in humans. RESULTS Virtually all studies agree that all conventional NSAIDs increase intestinal permeability in the human within 24 h of ingestion and that this is equally evident when they are taken long term. Various methods have been tried to limit the damage. The most promising agents are coadministration of synthetic prostaglandins, micronutrients, pre-NSAIDs, and COX-2 selective agents. However, their efficacy in preventing the development of NSAID enteropathy in the long term has not been studied in detail, and, in the case of COX-2 selective agents, small bowel damage is comparable to that which is seen with conventional NSAIDs. CONCLUSIONS NSAID enteropathy is associated with significant morbidity and occasionally mortality. There are no proven effective ways of preventing this damage. Because increased intestinal permeability appears to be a central mechanism in the pathogenesis of NSAID enteropathy, it becomes a potential therapeutic target for prevention. At present there are a number of ways to limit the increased permeability, but additional studies are required to assess if this approach reduces the prevalence and severity of NSAID enteropathy.
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ORAL PHOSPHATIDYLCHOLINE PRESERVES THE GASTROINTESTINAL MUCOSAL BARRIER DURING LPS-INDUCED INFLAMMATION. Shock 2008; 30:729-33. [DOI: 10.1097/shk.0b013e318173e8d4] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
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Kleinman RE. Protection of the gastrointestinal tract epithelium against damage from low pH beverages. J Food Sci 2008; 73:R99-105. [PMID: 18803726 DOI: 10.1111/j.1750-3841.2008.00863.x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Extensive consumption of low pH beverages such as citrus juices (pHs 2.3 to 4.3), alcoholic beverages (pHs 2.7 to 4.5), and soft drinks (pHs 2.3 to 4.2) has raised the question of whether exposure of the gastrointestinal (GI) tract to acidic beverages will cause damage to the epithelial lining. To evaluate the potential effects of low pH beverages on the GI tract epithelium, a detailed examination of the literature was undertaken. In some animal models, there is evidence of damage to GI epithelial cells following exposure to low pH beverages; however, in these studies there is no definitive relationship between acidity and the amount or severity of damage. Results from several other studies, conducted in both animals and humans, indicate a lack of adverse effects on epithelial cells. Furthermore, there is no evidence that damage is irreversible. Permanent damage from routine exposure to acidic beverages in humans would not be expected because of repair mechanisms that are available to maintain a healthy epithelium. Additionally, numerous physical, chemical, and biological mechanisms are in place to prevent damage to the epithelial cells. Finally, the safe history of consumption of low pH beverages, including various fruit juices, supports the conclusion that low pH beverage ingestion does not cause damage to the GI epithelium.
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Affiliation(s)
- R E Kleinman
- Massachusetts General Hospital, Pediatric Gastroenterology & Nutrition, Boston, MA 02114, USA.
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Laine L, Takeuchi K, Tarnawski A. Gastric mucosal defense and cytoprotection: bench to bedside. Gastroenterology 2008; 135:41-60. [PMID: 18549814 DOI: 10.1053/j.gastro.2008.05.030] [Citation(s) in RCA: 483] [Impact Index Per Article: 28.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2008] [Revised: 04/07/2008] [Accepted: 05/05/2008] [Indexed: 02/06/2023]
Abstract
The gastric mucosa maintains structural integrity and function despite continuous exposure to noxious factors, including 0.1 mol/L HCl and pepsin, that are capable of digesting tissue. Under normal conditions, mucosal integrity is maintained by defense mechanisms, which include preepithelial factors (mucus-bicarbonate-phospholipid "barrier"), an epithelial "barrier" (surface epithelial cells connected by tight junctions and generating bicarbonate, mucus, phospholipids, trefoil peptides, prostaglandins (PGs), and heat shock proteins), continuous cell renewal accomplished by proliferation of progenitor cells (regulated by growth factors, PGE(2) and survivin), continuous blood flow through mucosal microvessels, an endothelial "barrier," sensory innervation, and generation of PGs and nitric oxide. Mucosal injury may occur when noxious factors "overwhelm" an intact mucosal defense or when the mucosal defense is impaired. We review basic components of gastric mucosal defense and discuss conditions in which mucosal injury is directly related to impairment in mucosal defense, focusing on disorders with important clinical sequelae: nonsteroidal anti-inflammatory drug (NSAID)-associated injury, which is primarily related to inhibition of cyclooxygenase (COX)-mediated PG synthesis, and stress-related mucosal disease (SRMD), which occurs with local ischemia. The annual incidence of NSAID-associated upper gastrointestinal (GI) complications such as bleeding is approximately 1%-1.5%; and reductions in these complications have been demonstrated with misoprostol, proton pump inhibitors (PPIs) (only documented in high-risk patients), and COX-2 selective inhibitors. Clinically significant bleeding from SRMD is relatively uncommon with modern intensive care. Pharmacologic therapy with antisecretory drugs may be used in high-risk patients (eg, mechanical ventilation >or=48 hours), although the absolute risk reduction is small, and a decrease in mortality is not documented.
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Affiliation(s)
- Loren Laine
- Division of Gastrointestinal and Liver Diseases, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
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Lúcio M, Bringezu F, Reis S, Lima JLFC, Brezesinski G. Binding of nonsteroidal anti-inflammatory drugs to DPPC: structure and thermodynamic aspects. LANGMUIR : THE ACS JOURNAL OF SURFACES AND COLLOIDS 2008; 24:4132-4139. [PMID: 18336047 DOI: 10.1021/la703584s] [Citation(s) in RCA: 54] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/26/2023]
Abstract
The effect of nonsteroidal anti-inflammatory drugs (NSAIDs) on the phase transition and phase properties of 1,2-dipalmitoylphosphatidylcholine (DPPC) has been investigated in both 2D (monolayers at the air/water interface) and 3D (multilayers in lipid/water dispersions) model systems. The 2D membrane models have been characterized by means of pressure-area isotherms and grazing incidence X-ray diffraction (GIXD) measurements. Differential scanning calorimetry (DSC) and simultaneous small- and wide-angle X-ray diffraction have been applied to lipid aqueous dispersions. All NSAIDs studied altered the main transition temperature of the gel to liquid-crystalline phase transition, with the arylacetic acid derivatives (acemetacin and indomethacin) showing the largest effects. A comparison of the results reveals distinct structural features of the membrane models after interaction with the NSAID. All drugs induced perturbations in the lipid liquid-crystalline phase, suggesting a major change in the hydration behavior of DPPC. Again, the largest effects on the structural parameters are found for the arylacetic acid derivatives. The results obtained in the different model systems give indications of the role of the membrane/NSAID interactions that might also be important for NSAID gastric injury.
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Affiliation(s)
- Marlene Lúcio
- REQUIMTE, Faculdade de Farmácia, Universidade do Porto, Rua Aníbal Cunha, 4099-030 Porto, Portugal.
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A report on associations among gastric pH, bleeding, duodenogastric reflux, and outcomes after trauma. ACTA ACUST UNITED AC 2008; 64:105-10. [PMID: 18188106 DOI: 10.1097/ta.0b013e31815ebd99] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND The pathogenesis of multiple organ failure (MOF) in trauma patients may involve the gastrointestinal tract, but its exact origins remain elusive. In a prospective study, the gastric fluid of major torso trauma patients was examined for evidence of duodenogastric reflux and potential gastric injury, and was compared with patient outcomes regarding MOF. METHODS Patient samples were collected daily for 4 days by nasogastric tube and analyzed for pH, hemoglobin, and bile acid. Blood was collected for analysis of C-reactive protein (CRP). Outcomes were recorded for the presence or absence of MOF. RESULTS The results showed that most patients exhibited alkaline gastric contents (pH >/=4.9) and elevated levels of hemoglobin immediately after the trauma. Although non-MOF patients demonstrated a decline of both mean gastric pH and bleeding by day 4, MOF patients maintained significant elevations in pH during this time period. Mean total bile acid levels were increased in all patients, signifying the presence of duodenogastric reflux. However, there were no clear differences in mean bile acid concentrations between MOF and non-MOF patients over time, although MOF patients tended to exhibit higher levels. All patients showed a progressive rise in serum CRP during the first 24 hours after trauma, which was maintained for 4 days. The initial rise in serum CRP in MOF patients was delayed compared with that in non-MOF patients. CONCLUSIONS We conclude that duodenogastric reflux occurs in trauma patients in the first few days after trauma and may contribute to elevated gastric pH and bleeding. Further study is needed to verify whether monitoring the gastric juice of trauma patients during the first several days of hospitalization, for alkaline pH and excessive blood in the gastric lumen, could lead to better assessments of patient status.
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Corzo A, Kidd M, Dozier W, Pharr G, Koutsos E. Dietary Threonine Needs for Growth and Immunity of Broilers Raised Under Different Litter Conditions. J APPL POULTRY RES 2007. [DOI: 10.3382/japr.2007-00046] [Citation(s) in RCA: 54] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
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Treede I, Braun A, Sparla R, Kühnel M, Giese T, Turner JR, Anes E, Kulaksiz H, Füllekrug J, Stremmel W, Griffiths G, Ehehalt R. Anti-inflammatory effects of phosphatidylcholine. J Biol Chem 2007; 282:27155-27164. [PMID: 17636253 PMCID: PMC2693065 DOI: 10.1074/jbc.m704408200] [Citation(s) in RCA: 235] [Impact Index Per Article: 13.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Abstract
We recently showed that mucus from patients with ulcerative colitis, a chronic inflammatory disorder of the colon, is characterized by a low level of phosphatidylcholine (PC) while clinical studies reveal that therapeutic addition of PC using slow release preparations is beneficial. The positive role of PC in this disease is still elusive. Here we tested the hypothesis that exogenous application of PC has anti-inflammatory properties using three model systems. First, human Caco-2 cells were treated with tumor necrosis factor-alpha (TNF-alpha) to induce a pro-inflammatory response via activation of NF-kappaB. Second, latex bead phagosomes were analyzed for their ability to assemble actin in vitro, a process linked to pro-inflammatory signaling and correlating with the growth versus killing of mycobacteria in macrophages. The third system used was the rapid assembly of plasma membrane actin in macrophages in response to sphingosine 1-phosphate. TNF-alpha induced a pro-inflammatory response in Caco-2 cells, including 1) assembly of plasma membrane actin; 2) activation of both MAPKs ERK and p38; 3) transport of NF-kappaB subunits to the nucleus; and 4) subsequent up-regulation of the synthesis of pro-inflammatory gene products. Exogenous addition of most PCs tested significantly inhibited these processes. Other phospholipids like sphingomyelin or phosphatidylethanolamine showed no effects in these assays. PC also inhibited latex bead phagosome actin assembly, the killing of Mycobacterium tuberculosis in macrophages, and the sphingosine 1-phosphate-induced actin assembly in macrophages. TNF-alpha induces the activation of signaling molecules and the reorganization of the actin cytoskeleton in human intestinal cells. Exogenous application of PC blocks pro-inflammatory signaling in Caco-2 cells, in phagosomes in vitro and facilitates intracellular survival of mycobacteria. We provide further evidence that actin assembly by membranes is part of the pro-inflammatory response. Collectively, these results provide a molecular foundation for the clinical studies showing a beneficial effect of PC therapy in ulcerative colitis.
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Affiliation(s)
- Irina Treede
- Department of Gastroenterology, University Hospital Heidelberg, INF 345, Heidelberg 69120, Germany, the; Cell Biology Program, European Molecular Biology Laboratory, Postfach 102209, Heidelberg 69117, Germany, the
| | - Annika Braun
- Department of Gastroenterology, University Hospital Heidelberg, INF 345, Heidelberg 69120, Germany, the
| | - Richard Sparla
- Department of Gastroenterology, University Hospital Heidelberg, INF 345, Heidelberg 69120, Germany, the
| | - Mark Kühnel
- Cell Biology Program, European Molecular Biology Laboratory, Postfach 102209, Heidelberg 69117, Germany, the
| | - Thomas Giese
- Institute of Immunology, University of Heidelberg, Im Neuenheimer Feld 305, Heidelberg 69120, Germany, the
| | - Jerrold R Turner
- Department of Pathology, University of Chicago, MC-1089, 60637 Chicago, Illinois
| | - Elsa Anes
- Unidade dos Retrovirus e Infeccdoas Associades(URIA)-Molecular Pathogenesis Centre, Faculty of Pharmacy, University of Lisbon, av. das Forcas Armadas, Lisbon 1600-083, Portugal, and the
| | - Hasan Kulaksiz
- Department of Gastroenterology, University Hospital Heidelberg, INF 345, Heidelberg 69120, Germany, the
| | - Joachim Füllekrug
- Department of Gastroenterology, University Hospital Heidelberg, INF 345, Heidelberg 69120, Germany, the
| | - Wolfgang Stremmel
- Department of Gastroenterology, University Hospital Heidelberg, INF 345, Heidelberg 69120, Germany, the
| | - Gareth Griffiths
- Cell Biology Program, European Molecular Biology Laboratory, Postfach 102209, Heidelberg 69117, Germany, the
| | - Robert Ehehalt
- Department of Gastroenterology, University Hospital Heidelberg, INF 345, Heidelberg 69120, Germany, the.
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Bjarnason I, Scarpignato C, Takeuchi K, Rainsford KD. Determinants of the short-term gastric damage caused by NSAIDs in man. Aliment Pharmacol Ther 2007; 26:95-106. [PMID: 17555426 DOI: 10.1111/j.1365-2036.2007.03348.x] [Citation(s) in RCA: 48] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
BACKGROUND The short-term gastric damage seen with non-steroidal anti-inflammatory drugs (NSAIDs) in man may involve inhibition of cyclooxygenase (COX-1) and COX-2 as well as the topical irritancy, which is dependant on the acidity (pKa) and/or lipophilicity (log P(7.4)). AIM To study the quantitative relationship between NSAID-induced short-term gastric damage, their physicochemical properties and contrasting roles of COX-1 and COX-2 inhibition. METHODS We identified studies that allowed a qualitative comparison of the gastric injury (Lanza scores) induced by NSAIDs with their pKa and log P(7.4). Damage was correlated with gastric COX inhibition and potency to inhibit COX-1 and 2 and their COX-2/COX-1 selectivity ratio. RESULTS The gastric damage correlates significantly with pKa (r = -0.69; P < 0.01), log P (r = -0.58, P < 0.05) and potency of the NSAIDs to inhibit COX-1 (r = -0.61, P < 0.02), but not with COX-2 inhibition or COX-2/COX-1 selectivity. CONCLUSION Against a background of COX-1 and COX-2 inhibition, the physicochemical properties of NSAID appear to play an important role in short-term gastric damage.
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Affiliation(s)
- I Bjarnason
- Department of Medicine, Guy's, King's, St Thomas' Medical School, London, UK.
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Petruzzelli M, Vacca M, Moschetta A, Cinzia Sasso R, Palasciano G, van Erpecum KJ, Portincasa P. Intestinal mucosal damage caused by non-steroidal anti-inflammatory drugs: role of bile salts. Clin Biochem 2007; 40:503-510. [PMID: 17321514 DOI: 10.1016/j.clinbiochem.2007.01.015] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2006] [Revised: 12/22/2006] [Accepted: 01/15/2007] [Indexed: 12/18/2022]
Abstract
The strong analgesic, anti-inflammatory effects of non-steroidal anti-inflammatory drugs (NSAIDs) are hampered by high occurrence of gastrointestinal side effects. Therapeutic actions of NSAIDs result from cyclooxygenase (COX) enzymes inhibition with reduced synthesis of prostaglandins, major modulators of inflammation. Since prostaglandins also regulate key events in gut homeostasis -mucosal secretion, blood flow, epithelial regeneration - COX inhibition has been accepted as the reason for NSAID gastrointestinal toxicity. Several findings challenge this theory: first, intestinal damage by NSAIDs occurs also in COX-1 knockout mice, demonstrating that topical (non-prostaglandin mediated) mechanisms are involved; second, no correlation is found in vivo between the extent of intestinal injury and the degree of inhibition of prostaglandin synthesis; third, bile flow interruption in animal models completely prevents intestinal damage by parenterally administered NSAIDs. What is in bile that could play a role in NSAID toxicity? This timely review will critically discuss the role of bile salts in NSAID-dependent gut damage.
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Affiliation(s)
- Michele Petruzzelli
- Clinica Medica A. Murri, Department of Internal Medicine and Public Medicine (DIMIMP), University Medical School of Bari, Italy
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Tariq M, Elfaki I, Khan HA, Arshaduddin M, Sobki S, Al Moutaery M. Bromophenacyl bromide, a phospholipase A2 inhibitor attenuates chemically induced gastroduodenal ulcers in rats. World J Gastroenterol 2006; 12:5798-5804. [PMID: 17007045 PMCID: PMC4100660 DOI: 10.3748/wjg.v12.i36.5798] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2006] [Revised: 08/05/2006] [Accepted: 08/15/2006] [Indexed: 02/06/2023] Open
Abstract
AIM To study the effect of bromophenacyl bromide (BPB), a phospholipase A2 inhibitor on gastric secretion and to protect chemically induced gastric and duodenal ulcers in rats. METHODS Acid secretion studies were undertaken in pylorus-ligated rats with BPB treatment (0, 5, 15 and 45 mg/kg). Gastric and duodenal lesions in the rats were induced by ethanol and cysteamine respectively. The levels of gastric wall mucus, nonprotein sulfhydryls (NP-SH) and myeloperoxidase (MPO) were also measured in the glandular stomach of rats following ethanol induced gastric lesions. RESULTS BPB produced a dose-dependent inhibition of gastric acid secretion and acidity in rats. Pretreatment with BPB significantly attenuated the formation of ethanol induced gastric lesion. BPB also protected intestinal mucosa against cysteamine-induced duodenal ulcers. The antiulcer activity of BPB was associated with significant inhibition of ethanol-induced depletion of gastric wall mucus, NP-SH and MPO. These findings pointed towards the mediation of sulfhydryls in BPB induced gastrointestinal cytoprotection. CONCLUSION BPB possesses significant antiulcer and cytoprotective activity against experimentally induced gastroduodenal lesions.
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Affiliation(s)
- Mohammad Tariq
- Frcpath, Frsc Senior Consultant and Director of Research, Armed Forces Hospital, Po Box 7897 (W-912), Riyadh 11159, Kingdom of Saudi Arabia.
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