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1.
J Mol Med (Berl) ; 102(7): 927-945, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38758435

ABSTRACT

The development and progression of hyperglycemia (HG) and HG-associated atherosclerosis are exacerbated by mitochondrial dysfunction due to dysregulated mitochondria-derived ROS generation. We recently synthesized a novel mitochondria-targeted esculetin (Mito-Esc) and tested its dose-response therapeutic efficacy in mitigating HG-induced atherosclerosis in db/db mice. In comparison to simvastatin and pioglitazone, Mito-Esc administration resulted in a considerable reduction in body weights and improved glucose homeostasis, possibly by reducing hepatic gluconeogenesis, as indicated by a reduction in glycogen content, non-esterified free fatty acids (NEFA) levels, and fructose 1,6-bisphosphatase (FBPase) activity. Interestingly, Mito-Esc treatment, by regulating phospho-IRS and phospho-AKT levels, greatly improved palmitate-induced insulin resistance, resulting in enhanced glucose uptake in adipocytes and HepG2 cells. Also, and importantly, Mito-Esc administration prevented HG-induced atheromatous plaque formation and lipid accumulation in the descending aorta. In addition, Mito-Esc administration inhibited the HG-mediated increase in VACM, ICAM, and MAC3 levels in the aortic tissue, as well as reduced the serum pro-inflammatory cytokines and markers of senescence. In line with this, Mito-Esc significantly inhibited monocyte adherence to human aortic endothelial cells (HAECs) treated with high glucose and reduced high glucose-induced premature senescence in HAECs by activating the AMPK-SIRT1 pathway. In contrast, Mito-Esc failed to regulate high glucose-induced endothelial cell senescence under AMPK/SIRT1-depleted conditions. Together, the therapeutic efficacy of Mito-Esc in the mitigation of hyperglycemia-induced insulin resistance and the associated atherosclerosis is in part mediated by potentiating the AMPK-SIRT1 axis. KEY MESSAGES: Mito-Esc administration significantly mitigates diabetes-induced atherosclerosis. Mito-Esc improves hyperglycemia (HG)-associated insulin resistance. Mito-Esc inhibits HG-induced vascular senescence and inflammation in the aorta. Mito-Esc-mediated activation of the AMPK-SIRT1 axis regulates HG-induced endothelial cell senescence.


Subject(s)
Atherosclerosis , Hyperglycemia , Insulin Resistance , Mitochondria , Umbelliferones , Animals , Hyperglycemia/drug therapy , Atherosclerosis/drug therapy , Atherosclerosis/metabolism , Atherosclerosis/etiology , Umbelliferones/pharmacology , Umbelliferones/therapeutic use , Humans , Mice , Mitochondria/metabolism , Mitochondria/drug effects , Male , Hep G2 Cells , Sirtuin 1/metabolism , Disease Models, Animal , Mice, Inbred C57BL , Glucose/metabolism
2.
Mech Ageing Dev ; 219: 111931, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38554949

ABSTRACT

Impaired mitochondrial fatty acid ß-oxidation (FAO) plays a role in the onset of several age-associated diseases, including atherosclerosis. In the current work, we investigated the efficacies of mitochondria-targeted esculetin (Mito-Esc) and metformin in enhancing FAO in human aortic endothelial cells (HAECs), and its relevance in the delay of cellular senescence and age-associated atherosclerotic plaque formation in Apoe-/- mice. Chronic culturing of HAECs with either Mito-Esc or metformin increased oxygen consumption rates (OCR), and caused delay in senescence features. Conversely, etomoxir (CPT1 inhibitor) reversed Mito-Esc- and metformin-induced OCR, and caused premature endothelial senescence. Interestingly, Mito-Esc, unlike metformin, in the presence of etomoxir failed to preserve OCR. Thereby, underscoring Mito-Esc's exclusive reliance on FAO as an energy source. Mechanistically, chronic culturing of HAECs with either Mito-Esc or metformin led to AMPK activation, increased CPT1 activity, and acetyl-CoA levels along with a concomitant reduction in malonyl-CoA levels, and lipid accumulation. Similar results were observed in Apoe-/- mice aorta and liver tissue with a parallel reduction in age-associated atherosclerotic plaque formation and degeneration of liver with either Mito-Esc or metformin administration. Together, Mito-Esc and metformin by potentiating FAO, may have a role in the delay of cellular senescence by modulating mitochondrial function.


Subject(s)
Atherosclerosis , Cellular Senescence , Endothelial Cells , Fatty Acids , Metformin , Mitochondria , Oxidation-Reduction , Umbelliferones , Animals , Metformin/pharmacology , Umbelliferones/pharmacology , Cellular Senescence/drug effects , Mice , Oxidation-Reduction/drug effects , Mitochondria/metabolism , Mitochondria/drug effects , Humans , Atherosclerosis/metabolism , Atherosclerosis/drug therapy , Atherosclerosis/pathology , Fatty Acids/metabolism , Endothelial Cells/metabolism , Endothelial Cells/drug effects , Aging/metabolism , Aging/drug effects
3.
Geroscience ; 46(2): 2391-2408, 2024 Apr.
Article in English | MEDLINE | ID: mdl-37968424

ABSTRACT

Atherosclerosis, in general, is an age-associated cardiovascular disease wherein a progressive decline in mitochondrial function due to aging majorly contributes to the disease development. Mitochondria-derived ROS due to dysregulated endothelial cell function accentuates the progression of atherosclerotic plaque formation. To circumvent this, mitochondrially targeted antioxidants are emerging as potential candidates to combat metabolic abnormalities. Recently, we synthesized an alkyl TPP+ tagged esculetin (Mito-Esc), and in the current study, we investigated the therapeutic efficacies of Mito-Esc and metformin, a well-known anti-diabetic drug, in the amelioration of age-associated plaque formation in the aortas of 12 months aged Apoe-/- and 20 months aged C57BL/6 mice, in comparison to young C57BL/6 control mice. Administration of Mito-Esc or metformin significantly reduced age-induced atherosclerotic lesion area, macrophage polarization, vascular inflammation, and senescence. Further, chronic passaging of human aortic endothelial cells (HAEC) with either Mito-Esc or metformin significantly delayed cellular senescence via the activation of the AMPK-SIRT1/SIRT6 axis. Conversely, depletion of either AMPK/SIRT1/SIRT6 caused premature senescence. Consistent with this, Mito-Esc or metformin treatment attenuated NFkB-mediated inflammatory signaling and enhanced ARE-mediated anti-oxidant responses in comparison to late passage control HAECs. Importantly, culturing of HAECs for several passages with either Mito-Esc or metformin significantly improved mitochondrial function. Overall, Mito-Esc and metformin treatments delay age-associated atherosclerosis by regulating vascular senescence via the activation of AMPK-SIRT1/SIRT6 axis.


Subject(s)
Atherosclerosis , Metformin , Sirtuins , Umbelliferones , Mice , Animals , Humans , Aged , Metformin/pharmacology , Metformin/therapeutic use , AMP-Activated Protein Kinases/metabolism , Sirtuin 1 , Endothelial Cells/pathology , Mice, Inbred C57BL , Atherosclerosis/drug therapy , Atherosclerosis/metabolism , Mitochondria/metabolism , Antioxidants/pharmacology , Sirtuins/metabolism , Sirtuins/therapeutic use
5.
Int Immunopharmacol ; 124(Pt B): 111070, 2023 Nov.
Article in English | MEDLINE | ID: mdl-37862737

ABSTRACT

Mitochondrial dysfunction due to deregulated production of mitochondria-derived ROS is implicated in the development and progression of non-alcoholic fatty liver disease (NAFLD) to non-alcoholic steatohepatitis (NASH). Recently, we synthesized a novel mitochondria-targeted esculetin (Mito-Esc) and investigated its dose-response therapeutic efficacy in mitigating high-fat diet (HFD)-induced NAFLD and NASH in Apoe-/- mice. Mito-Esc administration, compared to simvastatin and pioglitazone, dose-dependently caused a significant reduction in body weight, improved lipid profile, glucose homeostasis, and pro-inflammatory cytokines level. Mito-Esc administration reduced adipose tissue hypertrophy and lipid accumulation presumably by regulating the levels of CD36, PPAR-γ, EBP-α, and their target genes. Mechanistically, Mito-Esc-induced activation of the AMPK1α-SIRT1 axis inhibited pre-adipocyte differentiation. Conversely, Mito-Esc failed to regulate pre-adipocyte differentiation under AMPK/SIRT1 depleted conditions. In parallel, Mito-Esc administration ameliorated HFD-induced steatosis, fibrosis of the liver, and NAFLD-associated atheromatous plaque formation in the aorta. Importantly, Mito-Esc administration inhibited HFD-induced infiltration of macrophages, a marker of steatohepatitis, in the adipose and liver tissues. The results of the in vitro studies showed that Mito-Esc treatment significantly inhibits TGF-ß-induced hepatic stellate cell differentiation as well as the fibrotic markers. Consistent with the above observations, Mito-Esc treatment by activating the AMPK-SIRT1 pathway markedly reversed palmitate-induced mitochondrial superoxide production, depolarization of mitochondrial membrane potential, and lipid accumulation in HepG2 cells. Together, the therapeutic efficacy of Mito-Esc in the mitigation of HFD-induced lipotoxicity, and the associated NASH is in part, mediated by potentiating the AMPK-SIRT1 axis.


Subject(s)
Non-alcoholic Fatty Liver Disease , Animals , Mice , Non-alcoholic Fatty Liver Disease/drug therapy , Non-alcoholic Fatty Liver Disease/metabolism , AMP-Activated Protein Kinases/metabolism , Sirtuin 1/metabolism , Signal Transduction/physiology , Liver/pathology , Mitochondria/metabolism , Fibrosis , Lipids/therapeutic use , Diet, High-Fat , Mice, Inbred C57BL
6.
Atherosclerosis ; 356: 28-40, 2022 09.
Article in English | MEDLINE | ID: mdl-35961209

ABSTRACT

BACKGROUND AND AIMS: Age is a dominant and independent risk factor for the development of atherosclerosis, a major cardiovascular disease, and if left untreated leads to myocardial infarction and death. Mitochondria-targeted anti-oxidants are evolving as a new class of compounds that can alter the pathophysiology of age-related diseases, including atherosclerosis, where mitochondrial dysfunction plays a critical role in disease progression. METHODS: We recently synthesized an alkyl TPP + -tagged esculetin (mitochondria-targeted esculetin or Mito-Esc). Apoe-/- mice were chronically (14 months) administered with Mito-Esc to investigate its efficacy in the mitigation of atherosclerosis in the setting of aging. We monitored BP, and performed various biochemical assays, histopathology, immunohistochemistry, inflammatory factors, qPCR, and Western blotting. Simultaneously, human aortic endothelial cells (HAECs) were used as a model system to study the mechanistic aspects. RESULTS: A chronic low-dose administration of Mito-Esc to Apoe-/- mice greatly prevented alterations in lipid profile, blood pressure, and atherosclerotic plaque formation in the setting of aging. Mito-Esc administration significantly reduced vascular senescence and pro-inflammatory cytokines levels and prevented dysregulation of mitochondrial biogenesis markers in aortic tissue. Further, Mito-Esc treatment prevented replicative and stress-induced premature senescence (SIPS) in HAEC. Importantly, Mito-Esc treatment delayed endothelial cell senescence by increasing human telomerase reverse transcriptase (hTERT) levels via SIRT1 activation. Moreover, Mito-Esc treatment by altering miR-19b and miR-30c via a SIRT1 activation significantly inhibited the increase in PAI-1 levels in HAEC as well as in the serum of Apoe-/- mice. In addition, Mito-Esc treatment improved mitochondrial function in late passage (aged) HAECs by enhancing the oxygen consumption rate (OCR). Furthermore, Mito-Esc administration counteracted the decline in GSH and nitrite levels in Apoe-/- mice and in HAECs. CONCLUSIONS: Overall, Mito-Esc alleviates atherosclerosis in the setting of aging by delaying vascular senescence and pro-inflammatory processes, and by improving mitochondrial biogenesis and function.


Subject(s)
Atherosclerosis , MicroRNAs , Aged , Aging , Animals , Apolipoproteins E/genetics , Apolipoproteins E/metabolism , Atherosclerosis/drug therapy , Atherosclerosis/genetics , Atherosclerosis/prevention & control , Cellular Senescence , Endothelial Cells/metabolism , Humans , Mice , MicroRNAs/metabolism , Mitochondria/metabolism , Sirtuin 1/metabolism , Umbelliferones
7.
Diabetes Obes Metab ; 24(11): 2090-2101, 2022 11.
Article in English | MEDLINE | ID: mdl-35676825

ABSTRACT

AIMS: To describe the in vitro characteristics and antidiabetic in vivo efficacy of the novel glucagon-like peptide-1 receptor agonist (GLP-1RA) GL0034. MATERIALS AND METHODS: Glucagon-like peptide-1 receptor (GLP-1R) kinetic binding parameters, cyclic adenosine monophosphate (cAMP) signalling, endocytosis and recycling were measured using HEK293 and INS-1832/3 cells expressing human GLP-1R. Insulin secretion was measured in vitro using INS-1832/3 cells, mouse islets and human islets. Chronic administration studies to evaluate weight loss and glycaemic effects were performed in db/db and diet-induced obese mice. RESULTS: Compared to the leading GLP-1RA semaglutide, GL0034 showed increased binding affinity and potency-driven bias in favour of cAMP over GLP-1R endocytosis and ß-arrestin-2 recruitment. Insulin secretory responses were similar for both ligands. GL0034 (6 nmol/kg) led to at least as much weight loss and lowering of blood glucose as did semaglutide at a higher dose (14 nmol/kg). CONCLUSIONS: GL0034 is a G protein-biased agonist that shows powerful antidiabetic effects in mice, and may serve as a promising new GLP-1RA for obese patients with type 2 diabetes.


Subject(s)
Diabetes Mellitus, Type 2 , Insulins , Adenosine Monophosphate , Animals , Blood Glucose , Cyclic AMP/metabolism , Diabetes Mellitus, Type 2/drug therapy , Glucagon-Like Peptide-1 Receptor/agonists , HEK293 Cells , Humans , Hypoglycemic Agents/pharmacology , Hypoglycemic Agents/therapeutic use , Ligands , Mice , Weight Loss , beta-Arrestins/metabolism
8.
Chem Commun (Camb) ; 57(92): 12329-12332, 2021 Nov 19.
Article in English | MEDLINE | ID: mdl-34740232

ABSTRACT

Herein, we document a self-assembling octyl-TPP tagged esculetin (Mito-Esc) as functionally active and as a novel small molecule siRNA delivery vector. While Mito-Esc itself induces selective breast cancer cell death, the amphiphilic nature of Mito-Esc delivers therapeutic siRNAs intracellularly without the need for any excipient to exacerbate the anti-proliferative effects.


Subject(s)
Mitochondria , RNA, Small Interfering , Cell Line, Tumor , Humans , Mitochondria/metabolism , RNA, Double-Stranded , Umbelliferones
9.
Biologics ; 12: 23-35, 2018.
Article in English | MEDLINE | ID: mdl-29430170

ABSTRACT

INTRODUCTION: Regulatory agencies recommend a stepwise approach for demonstrating biosimilarity between a proposed biosimilar and reference biological product emphasizing for functional and structural characterization to trace if there is any difference which may impact safety and efficacy. We studied the comparative structural and biological attributes of recombinant human chorionic gonadotropin (rhCG), SB005, with reference product, Ovidrel® and Ovitrelle®. Recombiant hCG was approved in 2000 by the US Food and Drug Administration for the induction of final follicular maturation, early luteinization in infertile women as part of assisted reproductive technology program. It is also indicated for the induction of ovulation and pregnancy in ovulatory infertile patients whose cause of infertility is not due to ovarian failure. MATERIALS AND METHODS: Primary structure was studied by intact mass analysis, peptide fingerprinting, peptide mass fingerprinting and sequence coverage analysis. Higher order structure was studied by circular dichroism, ultraviolet-visible spectroscopy, fluorescence spectroscopy, and disulfide bridge analysis. Different isoforms of reference product and SB005 were identified using capillary isoelectric focusing and capillary zone electrophoresis. Glycosylation was studied by N-glycan mapping using LC-ESI-MS, point of glycosylation, released glycan analysis using ultra performance liquid chromatography and sialic acid analysis. Product related impurities such as oligomer content analysis and oxidized impurities were studied using size exclusion chromatography and reverse phase high performance liquid chromatography, respectively. Biological activity in term of potency of reference product and SB005 was studied by in vivo analysis. RESULTS AND CONCLUSION: In this study we have compared analytical similarity of recombinant rhCG (SB005) produced at Sun Pharmaceuticals with the reference product with respect to its primary, higher order structure, isoforms, charge variants, glycosylation, sialyation pattern, pharmacodynamic and in vivo efficacy. Our studies show that the in house produced rhCG has a high degree of structural and functional similarity with the reference product available in the market.

10.
BMC Cancer ; 17(1): 405, 2017 Jun 06.
Article in English | MEDLINE | ID: mdl-28587612

ABSTRACT

BACKGROUND: Doxorubicin (DXR) hydrochloride (HCl) liposome injection is an important part of the treatment armamentarium for a number of cancers. With growing needs for affordable and effective anticancer treatments, the development of generics is becoming increasingly important to facilitate patient access to vital medications. We conducted studies in relevant mouse models of cancer to compare the preclinical antitumour efficacy and plasma pharmacokinetic profile of a proposed generic DXR HCl liposome injection developed by Sun Pharmaceutical Industries Ltd. (SPIL DXR HCl liposome injection) with Caelyx® (reference DXR HCl liposome injection). METHODS: Syngeneic fibrosarcoma (WEHI 164)-bearing BALB/c mice and athymic nude mice transplanted with MX-1 human mammary carcinoma xenografts were treated with SPIL DXR HCl liposome injection, reference DXR HCl liposome injection or placebo, to compare tumour volume, antitumour activity (percentage test/control [%T/C] ratio, tumour regression, and specific tumour growth delay) and toxicity (survival and weight changes) in response to treatment. The pharmacokinetic profile of the SPIL and reference product was also studied in syngeneic fibrosarcoma-bearing mice. RESULTS: Treatment with either SPIL or reference DXR HCl liposome injection resulted in significant reduction in tumour volume from baseline in both models at all doses tested. High antitumour activity (%T/C ≤ 10) was seen from Day 21 and Day 14 onwards in SPIL and reference DXR HCl liposome injection-treated syngeneic fibrosarcoma-bearing mice, respectively, at 9 mg/kg. Moderate antitumour activity (%T/C ≤ 20) was seen from Day 17 and Day 24 onwards in SPIL and reference DXR HCl liposome injection-treated MX-1-bearing mice, respectively, at 6 mg/kg. No significant differences in tumour volume and %T/C were observed between SPIL and reference DXR HCl liposome injection-treated groups at any dose (p ≥ 0.05). Toxicity profiles were considered to be generally comparable. Evaluation of test/reference (A/B) ratios and 90% confidence intervals (CIs) for peak serum concentration (Cmax) and area under the curve (AUC0-t, and AUC0-∞) demonstrated bioequivalence of SPIL and reference DXR HCl liposome injections. CONCLUSIONS: Establishing similarity is of critical importance during the development of generic treatments. SPIL and reference DXR HCl liposome injections were shown to be comparable with regards to antitumour activity, toxicity and pharmacokinetics.


Subject(s)
Breast Neoplasms/drug therapy , Doxorubicin/analogs & derivatives , Fibrosarcoma/drug therapy , Animals , Antibiotics, Antineoplastic/pharmacokinetics , Antibiotics, Antineoplastic/therapeutic use , Cell Line, Tumor , Disease Models, Animal , Doxorubicin/pharmacokinetics , Doxorubicin/therapeutic use , Female , Humans , Male , Mice , Mice, Nude , Polyethylene Glycols/pharmacokinetics , Polyethylene Glycols/therapeutic use , Therapeutic Equivalency , Treatment Outcome , Tumor Burden , Xenograft Model Antitumor Assays
11.
Clin Pharmacol Drug Dev ; 3(6): 428-38, 2014 11.
Article in English | MEDLINE | ID: mdl-27129118

ABSTRACT

A novel corticosteroid compound (short form of IUPAC name: SFDAC) has been discovered by Sun Pharma Advanced Research Company (SPARC) Ltd. A randomized, observer-blind, active-controlled, parallel-groups, intranasal multiple escalating dose study was conducted in healthy male subjects to assess safety, tolerability, pharmacokinetics, and pharmacodynamics of compound SFDAC formulated as an aqueous suspension for intranasal administration. Intranasal sprays of SFDAC, active control fluticasone propionate (FP) and placebo were administered once in a day for 14 days as per randomization. Various clinical evaluations including 24-hour serum cortisol and urinary free cortisol (UFC) profiles were carried out. Blood samples were collected at pre-defined time-points and analyzed using a validated chromatographic method for estimation of SFDAC and its metabolite. The results of the study indicate that multiple dose of SFDAC intranasal spray upto 3,200 µg is safe and tolerated. Clinically significant suppression of hypothalamic pituitary adrenal (HPA) axis was not observed. The plasma concentration of SFDAC was found to be below the lower limit of quantification (LLQ) at most time-points for all subjects. SFDAC M1 metabolite was detected only at picogram level in plasma. The safety and pharmacokinetic characteristics of SFDAC observed in this study support further clinical development of the SFDAC nasal spray.


Subject(s)
Adrenal Cortex Hormones/administration & dosage , Adrenal Cortex Hormones/pharmacokinetics , Hydroxytestosterones/administration & dosage , Hydroxytestosterones/pharmacokinetics , Administration, Intranasal , Adrenal Cortex Hormones/adverse effects , Adrenal Cortex Hormones/blood , Aerosols , Area Under Curve , Biomarkers/blood , Biomarkers/urine , Biotransformation , Cross-Over Studies , Half-Life , Healthy Volunteers , Humans , Hydrocortisone/blood , Hydrocortisone/urine , Hydroxytestosterones/adverse effects , Hydroxytestosterones/blood , Male , Metabolic Clearance Rate
12.
Eur J Med Chem ; 46(11): 5549-55, 2011 Nov.
Article in English | MEDLINE | ID: mdl-21963348

ABSTRACT

Central heteroaryl ring analogues belonging to a series of potent hydroxamate TACE inhibitors were synthesized. The TACE inhibitory activities of these compounds were evaluated by in vitro WBA and in silico molecular modeling studies using crystal structure of human TACE. Compound 14 showed very good in vitro inhibition, supported by the in silico docking studies.


Subject(s)
ADAM Proteins/antagonists & inhibitors , Chemistry Techniques, Synthetic , Hydroxamic Acids/chemical synthesis , Hydroxamic Acids/pharmacology , Models, Molecular , Protease Inhibitors/chemical synthesis , Protease Inhibitors/pharmacology , ADAM Proteins/chemistry , ADAM Proteins/metabolism , ADAM17 Protein , Drug Discovery , Humans , Hydroxamic Acids/chemistry , Protease Inhibitors/chemistry , Protein Conformation , Tumor Necrosis Factor-alpha/antagonists & inhibitors
13.
Int Immunopharmacol ; 11(11): 1646-62, 2011 Nov.
Article in English | MEDLINE | ID: mdl-21784174

ABSTRACT

Allergic rhinitis (AR) is an inflammation of nasal mucosa mediated by IgE-associated processes occurring independently, or concurrently with asthma. AR is characterized by sensitization-formation and expression of antigen specific IgE, followed by inflammation in two phases. The early phase response involves cross linking of IgE molecules leading to degranulation of mast cells and release of preformed mediators such as histamine and tryptase, or newly synthesized mediators such as prostaglandins and leukotrienes. The late phase response is predominated by the presence of eosinophils, lymphocytes, cytokines, and adhesion molecules. Newer insights reveal that the whole phenomenon of immunological inflammation is intricately knit with neural pathways, which strongly influence the process. Furthermore, AR can impact psychological health and vice versa. Classical pharmacotherapy of AR includes use of oral or topical antihistamines, oral antileukotrienes, topical corticosteroids, mast cell stabilizers, decongestants, and an anticholinergic agent. Among immunomodulatory treatments, immunotherapy is gaining widespread use, while antibody treatment is restricted mainly to resistant cases. Several small molecules with improved safety profile, or targeting novel mechanisms are in the clinical research. Newer antihistamines and corticosteroids with improved safety profile and antagonists of the prostaglandin D(2) (CRTH2) receptors are likely to be available for clinical use in the near future. Lack of properly validated animal models and complexities associated with clinical evaluation are some of the challenges facing the researchers in AR. Comprehensive understanding of immunological and neurological processes in AR would facilitate the future quest for more effective and safer management of this disease.


Subject(s)
Immunotherapy , Rhinitis, Allergic, Perennial/therapy , Rhinitis, Allergic, Seasonal/therapy , Adrenal Cortex Hormones/administration & dosage , Adrenal Cortex Hormones/therapeutic use , Asthma/complications , Asthma/epidemiology , Histamine Antagonists/administration & dosage , Histamine Antagonists/therapeutic use , Humans , Immunotherapy/methods , Immunotherapy/trends , Leukotriene Antagonists/administration & dosage , Leukotriene Antagonists/therapeutic use , Rhinitis, Allergic, Perennial/complications , Rhinitis, Allergic, Perennial/epidemiology , Rhinitis, Allergic, Perennial/immunology , Rhinitis, Allergic, Seasonal/complications , Rhinitis, Allergic, Seasonal/epidemiology , Rhinitis, Allergic, Seasonal/immunology
14.
Int Immunopharmacol ; 8(11): 1540-51, 2008 Nov.
Article in English | MEDLINE | ID: mdl-18627797

ABSTRACT

Ovalbumin-induced guinea pig model of rhinitis was assessed for its utility in the studies of rhinitis. Systemic sensitization and challenge with ovalbumin-induced rhinitis symptoms and an increase in anti-OVA-IgE and IgG titers, positive skin reactions and nasal lavage IL-4 concentration. Histopathology of nasal mucosa showed infiltration of eosinophils and other inflammatory cells consistent with the symptoms. Topical sensitization of ovalbumin yielded inconsistent symptoms of rhinitis. In systemic sensitization model, repeated challenge of ovalbumin caused similar response for at least 3 consecutive challenges. The symptoms were affected by relative humidity in the air and dosing volume of topical drugs. Sneezing and lacrimation were reduced by acute oral administration of the H1 receptor antagonists and steroids or the prophylactic oral administration of cysteinyl leukotriene (CysLT1) receptor antagonist montelukast or acute topical antihistamines, mast cell stabilizer sodium cromoglycate and anticholinergic agent ipratropium bromide, but not by a topical steroid. Nose rubbing was reduced significantly by some oral and topical antihistamines. Oral steroids offered excellent protection against all symptoms. Dexamethasone and montelukast also inhibited nasal lavage IL-4 concentration and inflammatory cell infiltration. Treatment with topical steroid fluticasone for 2 weeks had no effect on sneezing or rubbing. However, it caused complete inhibition of congestion. The cyclooxygenase inhibitor indomethacin had no effect on symptoms of rhinitis. The adrenergic alpha receptor agonist-decongestant oxymetazoline caused reduction in congestion. These results suggest that differential responsiveness to symptoms of rhinitis by a new agent can be very well profiled in the model in congruence with the mediation pathways and mechanism of action of drugs. The model provides complete symptomatic characterization of rhinitis and is a good tool for its study.


Subject(s)
Anti-Allergic Agents/administration & dosage , Disease Models, Animal , Guinea Pigs , Rhinitis, Allergic, Perennial , Administration, Oral , Administration, Topical , Animals , Female , Humidity , Immunoglobulin E/blood , Immunoglobulin G/analysis , Interleukin-4/analysis , Male , Ovalbumin/pharmacology , Passive Cutaneous Anaphylaxis/immunology , Rhinitis, Allergic, Perennial/drug therapy , Rhinitis, Allergic, Perennial/immunology , Rhinitis, Allergic, Perennial/pathology , Sneezing/drug effects , Sneezing/immunology
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