ABSTRACT
Rheumatoid arthritis (RA) and its animal model adjuvant arthritis (AA) are inflammatory diseases characterized by chronic inflammation, systemic oxidative stress and disturbed mitochondrial bioenergetics of skeletal muscle. The present study aimed to evaluate the effects of coenzyme Q10 - CoQ10 (100 mg/kg b.w.), omega-3-polyunsaturated fatty acids - omega-3-PUFA (400 mg/kg b.w.) and their combined treatment in AA on impaired skeletal muscle mitochondrial bioenergetics, inflammation and changes in levels CoQ9 and CoQ10 in plasma. Markers of inflammation (C-reactive protein, monocyte-chemotactic protein-1), antioxidant capacity of plasma, respiratory chain parameters of skeletal muscle mitochondria and concentrations of CoQ9 and CoQ10 in plasma and in muscle tissue were estimated. Treatment of the arthritic rats with CoQ10, omega-3-PUFA alone and in combination partially reduced markers of inflammation and increased antioxidant capacity of plasma, significantly increased concentrations of coenzyme Q in mitochondria and improved mitochondrial function in the skeletal muscle. Combined treatment has similar effect on the mitochondrial function as monotherapies; however, it has affected inflammation and antioxidant status more intensively than monotherapies. Long-term supplementary administration of coenzyme Q10 and omega-3-PUFA and especially their combination is able to restore the impaired mitochondrial bioenergetics and antioxidant status in AA.
Subject(s)
Arthritis, Experimental/diet therapy , Arthritis, Rheumatoid/diet therapy , Fatty Acids, Omega-3/therapeutic use , Mitochondria, Muscle/metabolism , Ubiquinone/analogs & derivatives , Animals , Antioxidants/metabolism , Arthritis, Experimental/blood , Arthritis, Rheumatoid/blood , C-Reactive Protein/metabolism , Chemokine CCL2/blood , Dietary Supplements , Male , Rats, Inbred Lew , Ubiquinone/metabolism , Ubiquinone/therapeutic useABSTRACT
In this study, two extracts from Fatsia japonica-Fatsiphloginum™ (extract of triterpene glycosides containing 45-50 % of fatsiosides (FS)) and purified triterpene-rich extract of saponins with code name PS-551 (PS) were administered in combination with methotrexate (MTX) and in monotherapy to rats suffering adjuvant arthritis (AA). The anti-inflammatory activities of extracts were evaluated as monotherapies in comparison with untreated AA. PS administered in higher dose showed on day 28 effective decrease of hind paw volume (HPV), decreased activity of gamma-glutamyl transferase (GGT) in joints, and also interleukin-17A was decreased significantly on day 14. The higher dose of PS was more effective than both doses of FS. Further, we evaluated the higher doses of PS and FS in combination with MTX. PS improved the effect of MTX in combination more effective than FS (HPV, body weight and activity of GGT in joint). However, FS was more effective in reducing the level of IL-17A on day 14 and activity of GGT in spleen than PS. In conclusion, our study showed that generally FS has higher anti-arthritic activity comparing to PS. Thus, the novel combination of Fatsiphloginum™ and methotrexate could be interesting for future clinical studies in patients suffering auto-immune diseases.
Subject(s)
Araliaceae/chemistry , Arthritis, Experimental/drug therapy , Plant Extracts/therapeutic use , Saponins/administration & dosage , Triterpenes/administration & dosage , Animals , Anti-Inflammatory Agents/administration & dosage , Interleukin-17/blood , Male , Methotrexate/administration & dosage , Rats , Rats, Inbred Lew , gamma-Glutamyltransferase/metabolismABSTRACT
Carnosine's (CARN) anti-inflammatory potential in autoimmune diseases has been but scarcely investigated as yet. The aim of this study was to evaluate the therapeutic potential of CARN in rat adjuvant arthritis, in the model of carrageenan induced hind paw edema (CARA), and also in primary culture of chondrocytes under H2O2 injury. The experiments were done on healthy animals, arthritic animals, and arthritic animals with oral administration of CARN in a daily dose of 150 mg/kg b.w. during 28 days as well as animals with CARA treated by a single administration of CARN in the same dose. CARN beneficially affected hind paw volume and changes in body weight on day 14 and reduced hind paw swelling in CARA. Markers of oxidative stress in plasma and brain (malondialdehyde, 4-hydroxynonenal, protein carbonyls, and lag time of lipid peroxidation) and also activity of gamma-glutamyltransferase were significantly corrected by CARN. CARN also reduced IL-1alpha in plasma. Suppression of intracellular oxidant levels was also observed in chondrocytes pretreated with CARN. Our results obtained on two animal models showed that CARN has systemic anti-inflammatory activity and protected rat brain and chondrocytes from oxidative stress. This finding suggests that CARN might be beneficial for treatment of arthritic diseases.
Subject(s)
Arthritis, Experimental/pathology , Carnosine/therapeutic use , Chondrocytes/pathology , Adjuvants, Immunologic , Aldehydes/metabolism , Animals , Arthritis, Experimental/blood , Arthritis, Experimental/drug therapy , Body Weight/drug effects , Carnosine/pharmacology , Carrageenan , Cell Survival/drug effects , Cells, Cultured , Chondrocytes/drug effects , Chondrocytes/metabolism , Edema/chemically induced , Edema/drug therapy , Edema/pathology , Hydrogen Peroxide/pharmacology , Interleukin-1alpha/blood , Intracellular Space/metabolism , Luminescent Measurements , Male , Malondialdehyde/metabolism , Oxidative Stress/drug effects , Protein Carbonylation/drug effects , Rats, Inbred Lew , Rats, WistarABSTRACT
There is evidence that a higher serum level of bilirubin (BIL) may be a protective factor for autoimmune diseases. We examined the effect of BIL supplementation in adjuvant-induced arthritis (AIA) where oxidative stress, inflammation and inadequate immune response are present. Male Lewis rats were randomized into groups: CO - control, AIA - untreated adjuvant-induced arthritis, AIA-BIL - adjuvant-induced arthritis administrated BIL (200 mg/kg b.w. daily i.p. during 14 days). Change of hind paw volume in the AIA-BIL group in comparison to the AIA group was significantly decreased after BIL administration. In CO and AIA groups we found almost untraceable levels of BIL. In the AIA-BIL group hyperbilirubinemia was observed. BIL administration significantly decreased plasma levels of C-reactive protein and ceruloplasmin in the AIA-BIL group in comparison to the AIA group. The values of white and red blood cells, hemoglobin and hematocrit were significantly decreased in AIA-BIL after BIL supplementation. Organs like spleen and thymus had a lower weight in AIA-BIL than in AIA. Histological findings showed decreased or even absent damage in hind paw joint of AIA-BIL animals. We observed an immunomodulatory effect of BIL on AIA development, which may also have a novel pharmacological impact.
Subject(s)
Arthritis, Experimental/blood , Arthritis, Experimental/pathology , Hyperbilirubinemia/blood , Hyperbilirubinemia/pathology , Animals , Bilirubin/blood , Biomarkers/blood , Male , Rats , Rats, Inbred LewABSTRACT
Carnosine (CARN) is an anti-glycating agent able to quench superoxide, and to neutralize 4-hydroxynonenal. Trolox-carnosine (CARN-T) was synthesized because of its resistance against degradation and to improve CARN antioxidant capacity. We evaluated the impact of trolox (TRO), CARN and its derivative CARN-T on oxidative stress (OS) in brain during rat adjuvant arthritis (AA). The experiments were done on healthy, control arthritic and arthritic animals with administration of CARN 150 mg/kg b.w., TRO 41 mg/kg b.w. and CARN-T 75 mg/kg b.w. in a daily dose during 28 days. Antioxidants did not affect the body weight on day 14, but on day 28 TRO enhanced the weight reduction. On day 14 and 28 CARN-T and TRO reduced arthritic score. IL-1beta, MCP-1 and MMP-9 were measured in plasma on day 14. MCP-1 was decreased by CARN-T and TRO. All antioxidants reduced IL-1beta and MMP-9 levels. Malondialdehyde, 4-hydroxynonenal and protein carbonyls were increased in brain. CARN, CARN-T and TRO prevented higher lipid and protein oxidation in brain. CARN and CARN-T caused no weight reduction like TRO that has an advantage in inflammatory arthritis. Moreover the antioxidants administered had a similar therapeutic effects on arthritic score, markers of inflammation in plasma and OS in brain.
Subject(s)
Arthritis, Experimental/drug therapy , Arthritis, Experimental/metabolism , Brain/metabolism , Carnosine/analogs & derivatives , Chromans/therapeutic use , Oxidative Stress/physiology , Animals , Antioxidants/pharmacology , Antioxidants/therapeutic use , Brain/drug effects , Carnosine/pharmacology , Carnosine/therapeutic use , Chromans/pharmacology , Male , Oxidative Stress/drug effects , Rats , Rats, Inbred LewABSTRACT
Novel therapies for rheumatoid arthritis also include the use of naturally occurring compounds possessing antioxidant properties. In the present work, the effects of oral administration of quercetin were investigated in a rat model of adjuvant arthritis. Arthritis was induced by a single intradermal injection of heat-inactivated Mycobacterium butyricum in incomplete Freund's adjuvant. The experimental groups were treated with an oral daily dose of 150 mg/kg b.w. of quercetin for 28 days. Results indicated that quercetin was able to ameliorate all markers of inflammation and oxidative stress measured. Quercetin lowered levels of interleukin-1ß, C-reactive protein, and monocyte chemotactic protein-1 and restored plasma antioxidant capacity. In addition, quercetin inhibited the enzymatic activity of pro-inflammatory 12/15-lipoxygenase in lung and liver and increased the expression of heme oxygenase-1 in joint and lung of arthritic rats. Finally, quercetin inhibited the 2-fold increase of NF-ÒB activity observed in lung, liver and joint after induction of arthritis.
Subject(s)
Antioxidants/metabolism , Arthritis, Experimental/prevention & control , Inflammation/prevention & control , Quercetin/pharmacology , Animals , Arthritis, Experimental/blood , Arthritis, Experimental/metabolism , Inflammation/blood , Inflammation/metabolism , Lipoxygenases/metabolism , Liver/drug effects , Liver/enzymology , Lung/drug effects , Lung/enzymology , NF-kappa B/metabolism , Rats , Rats, Inbred LewABSTRACT
OBJECTIVE: Rodent models of osteoarthritis and rheumatoid arthritis are useful tools to study these disease processes. Adjuvant arthritis (AAR) is a model of polyarthritis widely used for preclinical testing of antiarthritis substances. We report the effect of two different doses of highly purified chondroitin sulfate (CS) pharmaceutical grade in the AAR animal model after oral administration. DESIGN: AAR was induced by a single intradermal injection of heat-inactivated Mycobacterium butyricum in incomplete Freund's adjuvant. The experiments included healthy animals, untreated arthritic animals, arthritic animals having been administered 300 or 900 mg/kg of CS daily, 14 days before AAR induction until the end of the experiment (day 28), arthritic animals having been administered 300 or 900 mg/kg of CS daily, from day 1 until the end of the experiment. RESULTS: CS was capable of significantly reducing the severity of arthritis along with oxidative stress, a consequence of chronic inflammatory processes occurring in AAR. The CS pre-treatment regimen was effective throughout the whole subacute phase, while treatment from day 1 proved effective only in the chronic period. The effects were confirmed by improved total antioxidant status and γ-glutamyltransferase activity. CS administered under a pre-treatment regimen was also able to reduce the production of pro-inflammatory cytokines, C-reactive protein in plasma, phagocytic activity and the intracellular oxidative burst of neutrophils. CONCLUSIONS: CS proved to be effective in slowing down AAR development and in reducing disease markers, thus supporting its beneficial activity as a drug in humans.
Subject(s)
Arthritis, Experimental/drug therapy , Chondroitin Sulfates/pharmacology , Animals , Antioxidants/metabolism , C-Reactive Protein/analysis , Chondroitin Sulfates/administration & dosage , Cytokines/metabolism , Disease Models, Animal , Hindlimb , Male , Neutrophils/metabolism , Oxidative Stress/drug effects , Phagocytes/metabolism , Rats , Rats, Inbred Lew , gamma-Glutamyltransferase/metabolismABSTRACT
The purpose of this study was to evaluate the effect of ß-(1,3/1,6)-D: -glucan isolated from Pleurotus ostreatus (ß-glucan-PO) on prophylactic treatment of adjuvant arthritis (AA) with methotrexate (MTX) in rats. Groups of rats with AA were treated with methotrexate (1 mg/kg/week), ß-glucan-PO (1 mg/kg every second day) or their combination for the period of 28 days from adjuvant application. Body mass, hind paw swelling, arthrogram scores and a level of serum albumin were measured as markers of inflammation and arthritis. Treatment with low dose of MTX significantly inhibited the markers of both inflammation and arthritis. MTX and its combination with ß-glucan-PO significantly increased body mass of arthritic rats. ß-glucan-PO administered alone significantly decreased both the hind paw swelling and arthritic score. In combination with MTX, ß-glucan-PO markedly potentiated the beneficial effects of MTX, which resulted in a more significant reduction of hind paw swelling and arthritic scores. The concentration of albumin in the serum of arthritic controls was significantly lower than in healthy controls. Both MTX alone and the combination treatment with MTX + ß-glucan-PO significantly inhibited the decrease in serum albumin. ß-Glucan-PO increased the treatment efficacy of basal treatment of AA with MTX.
Subject(s)
Arthritis, Experimental/drug therapy , Methotrexate/therapeutic use , Pleurotus/chemistry , beta-Glucans/therapeutic use , Animals , Body Weight , Male , Rats , Rats, Inbred Lew , Serum Albumin/analysisABSTRACT
A certain relationship was observed between the gastrointestinal system, arthritis and immune system. Patients with rheumatoid arthritis have an altered microflora composition and disturbed intestinal defensive barrier. Effect of probiotic bacteria (Colinfant; COL) with known favorable effect on intestinal microflora was determined on the methotrexate (MTX) treatment of adjuvant arthritis. Rats with adjuvant arthritis were administered methotrexate 0.5 mg/kg body mass 2-times weekly per os, COL 1 mL/kg body mass every second day per os, and a combination of MTX+COL for a period of 28 d from the immunization. Levels of serum albumin, body mass, changes in hind paw swelling, and arthrogram score were estimated in rats as variables of inflammation and destructive arthritis-associated changes. Treatment with MTX, as well as with the combination treatment with MTX+COL significantly inhibited both inflammation and destructive arthritis-associated changes. The combination treatment inhibited both the hind paw swelling and arthrogram score more remarkably than MTX alone; on the other hand, the difference between combination treatment and MTX alone was not significant. Treatment with COL alone had no effect on adjuvant arthritis in rats. Colinfant can increase the preventive effect of MTX treatment in rat adjuvant arthritis by improving its antiarthritic effects.
Subject(s)
Antirheumatic Agents/administration & dosage , Arthritis, Experimental/therapy , Escherichia coli , Methotrexate/administration & dosage , Probiotics/administration & dosage , Animals , Arthritis, Experimental/drug therapy , Arthritis, Experimental/immunology , Combined Modality Therapy , Disease Models, Animal , Escherichia coli/physiology , Humans , Male , Rats , Rats, Inbred LewABSTRACT
We studied the anti-arthritic activity of glucomannan (GM) isolated from Candida utilis and of Imunoglukán, a beta-(1,3/1,6)-D-glucan (IMG) isolated from Pleurotus ostreatus. Adjuvant arthritis (AA) was induced intradermally by the injection of Mycobacterium butyricum in incomplete Freund's adjuvant to Lewis rats. Blood for biochemical and immunological analysis was collected on experimental days 1, 14, 21, and 28. A clinical parameter--hind paw volume (HPV)--was also measured. The detection of IL-1 alpha, IL-4, TNF alpha, and MCP-1 was done by immunoflowcytometry. On day 28--the end of the experiment--we determined spectrophotometrically: the total anti-oxidant status (TAS) of plasma samples along with thiobarbituric acid-reacting substances (TBARS) levels in plasma and we assessed the activity of gamma-glutamyl transferase (GGT) in hind paw joint homogenate. The experiments included healthy animals, arthritic animals without treatment, and arthritic animals with administration of glucomannan (GM-AA) in the oral daily dose of 15 mg/kg b.w. and of IMG (IMG-AA) in the oral daily dose of 2 mg/kg b.w. The progress of AA was manifested by all parameters monitored. Both substances had beneficial effects on HPV, TBARS levels, GGT activity, and TAS levels. For cytokine assessment, only IMG-AA samples were selected, considering the significant HPV improvement accompanied with the observed anti-oxidant action. IMG administration had a positive immunomodulating effect on all cytokine plasma levels measured, changed markedly due to arthritis progression. Thus, IMG may be considered as a candidate for combinatorial therapy of rheumatoid arthritis.
Subject(s)
Antirheumatic Agents/therapeutic use , Arthritis, Experimental/drug therapy , Arthritis, Rheumatoid/drug therapy , Glucans/therapeutic use , Immunologic Factors/therapeutic use , Mannans/therapeutic use , Animals , Arthritis, Experimental/metabolism , Arthritis, Rheumatoid/metabolism , Candida , Humans , Interleukin-1alpha/biosynthesis , Interleukin-4/biosynthesis , Male , Pleurotus , Rats , Rats, Inbred Lew , Tumor Necrosis Factor-alpha/biosynthesisABSTRACT
Non-steroidal anti-inflammatory drugs possess not only therapeutic but also adverse effects, mainly on the gastrointestinal tract. The aim of this pilot study was to establish the ulcerogenic dose caused by daily administration of indomethacin to male Lewis rats. Further, the model of rat adjuvant arthritis (AA) was used to evaluate the protective effect of stobadine dipalmitate against indomethacin-induced gastroenteropathy. Indomethacin was administered subcutaneously in the daily dose of 5, 7, 10, 20 and 30 mg/kg b.w. Survival of the animals and damage of gastric and intestinal mucosa were monitored, and some biochemical parameters were determined. In AA rats stobadine dipalmitate was administered orally in the daily dose of 15 mg/kg. For the chronical experiments on AA rats the subcutaneous indomethacin dose of 5 mg/kg was selected as the therapeutic dose and the dose of 7 mg/kg was chosen as the adequate dose for gastropathy induction. The additive adverse effect of arthritis induction and indomethacin administration was demonstrated on the basis of gastric mucosa damage observations. The supposed stobadine gastro-protection was not confirmed.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/toxicity , Gastric Mucosa/drug effects , Indomethacin/toxicity , Intestinal Mucosa/drug effects , Administration, Oral , Animals , Antioxidants/administration & dosage , Arthritis/drug therapy , Carbolines/administration & dosage , Disease Models, Animal , Male , Pilot Projects , Rats , Rats, Inbred LewABSTRACT
The contrasting pattern of cardiac inotropy induced by human peptide endothelin-1 (ET-1) has not been satisfactorily explained. It is not clear whether ET-1 is primarily responsible for increased myocardial ET-1 expression and release with resultant inotropic effects, or for the induction of myocardial hypertrophy and heart failure. There are at least two subtypes of endothelin receptors (ET(A) and ET(B)) and the inotropic effects of ET-1 differ depending on the receptor involved. Along with some other groups, we reported significant subtype-ET(B) endothelin receptor down-regulation in human cardiac cells preincubated with endothelin agonists (Drímal et al. 1999, 2000). The present study was therefore designed to clarify the subtype-selective mechanisms underlying the inotropic response to ET-1 and to its ET(B)-selective fragment (8-21)ET-1 in the isolated rat heart. The hearts were subjected to (1-21)ET-1 and to (8-21)ET-1, or to 30 min of stop-flow ischemia followed by 40 min of reperfusion, both before and after selective blockade of endothelin receptors. The present study revealed that both peptides, ET-1 and its (8-21)ET-1 fragment, significantly reduced coronary blood flow in nmolar and higher concentrations. The concomitant negative inotropy and chronotropy were marked after ET-1, while the infusion of the ET-1(8-21) fragment produced a slight but significant positive inotropic effect. Among the four endothelin antagonists tested in continuous infusion only the non-selective PD145065 and ET(B1/B2) selective BQ788 (in molar concentrations) slightly reduced the early contractile dysfunction of the heart induced by ischemia, whereas ET(A)-selective PD155080 partially protected the rat heart on reperfusion.
Subject(s)
Endothelin-1/analogs & derivatives , Endothelin-1/pharmacology , Heart Failure/physiopathology , Heart/physiology , Myocardial Contraction/physiology , Amino Acid Sequence , Animals , Coronary Circulation/drug effects , Coronary Circulation/physiology , Dioxoles/pharmacology , Endothelin-1/antagonists & inhibitors , Endothelin-1/chemistry , Endothelins/pharmacology , Heart/drug effects , Heart/physiopathology , Heart Failure/etiology , Heart Rate/drug effects , Heart Rate/physiology , Humans , In Vitro Techniques , Male , Myocardial Contraction/drug effects , Myocardial Ischemia/physiopathology , Myocardial Ischemia/prevention & control , Myocardial Reperfusion Injury/physiopathology , Myocardial Reperfusion Injury/prevention & control , Oligopeptides/pharmacology , Peptide Fragments/pharmacology , Perfusion , Piperidines/pharmacology , Rats , Rats, Wistar , Ventricular Function, Left/drug effects , Ventricular Function, Left/physiology , Ventricular Pressure/drug effects , Ventricular Pressure/physiologyABSTRACT
Serum levels of advanced glycation end products (s-AGEs) were investigated in children with poorly metabolically controlled diabetes to determine whether they may be correlated with HbA1c, fructosamine, glycaemia, albumin excretion rate, duration of diabetes and age. In this study, 17 children with Type 1 diabetes mellitus (age range 9 to 18 yr) and 8 healthy children (age range 7 to 17 yr) served as subjects. S-AGEs were found to be increased in poorly metabolically controlled children with diabetes (HbA1c>9%). A significant correlation (r=0.65;p<0.01) was found between s-AGEs and HbA1c in the group of diabetic children. In poorly metabolically controlled children with diabetes of pre-pubertal and pubertal age, the level of s-AGEs should be monitored as the risk of microvascular complications may be already present at this early stage of life.
Subject(s)
Diabetes Mellitus, Type 1/blood , Glycated Hemoglobin/analysis , Glycation End Products, Advanced/blood , Adolescent , Blood Glucose/analysis , Child , Humans , Spectrometry, FluorescenceABSTRACT
In its first part, this review paper discusses skin morphology and barrier function of the stratum corneum for drug permeation after its transdermal administration or topical application. Further, the paper presents the main methods for overcoming the skin permeation barrier, which plays an important role for transdermal drug administration. Focus is on the method of chemical permeation enhancement. The chemical enhancers are categorised by their chemical structure. Examples of the most effective enhancers are given for the chemical groups of alcohols, amines and amides, polyalcohols, terpenes, fatty acids and their esters, macro cyclic compounds, sulfoxides, tensides, and others, as e.g. soft enhancers.
Subject(s)
Pharmaceutical Preparations/metabolism , Skin Absorption/drug effects , Administration, Cutaneous , Animals , Biological Transport, Active/drug effects , Humans , Skin Physiological Phenomena/drug effects , Stimulation, ChemicalABSTRACT
Toxicological studies of radionuclide passage across the skin, which represents a crucial barrier of radiation, are important for ensuring the quality of the environment. Both (137)Cs and (90)Sr are most frequently involved in radionuclide contamination of the human body. In our study, we selected (90)Sr because this radionuclide is chemically very close to the bio-element calcium. The permeation of (90)Sr from donor solution across the intact skin of 5- or 9-day-old rats (5DR, 9DR) and across stripped and split skin of the 5DR was studied. The experiments in vitro were carried out using vertical diffusion cells. Strontium chloride (SrCl(2)) was used as carrier in the donor solution in different concentrations. Liquid scintillation spectrometry was applied for radiation detection. The experiments showed that: the permeated fraction of (90)Sr(2+) was indirectly proportional to the carrier concentration in the donor solution; the stratum corneum was found to be the principal penetration barrier of strontium; and in the case of the 9DR the dominant route of strontium penetration was along the follicles.
Subject(s)
Skin Physiological Phenomena , Strontium Radioisotopes/pharmacokinetics , Animals , Hair Follicle , Permeability , Rats , Rats, WistarABSTRACT
Nonenzymatic glycosylation of proteins is a weighty consequence of hyperglycaemia in diabetes. This study examines the possible effect of copper(II) ions on the glycosylation of human serum albumin (HSA) and the resulting formation of advanced glycosylation end products (AGEs). HSA in phosphate-buffered saline was incubated with 100 mmol/l glucose. The effect of addition of copper(II) ions and/or aminoguanidine bicarbonate (CAS 2582-30-1) was investigated. The determination of AGE levels derived from glycosylated/glycoxidated HSA was performed using a specific spectrofluorometric assay (excitation 346 nm; emission 418 nm). The results showed that the addition of copper(II) ions to the incubation medium containing glucose increased the formation of AGEs. Further, in the presence of copper(II) ions, a significant blockade of aminoguanidine inhibitory effect on the formation of AGEs was observed.
Subject(s)
Copper/chemistry , Glycation End Products, Advanced/chemistry , Guanidines/chemistry , Serum Albumin/chemistry , Enzyme-Linked Immunosorbent Assay , Glucose/chemistry , Humans , Spectrometry, FluorescenceABSTRACT
BACKGROUND: Advanced glycation endproducts (AGEs) have been established as one of the major factors responsible for the multi-organ damage seen in diabetes. AGEs and lipoxidation products, as e.g. MDA, and their adducts with proteins appear to be formed together in serum and tissues. A link between AGEs formation and increased lipoxidation at tissue damage is under investigation. AIM: The aim of the present study was to determine fructosamine (FAM), glycated haemoglobin (HbA1c) AGEs-specific fluorescence and MDA-protein adducts specific fluorescence in diabetic and in healthy children, with statistical evaluation of the relationship between the parameters assessed. SUBJECTS AND METHODS: Values of FAM and HbA1c (spectrophotometry) and of AGEs-specific fluorescence and MDA-protein adducts specific fluorescence were investigated in serum proteins of 17 children with poorly controlled type 1 diabetes mellitus (age range 9 to 18 years). Eight healthy children (age range 7 to 17 years) served as controls. RESULTS: In the diabetic group, all the parameters evaluated were significantly higher than in the control group. Furthermore, MDA-linked specific fluorescence of MDA-protein adducts (a biomarker of oxidative stress) was correlated with AGEs-specific fluorescence. In patients this correlation was extremely significant (r = 0.8176, p < 0.0001). CONCLUSION: The increased oxidative stress in children with type 1 diabetes may not be attributed to complications, though it could contribute to the development of complications. (Tab. 2, Fig. 7, Ref. 30.)
Subject(s)
Blood Proteins/metabolism , Diabetes Mellitus, Type 1/blood , Glycation End Products, Advanced/blood , Lipid Peroxidation , Adolescent , Child , Fructosamine/blood , Glycated Hemoglobin/analysis , Humans , Malondialdehyde/bloodABSTRACT
The aim of this paper is to provide a brief overview of most important results of stobadine kinetic studies in rats, dogs, and human volunteers. In these studies, stobadine dihydrochloride and stobadine dipalmitate was used for intravenous and oral administration, respectively. To evaluate kinetic properties of stobadine and its metabolites, TLC, HPLC, GLC, GC-MS, radiometric, and fluorometric methods were developed and used.
Subject(s)
Antioxidants/pharmacokinetics , Carbolines/pharmacokinetics , Animals , Area Under Curve , Dogs , Gas Chromatography-Mass Spectrometry , Half-Life , Humans , Intestinal Absorption , RatsABSTRACT
The pyridoindole stobadine is a novel drug with antioxidant and cardioprotective properties. The objective of this study was to compare the bioavailability and the main pharmacokinetic parameters of two different stobadine dosage forms, STBtest and STBref, after single oral dosing in the form of gelatine capsules to 6 dogs. The dose ranged from 2.9 to 4.7 mg/kg and a randomized two-period crossover design was applied. To quantify the drug in plasma, a GC/MS method was developed with a quantification limit of 1 ng/ml. The time profiles of stobadine plasma concentrations were fitted by pharmacokinetic models. The extent of relative bioavailability ranged between 0.71 and 1.56. Practically no difference was found between the bioavailability rate of the two capsules, expressed as Cmax/AUC, with values ranging from 0.0022-0.0047 min-1 for STBtest and 0.0022-0.0045 min-1 for STBref. In conclusion, the technological difference of the capsules investigated did not yield deviations in either their extent or rate of absorption. Therefore the two stobadine formulations were concluded to be bioequivalent.
Subject(s)
Anti-Arrhythmia Agents/pharmacokinetics , Antioxidants/pharmacokinetics , Carbolines/pharmacokinetics , Administration, Oral , Animals , Anti-Arrhythmia Agents/blood , Biological Availability , Capsules , Carbolines/blood , Dogs , Dose-Response Relationship, Drug , Gas Chromatography-Mass Spectrometry , Male , Therapeutic EquivalencyABSTRACT
Rheumatoid arthritis (RA) is a chronic disease affecting up to 3% of the population in most countries. The causes of RA have not been completely elucidated. This paper aims to review the role of reactive oxygen and nitrogen species in the etiopathogenesis of RA. Reactive oxygen species (ROS), such as superoxide radical, hydrogen peroxide, hydroxyl radical and hypochlorous acid, as well as reactive nitrogen species (RNS), such as nitric oxide and peroxynitrite, contribute significantly to tissue injury in RA. Several mechanisms are involved in the generation and action of ROS and RNS. Superoxide radical, hydrogen peroxide and nitric oxide do not directly damage the majority of biological molecules. They are however converted into the highly reactive hydroxyl radical, which reacts with almost all molecules in living cells. The resulting chronic inflammation process can be reduced with antioxidant therapy. To date, scavenging, preventive, and enzyme antioxidants are available. The most important mode is scavenging of the hydroxyl radical and of hypochlorous acid. Another important way is to inhibit production of RNS and ROS by neutrophils, monocytes, and macrophages. The control of inflammation in arthritic patients by natural as well as synthetic antioxidants could become a relevant component of antirheumatic prevention and therapy.