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Evaluation Studies 2006; 27(Suppl 2): 176-179 PubMed PMID: 17159809 Citation  Keywords:  Animals, Antibodies, Monoclonal:adverse effects, Antibodies, Monoclonal, Humanized, Antineoplastic Agents:adverse effects, Bevacizumab, Cardiomyopathies:chemically induced, Chemokine CCL2:metabolism, Cyclophosphamide:adverse effects, Doxorubicin:adverse e.   

OBJECTIVES: Although the mechanisms responsible for the occurrence of congestive heart failure after anti-cancer therapy are largely unknown, both the formation of free radicals in the myocardium and inflammatory cytokines with resultant production of neurohormones could be operative. The common manifestations of cardiovascular toxicity after anti-cancer therapy may include cardiac ischemia, ST-segment elevation, or depression, serious hypotension and bradyarrhythmias with resultant cardiac depression and congestive heart failure, or hyper-tension, serious ventricular tachycardia, cardiac edema, QT prolongation and thrombo-embolism.

METHODS & RESULTS: The mechanisms of cardiotoxicity of four representative anti-cancer agents 1) anthracycline doxorubicin, 2) and 3) alkylating agents cyclophosphamine and streptozotocin and 4) the new humanized monoclonal antibody bevacizumab (directed solely against myocardial and vascular endothelial growth factors), were investigated in chronic experiments on rodents for the occurrence and intensity of early electrocardiographic signs of cardiotoxicity, for late biochemical markers, and for the late production of congestive heart failure. Our results suggested a sneaking ascension of long-term multifactorial cardiotoxicity of the four anti-cancer agents tested. Of these quasi-selective bevacizumab (Avastin) that binds to and inhibits endothelial growth factor and thus neoangiogenicity in rats showed unexpectedly high overexpression of inflammatory cytokines and monocyte chemoattractant protein (mcp-1), both in plasma and in the myocardium.

CONCLUSIONS: Thus, suddenly increased and coincidental expression of inflammatory cytokines, neurohormones and chemoattractants in plasma during anti-cancer therapy could be the long-awaited markers of imminent cardiotoxicity....

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Comparative Study 2006; 27(Suppl 2): 148-151 PubMed PMID: 17159802 Citation  Keywords:  Benzothiepins:pharmacology, Histamine:pharmacology, Histamine H1 Antagonists:pharmacology, Humans, Loratadine:pharmacology, Neutrophils:drug effects, Peroxidase:metabolism, Superoxide Dismutase:metabolism, Tetradecanoylphorbol Acetate:pharmacology,.   

OBJECTIVES: To study the effect of H1-antihistamines dithiaden (Dit) and loratadine (Lor) and compare it with that of histamine (His) on phorbolmyristate acetate (PMA) stimulated chemiluminescence (CL) of whole blood, isolated neutrophils, release of myeloperoxidase (MPO), and on superoxide (SO) generation.

METHODS: Luminol- and isoluminol-enhanced CL was applied for measuring the oxidative burst, spectrophotometry was used for determination of MPO (o-dianisidine) and SO generation (superoxide dismutase inhibition of cytochrome c).

RESULTS: Dit and Lor dose-dependently inhibited CL of whole blood and significantly decreased oxidative burst both at the extra- and intracellular sites of neutrophils. Release of MPO was decreased with both drugs tested in 10-times lower concentrations than was SO inhibition. Histamine (His) was much less effective in the inhibition of the parameters investigated.

CONCLUSIONS: Histaminergic drugs of the 1st generation inhibited oxidative burst of human phagocytes in whole blood and in isolated neutrophils. The rank order of potency to inhibit CL, MPO release and SO generation in PMA stimulated phagocytes was: Dit>Lor>His....

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Comparative Study 2006; 27(Suppl 2): 141-143 PubMed PMID: 17159800 Citation  Keywords:  Brompheniramine:pharmacology, Chlorpheniramine:pharmacology, Extracellular Fluid:metabolism, Histamine H1 Antagonists:pharmacology, Humans, Intracellular Fluid:metabolism, Luminescence, Neutrophils:drug effects, Pheniramine:pharmacology, Reactive Oxygen S.   

BACKGROUND: Allergic inflammation was found to be accompanied by activation of neutrophils. Since this resulted in increased formation of reactive oxygen species, the antioxidative activity of antiallergic drugs was considered to decrease the risk of tissue damage. However, if the drug-induced inhibition of radical formation occurred intracellularly, it could disturb regulation of neutrophil functions and decrease bactericidal activity of these cells. Separate analysis of extra- and intracellular activity of antioxidative drugs is thus of particular importance.

OBJECTIVE: To differentiate the effects of three antiallergic H1-antihistamine drugs (pheniramine, chlor- and brompheniramine) on radical formation outside and inside human neutrophils.

METHODS: Formation of reactive oxygen species was determined in vitro using the chemiluminescence method. The chemiluminescence signal, initiated by phorbol-12-myristate-13-acetate, was enhanced either with isoluminol (extracellular) or with luminol in the presence of extracellular scavengers, superoxide dismutase and catalase (intracellular).

RESULTS: The antihistamines tested displayed dual activity - they inhibited the extracellular and potentiated the intracellular chemiluminescence. Chlor- and brompheniramine were found to be more effective than pheniramine.

CONCLUSION: Compared to other H1-antihistamines (such as dithiaden or loratadine, active both extra- and intracellularly), the observed inhibition caused by the pheniramines tested was unique since it occurred selectively outside neutrophils. This might indicate the ability of these drugs to minimise toxic effects of extracellular radicals without affecting intracellular oxidant production involved in regulation of neutrophil functions and in microbial killing....

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Clinical Trial 2006; 27(Suppl 2): 138-140 PubMed PMID: 17159799 Citation  Keywords:  Adrenergic beta-Antagonists:pharmacology, Aged, Antihypertensive Agents:therapeutic use, Antioxidants:pharmacology, Carbazoles:pharmacology, Diabetes Mellitus, Type 2:blood, Diabetic Angiopathies:blood, Female, Heart Failure:blood, Humans, In Vitro Techni.   

OBJECTIVES: In the present study we investigated whether the beta-adrenoceptor antagonist carvedilol (CARV) [Dilatrend] prevented reactive oxygen metabolite (ROM) production in human polymorphonuclear leukocytes (PMNL) or interfered with ROM already generated. To specify the site of action of CARV, we evaluated its effect on extra- and intracellular ROM generation. In addition, we studied the effect of CARV therapy on ROM production in whole blood obtained from patients with congestive heart failure (CHF) combined with type II diabetes mellitus.

METHODS: ROM generation in whole blood and isolated PMNL was determined after phorbol 12-myristate-13-acetate (PMA-0.05 micromol/l) stimulation by luminol/isoluminol-enhanced chemiluminescence (CL) in the microplate luminometer Immunotech LM-01T.

RESULTS: CARV significantly decreased CL of human whole blood in the concentrations of 10, 20, 50 and 100 micromol/l, both when applied simultaneously and after stimulation. In isolated PMNL, CARV significantly decreased extracellular CL in the concentrations of 50 and 100 micromol/l, intracellular CL was decreased in the concentrations of 20, 50 and 100 micromol/l. The nonstimulated and PMA stimulated CL of whole blood was increased in patients before therapy in comparison with healthy controls. After CARV therapy, 25 mg/day and 50 mg/day, there was a trend to reduce CL as compared to values before therapy.

CONCLUSIONS: In human PMNL, CARV interfered in vitro and ex vivo with ROM generation as well as with already generated ROM, suggestive of its both "preventive" and "therapeutic" effect....

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Clinical Trial 2006; 27(Suppl 2): 134-137 PubMed PMID: 17159798 Citation  Keywords:  Aged, Cells, Cultured, Combined Modality Therapy, Diabetic Foot:surgery, Humans, Mesenchymal Stem Cell Transplantation:methods, Skin Transplantation:methods, Transplantation, Autologous, Wound Healing,.   

OBJECTIVES: This study was performed to test a new technique for treatment of chronic non-healing wound (diabetic ulcer) using autologous biograft composed of autologous skin fibroblasts on biodegradable collagen membrane (Coladerm) in combination with autologous mesenchymal stem cells (MSC) derived from the patient's bone marrow.

DESIGN: The bone marrow aspirate of the patient with diabetic foot was applied directly to the wound and injected into the edges of the wound, finally covered with prepared autologous biograft. The patient received two additional treatments with cultured MSC on day 7 and 17.

RESULTS: The wound showed a steady overall decrease in wound size and an increase in the vascularity of the dermis and in the dermal thickness of the wound bed after 29 days of combined treatment.

CONCLUSIONS: Closing and healing of the non-healing diabetic ulcer was achieved by using the given combined therapy....

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Journal Article 2006; 27(Suppl 2): 130-133 PubMed PMID: 17159797 Citation  Keywords:  Adult, Chromatography, High Pressure Liquid:methods, Dose-Response Relationship, Drug, Female, Humans, Male, Methadone:analogs & derivatives, Molecular Conformation, Opioid-Related Disorders:blood, Sensitivity and Specificity,.   

OBJECTIVES: A stereoselective HPLC method was developed to separate and quantify both enantiomers of methadone and its main metabolite EDDP in serum and urine. The method was used to establish that there is a relationship between the dose of methadone prescribed and its serum concentration as well as urine excretion of methadone and its metabolite enantiomers.

METHODS: The chiral alpha1-glycoprotein stationary phase was used for enantioseparation of (R)-methadone, (S)-methadone and (R)-EDDP (S)-EDDP. The enantiomers of methadone and EDDP were extracted from urine and serum by a simple solidphase procedure.

RESULTS: The validated method was applied to the analysis of 31 serum and urine samples obtained from methadone-maintained outpatients (65% male, age 28.8+/-4; methadone dose 146+/-47 mg). A significant correlation (Pearson) r=0.67 (p<0.001) between methadone dose and serum concentration of (R)-methadone was found. Due to the large variation in results obtained from analysis of the subjects' urine specimens, no statistically significant relationship between methadone dose and urine excretion of methadone and EDDP enantiomers was established. The rate of R/S methadone (1.38 in serum, 2.43 in urine) and R/S EDDP (0.83 in urine) confirmed stereoselectivity in methadone metabolism with high individual variability.

CONCLUSIONS: The enantioselective evaluation of serum methadone concentration might be an interesting tool in methadone maintenance programme. On the other hand, the urinary excretion of methadone and EDDP enantiomers is not reliable as marker of methadone compliance but could be useful for monitoring individual metabolism or for studying the stereoselectivity in pharmacokinetics and metabolism of methadone....

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Evaluation Studies 2006; 27(Suppl 2): 125-129 PubMed PMID: 17159796 Citation  Keywords:  Chromatography, Thin Layer, Forensic Toxicology:methods, Gas Chromatography-Mass Spectrometry, Hallucinogens:blood, Humans, Models, Biological, Substance Abuse Detection:methods,.   

OBJECTIVES: Until recently, routine toxicological analysis of some hallucinogens in biological material posed problems which were only resolved after the introduction of modern analytic systems into toxicological laboratories. The most frequent hallucinogens in clinical and forensic toxicology can be grouped as: cannabinoids, tropane alkaloids, N,N-dimethyltryptamine derivatives and synthetic or semisynthetic hallucinogens.

METHODS & RESULTS: There are several methods currently used for their analysis. Immunoassay analysis of abused hallucinogens is limited to the cannabinoids. Thin layer chromatography (TLC) is able to detect higher concentrations of 1-nor-delta- 9-tetrahydrocannabinol-9-carboxylic acid (THC-COOH), tropane alkaloids (atropine and scopolamine) and ketamine (synthetic hallucinogen) in urine but for lower concentrations and for some other substances it lacks sensitivity. A reliable solution to the demand for specific and sensitive analysis of hallucinogens in biological material is gas chromatography - mass spectrometry (GC-MS). Thus, at present, analysis of cannabinoids, tropane alkaloids, ketamine as well as psilocin (N,N-dimethyltryptamine derivative) is well-managed.

CONCLUSIONS: The introduction of GC-MS systems appears to be indispensable for satisfactory qualitative and quantitative analysis of drugs of abuse, particularly hallucinogens in biological material....

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Evaluation Studies 2006; 27(Suppl 2): 121-124 PubMed PMID: 17159795 Citation  Keywords:  Amphetamines:urine, Designer Drugs:analysis, Gas Chromatography-Mass Spectrometry:methods, Humans, Reproducibility of Results, Sensitivity and Specificity, Substance Abuse Detection:methods,.   

OBJECTIVES: The purpose of this study is to evaluate the gas chromatographicmass spectrometric method (GC-MS) for assay of stimulants of amphetamine type: amphetamine (AMP), methamphetamine (MAMP), ephedrine (EPH), norephedrine (NOREPH), and the amphetamine-derived designer drugs 3,4-methylenedioxyamphetamine (MDA), 3,4-methylenedioxymethamphetamine (MDMA, ecstasy), 3,4-methylenedioxy-N-ethylamphetamine (MDEA) and N-methyl-benzodioxolylbutanamine (MBDB) in urine. These drugs are often encountered in forensic and clinical toxicological analysis.

METHODS: GC-MS method after mixed-mode solid-phase extraction (SPE) and derivatization with heptafluorobutyric anhydride (HFBA) is presented for quick and reliable screening as well as identification and quantification of amphetamines and amphetamine derived designer drugs in urine.

RESULTS: The measurement of calibration dependence allowed to determine the extent of linearity in the concentration range from 10 to 2,000 ng/ml for all amphetamines except AMP and for all amphetamine-derived designer drugs with correlation coefficients exceeding 0.98. Detection limits were established at 5 ng/ml and quantification limits at 10 ng/ml for all analytes, except AMP. LOD for AMP was established at 20 ng/ml and LOQ at 50 ng/ml. Extraction efficiency for all analytes at concentration levels 50 and 500 ng/ml (n=6) was established in the range 60-99%. Repeatability was measured at concentration levels 50 and 500 ng/ml (n=6), relative standard deviations (RSDs) were under 10% for all analytes.

CONCLUSIONS: The GC-MS method after mix-mode solid-phase extraction and derivatization with heptafluorobutyric anhydride is presented for screening followed by identification and quantification of AMP, MAMP, EPH, NOREPH, MDA, MDMA, MDEA, and MBDB. The applicability of the GC-MS method was proven by analyzing authentic urine samples....

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