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1.
Oncogene ; 35(6): 793-9, 2016 Feb 11.
Article in English | MEDLINE | ID: mdl-25961932

ABSTRACT

Regions of hypoxia occur in most solid tumors, and they are associated with a poor prognostic outcome. Despite the absence of detectable DNA damage, severe hypoxia (<0.1% O2) induces a DNA damage response, including the activation of p53 and subsequent induction of p53-dependent apoptosis. Factors affecting hypoxia-induced p53-dependent apoptosis are unclear. Here we asked whether H3K9me3, through mediating gene repression, could regulate hypoxia-induced p53-dependent apoptosis. Under hypoxic conditions, increases in H3K9me3 occur in an oxygen-dependent but HIF-1-independent manner. We demonstrate that under hypoxic conditions, which induce p53 activity, the negative regulator of p53, APAK, is repressed by increases in H3K9me3 along the APAK loci. APAK repression in hypoxia is mediated by the methyltransferase SETDB1 but not Suv39h1 or G9a. Interestingly, increasing hypoxia-induced H3K9me3 through pharmacological inhibition of JMJD2 family members leads to an increase in apoptosis and decreased clonogenic survival and again correlates with APAK expression. The relevance of understanding the mechanisms of APAK expression regulation to human disease was suggested by analysis of patients with colorectal cancer, which demonstrates that high APAK expression correlates with poor prognosis. Together, these data demonstrate the functional importance of H3K9me3 in hypoxia, and they provide a novel mechanistic link between H3K9me3, p53 and apoptosis in physiologically relevant conditions of hypoxia.


Subject(s)
Apoptosis Regulatory Proteins/genetics , Apoptosis/genetics , DNA-Binding Proteins/genetics , Histone-Lysine N-Methyltransferase/metabolism , Histones/metabolism , Histones/physiology , Tumor Suppressor Protein p53/physiology , Apoptosis/drug effects , Apoptosis Regulatory Proteins/metabolism , Cell Hypoxia/genetics , DNA-Binding Proteins/metabolism , Gene Expression Regulation, Neoplastic/drug effects , Gene Knockdown Techniques , HCT116 Cells , Humans , Hypoxia-Inducible Factor 1, alpha Subunit/genetics , Oxygen/pharmacology , Tumor Cells, Cultured
2.
Mol Cell Biochem ; 385(1-2): 249-55, 2014 Jan.
Article in English | MEDLINE | ID: mdl-24096735

ABSTRACT

To assess the influence of monoclonal anti-Lewis b, anti-H type 1, and anti-sialyl Lewis x addition on interactions of sugar structures of MUC1 mucin with Helicobacter pylori. The investigations were carried out on gastric juices of 11 patients and 12 H. pylori strains. The levels of Lewis b and sialyl Lewis x antigens on MUC1 were assessed by sandwich ELISA tests. Anti-Lewis b, anti-H type 1 or anti-sialyl Lewis x monoclonal antibodies were added to MUC1 to determine whether the adhesion activities of H. pylori isolates to examined mucin would be affected. Binding of bacteria to MUC1 was assessed by ELISA test. Clear inhibitory effect of examined antibodies was revealed in 6 of 12 examined H. pylori isolates independently on babA2 status. In the rest of strains this effect was negligible. We confirmed participation of Lewis b, H type 1 and also sialyl Lewis x of MUC1 mucin in interactions with H. pylori independently on babA genopositivity. Not full inhibition and a lack of this effect in some strains suggest an existence of other mechanisms of H. pylori adherence to mucin.


Subject(s)
Antibodies, Monoclonal/pharmacology , Antigens, Differentiation/immunology , Bacterial Adhesion/drug effects , Helicobacter pylori/physiology , Lewis Blood Group Antigens/immunology , Lewis X Antigen/immunology , Mucin-1/metabolism , Humans , Sialyl Lewis X Antigen
3.
J Appl Microbiol ; 110(1): 229-38, 2011 Jan.
Article in English | MEDLINE | ID: mdl-20961363

ABSTRACT

AIMS: Ceragenin CSA-13 is a synthetic mimic of cationic antibacterial peptides, with facial amphiphilic morphology reproduced using a cholic acid scaffold. Previous data have shown that this molecule displays broad-spectrum antibacterial activity, which decreases in the presence of blood plasma. However, at higher concentrations, CSA-13 can cause lysis of erythrocytes. This study was designed to assess in vitro antibacterial and haemolytic activity of CSA-13 in the presence of pluronic F-127. METHODS AND RESULTS: CSA-13 bactericidal activity against clinical strains of bacteria associated with topical infections and in an experimental setting relevant to their pathophysiological environment, such as various epithelial tissue fluids and the airway sputum of patients suffering from cystic fibrosis (CF), was evaluated using minimum inhibitory and minimum bactericidal concentration (MIC/MBC) measurements and bacterial killing assays. We found that in the presence of pluronic F-127, CSA-13 antibacterial activity was only slightly decreased, but CSA-13 haemolytic activity was significantly inhibited. CSA-13 exhibits bacterial killing activity against clinical isolates of Staphylococcus aureus, including methicillin-resistant strains, Pseudomonas aeruginosa present in CF sputa, and biofilms formed by different Gram (+) and Gram (-) bacteria. CSA-13 bactericidal action is partially compromised in the presence of plasma, but is maintained in ascites, cerebrospinal fluid, saliva, and bronchoalveolar lavage fluid. The synergistic action of CSA-13, determined by the use of a standard checkerboard assay, reveals an increase in CSA-13 antibacterial activity in the presence of host defence molecules such as the cathelicidin LL-37 peptide, lysozyme, lactoferrin and secretory phospholipase A (sPLA). CONCLUSION: These results suggest that CSA-13 may be useful to prevent and treat topical infection. SIGNIFICANCE AND IMPACT OF THE STUDY: Combined application of CSA-13 with pluronic F-127 may be beneficial by reducing CSA-13 toxicity.


Subject(s)
Anti-Bacterial Agents/pharmacology , Poloxamer , Steroids/pharmacology , Surface-Active Agents , Anti-Bacterial Agents/administration & dosage , Anti-Bacterial Agents/therapeutic use , Antimicrobial Cationic Peptides/chemistry , Biofilms/drug effects , Cholic Acid/chemistry , Cystic Fibrosis/microbiology , Hemolysis/drug effects , Humans , Pseudomonas Infections/drug therapy , Pseudomonas aeruginosa/drug effects , Pseudomonas aeruginosa/growth & development , Skin Diseases, Bacterial/drug therapy , Staphylococcus aureus/drug effects , Steroids/administration & dosage , Steroids/therapeutic use
4.
Adv Med Sci ; 55(2): 167-71, 2010.
Article in English | MEDLINE | ID: mdl-20934966

ABSTRACT

PURPOSE: Helicobacter pylori present in the oral cavity can be a source of gastric infection. Since in the oral cavity H. pylori is mostly found in dental plaque, the aim of the study was to determine whether the oral health status and oral hygiene practices affect the incidence of H. pylori antigens in dental plaque. MATERIALS AND METHODS: The study was performed in 155 patients aged 19-78 years. Patients who had taken antibiotics within 4 weeks preceding the study and those with a past history of H. pylori eradication were excluded. Each patient filled out a questionnaire on the procedures of dental plaque removal from natural teeth and dentures, and underwent oral examination. H. pylori antigens in supragingival plaque were determined by the immunological method with the use of a kit for detection of H. pylori antigens in stool samples. RESULTS: The presence of H. pylori antigens in dental plaque was found in 65.6% of the study subjects. The oral health status, frequency of dentist visits as well as the number and technique of dental plaque removal from natural teeth and dentures did not differ significantly between patients with infected and non-infected dental plaque. CONCLUSIONS: The occurrence of H. pylori antigens in dental plaque of natural teeth is not associated with oral health status or dental plaque removal practices from both natural teeth and removable dentures.


Subject(s)
Dental Plaque/microbiology , Helicobacter Infections/diagnosis , Helicobacter pylori/pathogenicity , Oral Health , Oral Hygiene , Adult , Aged , Female , Helicobacter pylori/isolation & purification , Humans , Male , Middle Aged , Young Adult
5.
Adv Med Sci ; 55(2): 161-6, 2010.
Article in English | MEDLINE | ID: mdl-20639184

ABSTRACT

PURPOSE: Culture is one of the methods used for detecting Helicobacter pylori in the stomach. However, since it is costly, labor-consuming, and in a number of infected subjects gives a false negative result, the procedure is not routinely used. The aim of the study was to analyze some of the factors that may affect the outcome of H. pylori culture from endoscopic gastric mucosal specimens. MATERIAL AND METHODS: The study was conducted in a group of 265 subjects. The culture of gastric mucosal specimens was verified by urease test and histological examination. If the culture result was not consistent with one or two verifying tests, an additional two tests were used, i.e. H. pylori antigens in stool samples and anti-H. pylori antibodies in blood serum. RESULTS: In patients infected with H. pylori (at least two positive diagnostic tests), the analysis of factors that may affect the culture outcome revealed that neither age, gender, smoking, history of eradication, endoscopic diagnosis, use of proton pump inhibitors, ultrasonography of the abdomen or chest radiology performed the day before or on the day of gastroscopy, nor preparation for colonoscopy using osmotic fluids 1-2 days prior to gastroscopy had an effect on the culture outcome. Only high activity of gastritis (neutrophil infiltration) and low bacterial load in gastric mucosal specimens as well as drinking alcohol and the use of histamine H2 receptor blockers reduced culture efficacy in infected subjects. CONCLUSIONS: High activity of gastritis, low bacterial load, drinking alcohol and the use of histamine H2 receptor blockers can be the cause of failed H. pylori culture from gastric mucosa in the infected subjects. These factors should be taken into consideration when qualifying patients for the test and interpreting the results.


Subject(s)
Gastric Mucosa/microbiology , Helicobacter Infections/diagnosis , Helicobacter Infections/microbiology , Helicobacter pylori/growth & development , Adult , Aged , Antibodies, Bacterial/blood , Antigens, Bacterial/analysis , Endoscopy, Gastrointestinal , Feces/microbiology , Female , Gastritis/microbiology , Gastritis/physiopathology , Helicobacter Infections/blood , Helicobacter pylori/immunology , Helicobacter pylori/isolation & purification , Humans , Male , Middle Aged , Young Adult
6.
Adv Med Sci ; 54(2): 194-8, 2009.
Article in English | MEDLINE | ID: mdl-20034921

ABSTRACT

PURPOSE: The aim of this study was to determine the viability of the commercial test currently used for detection of H. pylori antigens in the stool for detection of H. pylori antigens in dental plaque. MATERIALS AND METHODS: A total of 164 dyspeptic patients entered the study; 95 H. pylori infected (positive result of at least 4 of 5 diagnostic tests: Campylobacter-like organisms test (CLO test), histology, culture, stool antigens, serology) and 69 noninfected (negative results of 4 diagnostic tests: CLO test, histology, culture, stool antigens). Dental plaque was collected from natural teeth of the patients and incubated in microaerophilic conditions for 72 hours before immunoassay. RESULTS: Experimental findings included that optimal dental plaque weight to perform the examination was over 2 mg and that preliminary incubation increased significantly the number of positive results (p<0.002). It was also found that H. pylori antigens in the dental plaque were positive in 81.2% of infected and only 17.7% of non-infected subjects (p<0.001), while the reproducibility of results was 95%. CONCLUSIONS: The immunoassay for detection of H. pylori antigens in the stool may be used, after minor adaptations (specifically pre-incubation in microaerophilic conditions) for H. pylori antigen detection in dental plaque.


Subject(s)
Antigens, Bacterial/analysis , Dental Plaque/immunology , Helicobacter pylori/immunology , Adult , Aged , Antigens, Bacterial/blood , Bacteriological Techniques , Biopsy , Campylobacter/immunology , Dental Plaque/microbiology , Dyspepsia/microbiology , Feces/microbiology , Female , Gastric Mucosa/microbiology , Gastric Mucosa/pathology , Gastroscopy , Helicobacter Infections/immunology , Humans , Immunoassay , Immunoglobulin A/analysis , Immunoglobulin G/analysis , Male , Middle Aged , Reproducibility of Results , Young Adult
7.
Dis Esophagus ; 22(4): 368-73, 2009.
Article in English | MEDLINE | ID: mdl-19222537

ABSTRACT

In some populations, Helicobacter pylori eradication is associated with development of erosive esophagitis. The aim of this study was to evaluate the contribution of salivary bicarbonate and glycoprotein secretion to the pathogenesis of erosive esophagitis developing after H. pylori eradication. Gastroscopy and saliva collection were performed at recruitment and 12 months after completion of eradication therapy. Eighty-eight patients with duodenal ulcer were recruited to the study. Erosive esophagitis was found in 13 patients (grade A, 8 patients; grade B, 4 patients; grade C, 1 patient). Among the 74 subjects who completed the study, erosive esophagitis was detected in 21 patients (grade A, 15 patients; grade B, 6 patients); they all were successfully eradicated. Bicarbonate and glycoprotein secretion was not found to differ significantly between the subjects with and without erosive esophagitis both before and 1 year after H. pylori eradication. However, it was lower in H. pylori-infected (baseline) than in H. pylori-noninfected erosive esophagitis subjects (1 year after successful eradication) (bicarbonate 2.34 [1.29-3.40)]vs. 3.64 [2.70-4.58]micromol/min and glycoprotein 0.23 [0.15-0.31]vs. 0.35 [0.28-0.43] mg/min, P= 0.04 and P= 0.04, respectively). We conclude that changes in salivary bicarbonate and glycoprotein secretion related to H. pylori eradication do not promote the development of erosive esophagitis in duodenal ulcer patients.


Subject(s)
Duodenal Ulcer/epidemiology , Esophagitis, Peptic/epidemiology , Helicobacter Infections/drug therapy , Helicobacter Infections/epidemiology , Helicobacter pylori/drug effects , Saliva/chemistry , Adolescent , Adult , Aged , Anti-Bacterial Agents/administration & dosage , Anti-Ulcer Agents/therapeutic use , Bicarbonates/chemistry , Breath Tests , Cohort Studies , Comorbidity , Drug Therapy, Combination , Duodenal Ulcer/diagnosis , Duodenal Ulcer/drug therapy , Esophagitis, Peptic/diagnosis , Esophagitis, Peptic/drug therapy , Esophagoscopy/methods , Glycoproteins/metabolism , Helicobacter Infections/diagnosis , Helicobacter pylori/isolation & purification , Humans , Middle Aged , Probability , Prognosis , Saliva/metabolism , Severity of Illness Index , Statistics, Nonparametric , Treatment Outcome , Young Adult
8.
Adv Med Sci ; 53(2): 305-9, 2008.
Article in English | MEDLINE | ID: mdl-18930874

ABSTRACT

PURPOSE: Erosive esophagitis frequently develops after successful Helicobacter pylori eradication. Since salivary secretion of epidermal growth factor (EGF) plays a crucial role in the pathogenesis of gastroesophageal reflux disease, the current study objective was to find out whether erosive esophagitis development after Helicobacter pylori eradication is associated with the secretion of EGF in saliva. MATERIALS AND METHODS: A total of 115 H. pylori infected patients (positive results of CLO-test, histology and serology) with a duodenal ulcer were recruited for the study. Gastroscopic examinations and saliva collections were performed twice, prior to H. pylori eradication and one year after its cessation. The salivary EGF was determined using a radioimmunological method. RESULTS: Salivary EGF secretion was lower in H. pylori infected subjects with erosive esophagitis than without (0.82+/-0.66 vs 1.70+/-3.49 ng/min, p=0.021). However, a year after successful H. pylori eradication, salivary EGF did not differ between the groups (2.17+/-2.06 vs 1.79+/-2.06 ng/min); the lack of difference was due to high peptide secretion in patients who developed erosive esophagitis after eradication. CONCLUSION: Erosive esophagitis development following H. pylori eradication is not the result of decreased salivary EGF secretion.


Subject(s)
Duodenal Ulcer/metabolism , Duodenal Ulcer/microbiology , Epidermal Growth Factor/metabolism , Esophagitis/metabolism , Helicobacter Infections/prevention & control , Helicobacter pylori , Saliva/metabolism , Adolescent , Adult , Aged , Duodenal Ulcer/prevention & control , Esophagitis/etiology , Female , Follow-Up Studies , Humans , Male , Middle Aged , Young Adult
9.
Adv Med Sci ; 53(2): 310-5, 2008.
Article in English | MEDLINE | ID: mdl-18952538

ABSTRACT

PURPOSE: The aim of the study was to evaluate the effect of smoking and drinking habits, in separate and joint analyses, on the efficacy of H. pylori eradication. MATERIALS AND METHODS: A total of 250 patients were recruited. They were treated with a 7-day course of omeprazole, amoxicillin, tinidazole (OAT), omeprazole amoxicillin, clarithromycin (OAC) or omeprazole, clarithromycin, tinidazole (OCT). The efficacy of H. pylori eradication was tested with a CLO-test and histology 4 weeks after the completion of antibacterial therapy. RESULTS: Drinking was found not to affect the efficacy of H. pylori eradication in any therapeutic group, while smoking decreased it in the OAC group (smokers 69.6%, non-smokers 94.3%, p=0.006). In the OAT treated group H. pylori eradication rate was lower in smokers-non-drinkers than in smokers-drinkers and non-smokers-non-drinkers (38.9% vs 83.2% and 70.0%, p=0.002 and p=0.034, respectively), while in the OAC treated group, smokers-non-drinkers had lower eradication efficacy than non-smokers-drinkers and non-smokers-non-drinkers (59.1% vs 100% and 91.3%, p=0.01 and p=0.012, respectively). In the OCT treated group, differences between subgroups were not significant. CONCLUSIONS: Smoking and drinking habits when analyzed jointly are more useful to predict the outcome of H. pylori eradication than when analyzed separately.


Subject(s)
Alcohol Drinking/epidemiology , Duodenal Ulcer/microbiology , Helicobacter Infections/diagnosis , Helicobacter Infections/drug therapy , Helicobacter pylori/drug effects , Peptic Ulcer/microbiology , Smoking/epidemiology , Anti-Bacterial Agents/therapeutic use , Anti-Ulcer Agents/therapeutic use , Drug Therapy, Combination , Duodenal Ulcer/drug therapy , Female , Humans , Male , Middle Aged , Peptic Ulcer/drug therapy , Predictive Value of Tests
10.
Rocz Akad Med Bialymst ; 50 Suppl 1: 26-30, 2005.
Article in English | MEDLINE | ID: mdl-16119620

ABSTRACT

PURPOSE: The contamination of the indoor environment with yeast-like fungi and moulds in social welfare home in Czerewki was evaluated. MATERIAL AND METHODS: The concentration of airborne fungi (in front of the building and in the corridors, patient rooms, study rooms, recreation rooms, kitchens, bathrooms, toilets) was determined using SAS-Super 100 (Pbi International). The fungal concentration on walls was assessed using the Count-Tact applicator and the plate Count-Tact irradiated (BioMerieux). Swabs were taken from the skin of the interdigital spaces of feet and hands, nails and the oral cavity of the residents. The fungi from the swabs were cultured on Sabouraud medium. Fungi were identified using standard microbial procedures. RESULTS: Tests of air and walls revealed significant differences in mycological flora in depending on the place isolation (e.g. corridor, rooms, reading room, nurse, room, kitchen, dining room, bathroom) and season (summer, autumn, winter, spring). A significant increase in the fungi isolated from the air and walls in the social welfare home was found, depending on the season. CONCLUSION: An increase in the fungi isolated from residents was found in relation to the season.


Subject(s)
Air Pollution, Indoor/statistics & numerical data , Environmental Exposure/statistics & numerical data , Environmental Monitoring/statistics & numerical data , Fungi/isolation & purification , Epidemiological Monitoring , Humans , Poland/epidemiology , Residence Characteristics/statistics & numerical data , Seasons , Social Welfare
11.
Rocz Akad Med Bialymst ; 50 Suppl 1: 70-3, 2005.
Article in English | MEDLINE | ID: mdl-16119631

ABSTRACT

PURPOSE: This work is an attempt to evaluate the extent of knowledge concerning patient's rights and chances to execute these rights in everyday hospital reality. We have collected opinions of the patients from the maternity ward of Independent Central Public Clinical Hospital of Medical University of Silesia in Katowice. We also interested in participation of medical staff in respecting and realization of patient's rights it has become the main objective of this work. MATERIAL AND METHODS: To collect the patient's opinions we used a specially prepared questionnaire which has measured obeying patient's rights in the following aspects: the rights to make decisions, the rights to information including the right to inspect medical data, the right to respect privacy and dignity, the right to treatment and care, the right to be in touch with relatives, the right the priest's care, the rights to file a complaint, the right to obey patient's rights. CONCLUSIONS: Patient's rights in a delivery room and a maternity ward are not respected to a satisfactory extent which is confirmed by the research results. During the hospitalization the patients aren't informed and they do not acquire almost any knowledge concerning their rights. The patient staying in a maternity ward is in most cases only a passive receiver of medical service.


Subject(s)
Delivery Rooms/standards , Patient Rights , Delivery of Health Care , Disclosure , Female , Humans , Patient Education as Topic , Pregnancy , Surveys and Questionnaires
12.
Med Dosw Mikrobiol ; 49(1-2): 55-60, 1997.
Article in Polish | MEDLINE | ID: mdl-9411073

ABSTRACT

The study was undertaken to evaluate the incidence of Moraxella catarrhalis in patients with respiratory tract infections. Overall 514 specimens including 370 throat swabs and 114 sputum specimens were examined. The 78 strains isolated basing on morphological and biochemical characteristics were classified as Moraxella catarrhalis. The sensitivity of the strains to antibiotics was also estimated. The frequency of M. catarrhalis isolation from the throat swabs (15.9%) was higher than from the sputum (13.2%). Selected 25 specimens of sputum were tested simultaneously by quantitative and qualitative methods. Quantitative method was more sensitive (84% positive findings) than qualitative method (60% positive findings). Resistance to ampicillin was found in 52 (66.7%) strains of M. catarrhalis determined mainly by beta-lactamase production (over 70% strains were producers of beta-lactamase). All strains were sensitive to ofloxacin and amoxycillin/clavulanic acid combination. The frequency of M. catarrhalis isolation was higher in autumn-winter period than in summer (May-September). We conclude that M. catarrhalis, beside Streptococcus pyogenes (20.2%) and Streptococcus pneumoniae (17.1%), are the most frequently isolated bacteria in patients with respiratory tract infections.


Subject(s)
Moraxella catarrhalis/isolation & purification , Respiratory Tract Infections/microbiology , Amoxicillin-Potassium Clavulanate Combination/pharmacology , Ampicillin Resistance , Drug Resistance, Microbial , Humans , Incidence , Microbial Sensitivity Tests , Moraxella catarrhalis/drug effects , Ofloxacin/pharmacology , Pharynx/microbiology , Seasons , Sensitivity and Specificity , Sputum/microbiology
13.
Appl Environ Microbiol ; 61(2): 561-6, 1995 Feb.
Article in English | MEDLINE | ID: mdl-7574597

ABSTRACT

The Lactococcus lactis gene encoding trimethoprim resistance has been cloned and expressed in Escherichia coli and Bacillus subtilis. Several lines of evidence indicate that the cloned gene encodes dihydrofolate reductase (DHFR). (i) It fully complements the fol "null" mutation in E. coli. (ii) Nucleotide sequencing of the cloned fragment revealed the presence of one open reading frame encoding a protein that shares homology with the family of bacterial DHFR enzymes. (iii) Overexpression of this open reading frame in E. coli resulted in the appearance in cell extracts of a protein of the expected size as well as in a dramatic increase of DHFR activity. In cell extracts, the DHFR activity was not inhibited by low trimethoprim concentration. By Northern (RNA) blotting and primer extension analyses, the size and the start point of the dhfr transcript, respectively, have been determined. Results of these experiments indicate that in L. lactis the dhfr gene represents part of a larger transcription unit.


Subject(s)
Genes, Bacterial , Lactococcus lactis/enzymology , Lactococcus lactis/genetics , Tetrahydrofolate Dehydrogenase/genetics , Amino Acid Sequence , Bacillus subtilis/genetics , Base Sequence , Cloning, Molecular , DNA, Bacterial/genetics , Drug Resistance, Microbial/genetics , Escherichia coli/genetics , Gene Expression , Lactococcus lactis/drug effects , Molecular Sequence Data , Phenotype , Sequence Homology, Amino Acid , Transcription, Genetic , Trimethoprim/pharmacology
14.
Methods Find Exp Clin Pharmacol ; 15(6): 357-69, 1993.
Article in English | MEDLINE | ID: mdl-8231455

ABSTRACT

ICI 206,970, an aminomethylphenol pyrazine derivative, produced diuretic and saluretic effects, but caused only minimal alterations in kaliuresis in dogs and rats after oral and parenteral administration. ICI 206,970, unlike HCTZ, increased diuretic activity in a more clearly defined dose-related manner, and did not reach the plateau level even up to a dose of 100 mg/kg p.o. The diuretic and natriuretic response is believed to be a combination of a direct effect on tubule function and changes in GFR, particularly at higher doses. Based upon studies in in vitro amphibian models for mimicking mammalian nephron, ICI 206,970 appeared to possess a furosemide-like activity in toad cornea and amiloride-like activity in toad bladder. It is concluded that ICI 206,970 is a potent eukalemic diuretic with the potential of multiple sites of renal action.


Subject(s)
Calcium Channel Blockers/pharmacology , Diuretics/pharmacology , Potassium/blood , Pyrazines/pharmacology , Animals , Bufo marinus , Cornea/drug effects , Dogs , Dose-Response Relationship, Drug , Drug Interactions , Electrolytes/urine , Female , Hydrochlorothiazide/pharmacology , Indomethacin/pharmacology , Kidney Function Tests , Male , Pyrazines/chemistry , Rats , Rats, Wistar , Urinary Bladder/drug effects
15.
J Pharmacol Toxicol Methods ; 27(2): 85-93, 1992 Apr.
Article in English | MEDLINE | ID: mdl-1591408

ABSTRACT

This report introduces a simple and easy technique for animal handling and drug administration into the sciatic nerve area for determining local anesthesia and neuromuscular blocking activity in mice. The drugs were injected into the popliteal space of the right hindlimb (i.e., the sciatic nerve area). The loss of motor activity of the right hindlimb was taken as a sign of producing local anesthesia. A positive local anesthetic activity was recorded when a mouse was only able to walk using three limbs on an inverted wire mesh screen and the injected limb was hanging in the air. This method is superior to the commonly used techniques of applying drugs to the rabbit's cornea, the guinea pig's back skin, or the root of the mouse tail to determine the reduced reflex responses and to assess the local anesthetic activity. The present method has evaluated a number of drugs (cocaine, lidocaine, procaine, propranolol, quinidine, quinacrine, verapamil, and diltiazem), which are known to produce local anesthesia. The sciatic nerve blockade technique is also capable of determining neuromuscular blocking activity of drugs, in which the end point of activity taken is different from that for local anesthetic drugs. The method reported here has been validated by reference neuromuscular blocking agents (d-tubocurarine, decamethonium, and succinylcholine). A positive neuromuscular blockade was recorded when a mouse was unable to stay on the inverted wire mesh screen. The information provides not only the local anesthetic or neuromuscular blocking potency of drugs but also duration of action of drugs.


Subject(s)
Anesthetics, Local , Drug Evaluation, Preclinical/methods , Nerve Block/methods , Neuromuscular Blocking Agents/pharmacology , Animals , Male , Mice , Sciatic Nerve
16.
J Pharmacol Exp Ther ; 260(2): 450-7, 1992 Feb.
Article in English | MEDLINE | ID: mdl-1738094

ABSTRACT

ICI 207,828, an aminomethylphenol pyrazine derivative, produces water diuretic effects with only minimal alterations in kaliuresis in dogs and rats after oral and parenteral administration. In the dog, ICI 207,828 reached maximum activity at a dose of 10 mg/kg, p.o. This was comparable to that of hydrochlorothiazide (HCTZ) at a dose of 5 mg/kg, p.o. or higher. In the rat, a dose of 30 mg/kg, p.o. of ICI 207,828 was comparable to the maximum of water diuretic and saluretic response obtained with HCTZ at a dose of 10 mg/kg, p.o. Based upon studies using in vitro amphibian models of the mammalian nephron, ICI 207,828 appeared to act on both the thick ascending limb of the loop of Henle and the late distal nephron. In the toad bladder preparation, ICI 207,828 inhibited Na+ transport when placed on either the mucosal (amiloride-like) or serosal (thiazide-like or loop diuretic-like) sides. This compound also inhibited Cl- transport in the toad cornea preparation (loop diuretic-like). ICI 207,828 did not change plasma K+ significantly in dogs dosed for 14 days at doses having diuretic effects (5 and 10 mg/kg, p.o., daily). In contrast, HCTZ consistently decreased plasma K+, whereas amiloride increased it significantly. ICI 207,828 demonstrated antihypertensive effects in spontaneously hypertensive rats. At 30 mg/kg, p.o., b.i.d., ICI 207,828 and HCTZ produced approximately equal antihypertensive activities during a 3 1/2-day treatment period. The pharmacological profile of ICI 207,828 indicates that this compound is a potent eukalemic diuretic and antihypertensive agent in animals.


Subject(s)
Antihypertensive Agents/pharmacology , Diuretics/pharmacology , Kidney/drug effects , Pyrazines/pharmacology , Amiloride/pharmacology , Animals , Bufonidae , Cornea/drug effects , Dogs , Dose-Response Relationship, Drug , Drug Interactions , Female , Furosemide/pharmacology , Hydrochlorothiazide/pharmacology , In Vitro Techniques , Indomethacin/pharmacology , Kidney/physiology , Male , Potassium/blood , Potassium/urine , Rats , Rats, Inbred SHR , Rats, Inbred Strains , Urinary Bladder/drug effects
17.
Pharmacology ; 45(1): 34-40, 1992.
Article in English | MEDLINE | ID: mdl-1508966

ABSTRACT

We investigated the natriuretic and kaliuretic effect of distal tubular diuretics in saline-loaded spontaneously hypertensive Wistar rats (SHR) from three different sources and normotensive Wistar rats (NWR). Orally administered early distal tubular diuretics (hydrochlorothiazide, chlorthalidone, metolazone, indapamide and cicletanine) caused much less potassium excretion in SHR than in NWR, whereas the magnitude of concurrent natriuresis was similar in both NWR and SHR. The intriguing renal handling of potassium excretion was exemplified by hydrochlorothiazide, for which enhanced kaliuresis was dose dependent in NWR but not in SHR. The doses tested ranged from 1 to 100 mg/kg, p.o. Amiloride, a late distal tubular diuretic, was also evaluated for its effect on sodium and potassium excretion in NWR and SHR. Amiloride produced potassium retention more effectively in NWR than in SHR, although the magnitude of natriuresis was similar. The difference between SHR and NWR with regard to potassium-retaining activity of amiloride was consistent at all doses tested (1-30 mg/kg, p.o.). In conclusion, it was suggested that SHR appear to have a genetic defect in potassium transport in the distal nephron.


Subject(s)
Hypertension/metabolism , Kidney Tubules, Distal/metabolism , Potassium/metabolism , Administration, Oral , Animals , Diuretics/administration & dosage , Hypertension/genetics , Kidney Tubules, Distal/drug effects , Potassium/urine , Rats , Rats, Inbred SHR , Rats, Inbred Strains , Renal Tubular Transport, Inborn Errors/genetics , Renal Tubular Transport, Inborn Errors/metabolism , Sodium/urine
18.
Jpn J Pharmacol ; 57(3): 263-77, 1991 Nov.
Article in English | MEDLINE | ID: mdl-1813657

ABSTRACT

ICI 181,037, the most active compound from a series of 1,1-diarylcarbin-1-ol-2 amines, was evaluated for diuretic and cardiovascular activity. In saline-loaded rats, the magnitude of water diuresis and saluresis produced by ICI 181,037 (10 mg/kg, p.o.) was equal to that of hydrochlorothiazide. Water diuresis and saluresis produced by ICI 181,037 were enhanced with SKF 525A, ampicillin or neomycin plus lincomycin, suggesting that ICI 181,037 is an active diuretic. In conscious dogs, the saluretic activity of ICI d-181,037 (5 mg/kg, p.o.) was about 80% of the corresponding hydrochlorothiazide value, whereas the l-isomer demonstrated only minimum saluretic activity. In both rats and dogs, the concurrent kaliuresis after ICI 181,037 or its enantiomers was minimal as compared to hydrochlorothiazide. Following chronic dosing with diuretic doses, the basal levels of plasma potassium in dogs were not altered. In amphibian in vitro models for mimicking mammalian nephron, ICI 181,037 and its enantiomers demonstrated antinatriferic and antichloriferic activities, suggesting multiple renal sites of action for this agent. Racemic ICI 181,037 and its isomers reversed ouabain-induced arrhythmia in dogs and/or reduced the ouabain-induced mortality in mice after intravenous administration. It is concluded that ICI 181,037, particularly its d-isomer, is a novel eukalemic diuretic and possesses antiarrhythmic activity.


Subject(s)
Acetamides/pharmacology , Anti-Arrhythmia Agents/pharmacology , Diuretics/pharmacology , Anesthetics , Animals , Arrhythmias, Cardiac/chemically induced , Arrhythmias, Cardiac/drug therapy , Autonomic Nervous System/drug effects , Cardiovascular System/drug effects , Dogs , Female , Male , Mice , Ouabain/antagonists & inhibitors , Ouabain/pharmacology , Potassium/blood , Rats , Rats, Inbred Strains
19.
Methods Find Exp Clin Pharmacol ; 12(7): 481-6, 1990 Sep.
Article in English | MEDLINE | ID: mdl-2087148

ABSTRACT

2-Aminoethyl-4-(1,1-dimethylethyl)-6-iodophenol hydrochloride (MK447) is a chemically novel diuretic that has oral efficacy and potency greater than furosemide (FUR). In this study, the relative efficacy and potency of MK447 and FUR were assessed following oral, i.v. bolus and i.v. infusion administration in rats and dogs. MK447 was more potent than furosemide but the two were equally efficacious when administered orally to rats and dogs. The relative potency remained unchanged when administered as an i.v. bolus to rats (1 mg/kg). However, when infused continuously there was no difference in potency or efficacy between the two compounds. These observations lead to the conclusion that pharmacokinetic differences between the two compounds play a major role in determining their relative oral potency. Comparative studies of the effects of compounds given by different routes of administration are useful in providing insight into the role of pharmacokinetics in overall response to different compounds.


Subject(s)
Butylated Hydroxytoluene/administration & dosage , Diuretics/administration & dosage , Furosemide/administration & dosage , Administration, Oral , Animals , Butylated Hydroxytoluene/pharmacokinetics , Diuretics/pharmacokinetics , Dogs , Female , Furosemide/pharmacokinetics , Infusions, Intravenous , Injections, Intravenous , Kidney/metabolism , Male , Rats , Rats, Inbred Strains , Species Specificity
20.
Med Pr ; 41(2): 114-8, 1990.
Article in Polish | MEDLINE | ID: mdl-2215200

ABSTRACT

Social acceptance of periodical examinations was evaluated via a survey conducted among a group of 530 machine industry workers. A questionnaire for prophylactic examinations was used which was worked out at the Department of Epidemiology and Statistics of the Nofer Institute of Occupational Medicine in Lódz, with additional questions concerning the level of acceptance of a new medical examination mode. In order to determine the letter the subject area was limited to elicit an answer to a question whether a new examination instrument at a periodical check-up meets the needs of the workers. The paper discusses the method of the study, characteristics of the population examined, including age, occupational exposure and work strenuousness. The findings revealed that 96.8% of subjects had accepted the new mode of periodical examinations which allows a conclusion that the method satisfies the workers' expectations as they find it suitable for managing their health problems. It is suggested that the form of periodical examinations should be modified since those presently applied do not facilitate early diagnosis or comprehensive evaluation of workers' health conditions.


Subject(s)
Engineering/statistics & numerical data , Mass Screening/methods , Occupational Health Services/statistics & numerical data , Patient Acceptance of Health Care/statistics & numerical data , Adolescent , Adult , Aged , Consumer Behavior , Humans , Male , Middle Aged , Poland , Surveys and Questionnaires
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