Biomedical subjects

K Toth

Publications and source records attributed to K Toth.

At least 37 records · Page 2Linked to original sources

PubMed2001

Tissue-specific, tumor-selective, replication-competent adenovirus vector for cancer gene therapy.

We have previously described two replication-competent adenovirus vectors, named KD1 and KD3, for potential use in cancer gene therapy. KD1 and KD3 have two small deletions in the E1A gene that restrict efficient replication of these vectors to human cancer cell lines. These vectors also have increased capacity to lyse cells and spread from cell to cell because they overexpress the adenovirus death protein, an adenovirus protein required for efficient cell lysis and release of adenovirus from the cell. We now describe a new vector, named KD1-SPB, which is the KD1 vector with the E4 promoter replaced by the promoter for surfactant protein B (SPB). SPB promoter activity is restricted in the adult to type II alveolar epithelial cells and bronchial epithelial cells. Because KD1-SPB has the E1A mutations, it should replicate within and destroy only alveolar and bronchial cancer cells. We show that KD1-SPB replicates, lyses cells, and spreads from cell to cell as well as does KD1 in H441 cells, a human cancer cell line where the SPB promoter is active. KD1-SPB replicates, lyses cells, and spreads only poorly in Hep3B liver cancer cells. Replication was determined by expression of the E4ORF3 protein, viral DNA accumulation, fiber synthesis, and virus yield. Cell lysis and vector spread were measured by lactate dehydrogenase release and a "vector spread" assay. In addition to Hep3B cells, KD1-SPB also did not express E4ORF3 in HT29.14S (colon), HeLa (cervix), KB (nasopharynx), or LNCaP (prostate) cancer cell lines, in which the SPB promoter is not expected to be active. Following injection into H441 or Hep3B tumors growing in nude mice, KD1-SPB caused a three- to fourfold suppression of growth of H441 tumors, similar to that seen with KD1. KD1-SPB had only a minimal effect on the growth of Hep3B tumors, whereas KD1 again caused a three- to fourfold suppression. These results establish that the adenovirus E4 promoter can be replaced by a tissue-specific promoter in a replication-competent vector. The vector has three engineered safety features: the tissue-specific promoter, the mutations in E1A that preclude efficient replication in nondividing cells, and a deletion of the E3 genes which shield the virus from attack by the immune system. KD1-SPB may have use in treating human lung cancers in which the SPB promoter is active.

Adenovirus E1A Proteins↗

PubMed2001

Red blood cell aggregation measurements in whole blood and in fibrinogen solutions by different methods.

Red blood cell (RBC) aggregation is an important component of whole blood viscosity, especially at low shear rates, and is the major cause of the non-Newtonian flow properties of normal blood. In different laboratories several methods are used to determine RBC aggregation, therefore the standardization of aggregation measurements is especially important for getting comparable results. Aggregation indices of 62 human blood samples were determined by two different methods; LORCA (Laser-assisted Optical Rotational Cell Analyzer) and Myrenne aggregometers and related to plasma fibrinogen concentration. Our results show closer correlation values between RBC aggregation and fibrinogen concentration, when RBC aggregation was measured by LORCA (p<0.001), although correlation could be revealed with Myrenne, when plasma fibrinogen level was less than 4.5 g/l. Correlation coefficient between aggregation indices measured by LORCA and Myrenne aggregometers was also closer below this fibrinogen level. In vitro examination of RBC aggregation in fibrinogen solutions showed that higher fibrinogen concentration results in higher RBC aggregation only up to a certain level similarly to that found in human whole blood samples. Our results show that plasma fibrinogen level has an important, concentration dependent effect on RBC aggregation in human blood, but above a certain level it may not cause further aggregate formation.

Adult↗

PubMed2001

Hepatobiliary scanning in the diagnosis of biliary atresia.

Early diagnosis is vital in the neonatal cholestasis. The aim of this study was to assess the usefulness of hepatobiliary scanning in the diagnosis of biliary atresia. 33 hepatobiliary scannings performed in 30 children with cholestasis over the last two years were analysed. The mean age at the diagnosis was 6.6 weeks. The investigation was carried out with Multispect camera using intravenous infusion of 99mTc-MBrIDA. In 23 patients there was no passage of the radiolabelled substance into the intestinal tract. In 18 patients biliary atresia was diagnosed. One patient with a clinical suspicion of Alagille syndrome had two scannings performed at the interval of two weeks. In 1 child a common biliary tract cyst with total obstruction of extrahepatic biliary tree was diagnosed. In 18 children with biliary atresia the diagnosis was confirmed during the operation and Kasai procedure was performed. In 2 children the second scanning showed bile drainage. In 3 children intrahepatic cholestasis was diagnosed in addition to the bile passage failure. Hepatobiliary scanning in the diagnosis of neonatal cholestasis was characterised by high sensitivity (100%) but lower specificity (75%). In difficult cases the final diagnosis should be made on a basis of complex clinical, biochemical and radiological techniques and, if necessary, it should be verified by intraoperative cholangiography.

Biliary Atresia↗

PubMed2000

Sequence and analysis of chromosome 5 of the plant Arabidopsis thaliana.

The genome of the model plant Arabidopsis thaliana has been sequenced by an international collaboration, The Arabidopsis Genome Initiative. Here we report the complete sequence of chromosome 5. This chromosome is 26 megabases long; it is the second largest Arabidopsis chromosome and represents 21% of the sequenced regions of the genome. The sequence of chromosomes 2 and 4 have been reported previously and that of chromosomes 1 and 3, together with an analysis of the complete genome sequence, are reported in this issue. Analysis of the sequence of chromosome 5 yields further insights into centromere structure and the sequence determinants of heterochromatin condensation. The 5,874 genes encoded on chromosome 5 reveal several new functions in plants, and the patterns of gene organization provide insights into the mechanisms and extent of genome evolution in plants.

Animals↗

PubMed2000

Differential mechanisms of transmission at three types of mossy fiber synapse.

The axons of the dentate gyrus granule cells, the so-called mossy fibers, innervate their inhibitory interneuron and pyramidal neuron targets via both anatomically and functionally specialized synapses. Mossy fiber synapses onto inhibitory interneurons were comprised of either calcium-permeable (CP) or calcium-impermeable (CI) AMPA receptors, whereas only calcium-impermeable AMPA receptors existed at CA3 principal neuron synapses. In response to brief trains of high-frequency stimuli (20 Hz), pyramidal neuron synapses invariably demonstrated short-term facilitation, whereas interneuron EPSCs demonstrated either short-term facilitation or depression. Facilitation at all CI AMPA synapses was voltage independent, whereas EPSCs at CP AMPA synapses showed greater facilitation at -20 than at -80 mV, consistent with a role for the postsynaptic unblock of polyamines. At pyramidal cell synapses, mossy fiber EPSCs possessed marked frequency-dependent facilitation (commencing at stimulation frequencies >0.1 Hz), whereas EPSCs at either type of interneuron synapse showed only moderate frequency-dependent facilitation or underwent depression. Presynaptic metabotropic glutamate receptors (mGluRs) decreased transmission at all three synapse types in a frequency-dependent manner. However, after block of presynaptic mGluRs, transmission at interneuron synapses still did not match the dynamic range of EPSCs at pyramidal neuron synapses. High-frequency stimulation of mossy fibers induced long-term potentiation (LTP), long-term depression (LTD), or no change at pyramidal neuron synapses, interneuron CP AMPA synapses, and CI AMPA synapses, respectively. Induction of LTP or LTD altered the short-term plasticity of transmission onto both pyramidal cells and interneuron CP AMPA synapses by a mechanism consistent with changes in release probability. These data reveal differential mechanisms of transmission at three classes of mossy fiber synapse made onto distinct targets.

Animals↗

PubMed2000

Simultaneous high-performance liquid chromatographic determination of the antiretroviral agents amprenavir, nelfinavir, ritonavir, saquinavir, delavirdine and efavirenz in human plasma.

This article describes a method for the simultaneous determination of four licensed HIV protease inhibitors (amprenavir, nelfinavir, saquinavir and ritonavir) and two novel non-nucleoside reverse transcriptase inhibitors (efavirenz and delavirdine) in human plasma in a single run. Plasma samples (500 microl) were treated by liquid-liquid extraction with methyl tert.-butyl ether. The compounds were separated by reversed-phase liquid chromatography on a C(18) column with spectrophotometric detection at 260 nm. The method is linear over the specific ranges investigated, accurate (inaccuracy <11.7%) and showed intra-day and inter-day precision within the ranges of 0.9-7.0 and 1.9-8.8%, respectively. The six compounds were stable in plasma after 6 months of storage at -20 degrees C and after five freeze-thaw cycles.

Anti-HIV Agents↗

PubMed2000

Peptide and peptide mimetic inhibitors of antigen presentation by HLA-DR class II MHC molecules. Design, structure-activity relationships, and X-ray crystal structures.

Molecular features of ligand binding to MHC class II HLA-DR molecules have been elucidated through a combination of peptide structure-activity studies and structure-based drug design, resulting in analogues with nanomolar affinity in binding assays. Stabilization of lead compounds against cathepsin B cleavage by N-methylation of noncritical backbone NH groups or by dipeptide mimetic substitutions has generated analogues that compete effectively against protein antigens in cellular assays, resulting in inhibition of T-cell proliferation. Crystal structures of four ternary complexes of different peptide mimetics with the rheumatoid arthritis-linked MHC DRB10401 and the bacterial superantigen SEB have been obtained. Peptide-sugar hybrids have also been identified using a structure-based design approach in which the sugar residue replaces a dipeptide. These studies illustrate the complementary roles played by phage display library methods, peptide analogue SAR, peptide mimetics substitutions, and structure-based drug design in the discovery of inhibitors of antigen presentation by MHC class II HLA-DR molecules.

Antigen Presentation↗

PubMed2000

Tumor-specific, replication-competent adenovirus vectors overexpressing the adenovirus death protein.

We have constructed two novel adenovirus (Ad) replication-competent vectors, named KD1 and KD3, that may have use in anticancer therapy. The vectors have two key features. First, they markedly overexpress the Ad death protein (ADP), an Ad nuclear membrane glycoprotein required at late stages of infection for efficient cell lysis and release of Ad from cells. Overexpression of ADP was achieved by deleting the E3 region and reinserting the adp gene. Because ADP is overexpressed, KD1 and KD3 are expected to spread more rapidly and effectively through tumors. Second, KD1 and KD3 have two E1A mutations (from the mutant dl1101/1107) that prevent efficient replication in nondividing cells but allow replication in dividing cancer cells. These E1A mutations preclude binding of E1A proteins to p300 and pRB. As a result, the virus should not be able to drive cells from G(0) to S phase and therefore should not be able to replicate in normal tissues. We show that KD1 and KD3 do not replicate well in quiescent HEL-299 cells or in primary human bronchial epithelial cells, small airway epithelial cells, or endothelial cells; however, they replicate well in proliferating HEL-299 cells and human A549 lung carcinoma cells. In cultured A549 cells, KD1 and KD3 lyse cells and spread from cell to cell more rapidly than their control virus, dl1101/1107, or wild-type Ad. They are also more efficient than dl1101/1107 or wild-type Ad in complementing the spread from cell to cell of an E1(-) E3(-) replication-defective vector expressing beta-galactosidase. A549 cells form rapidly growing solid tumors when injected into the hind flanks of immunodeficient nude mice; however, when A549 cells were infected with 10(-4) PFU of KD3/cell prior to injection into mice, tumor formation was nearly completely suppressed. When established A549 tumors in nude mice were examined, tumors injected with buffer grew 13.3-fold over 5 weeks, tumors injected with dl1101/1107 grew 8-fold, and tumors injected with KD1 or KD3 grew 2.6-fold. Hep 3B tumors injected with buffer grew 12-fold over 3.5 weeks, whereas tumors injected with KD1 or KD3 grew 4-fold. We conclude that KD1 and KD3 show promise as anticancer therapeutics.

Adenovirus E3 Proteins↗

PubMed2000

Inhibition of polymer-induced red blood cell aggregation by poloxamer 188.

Previous reports have suggested that non-ionic poloxamer surfactants of appropriate molecular mass and composition can reduce red blood cell (RBC) aggregation in whole blood and in RBC-plasma suspensions. We have thus evaluated this phenomenon for RBC aggregated by several water-soluble polymers, using poloxamer 188 (P188), a non-ionic, tri-block molecule (total molecular mass of 8.40 kDa, 80% polyoxyethylene). Human RBC were washed, then re-suspended in isotonic solutions of dextran 70 (70.3 kDa), dextran 500 (476 kDa), PVP (360 kDa) or P-L-GLU (61.2 kDa); density-separated RBC were also studied. RBC aggregation was quantitated via a computerized Myrenne Aggregometer (extent, strength) and by the Microscopic Aggregation Index (MAI) method. Over the range of 0.5 to 5 mg/ml, poloxamer 188 inhibited both the extent and strength of aggregation in a dose-dependent manner, with the magnitude of the decrease related to polymer type (e.g., at 5 mg/ml, 62% decrease for dextran 70 vs. 14% decrease for P-L-GLU); MAI results with dextran 70 also showed a dose-dependent decrease. Poloxamer 188 at 5 mg/ml was more effective with younger, less-dense cells. Based upon the depletion model for polymer-induced aggregation, these findings suggest that poloxamer 188 acts by penetrating the depletion layer near the glycocalyx, thereby reducing the osmotic gradient between the intercellular gap and the suspending medium. Regardless of the specific mechanism(s) of action, poloxamers appear to offer interesting approaches for future basic science and clinical studies, and thus the possibility for greater insight into RBC aggregation.

Cells, Cultured↗

PubMed1999

Nabumetone induces less gastrointestinal mucosal changes than diclofenac retard.

The aim of the study was to compare the efficacy and the effects on the mucosa of the gastrointestinal tract (GIT) of nabumetone and diclofenac retard in patients with osteoarthritis (OA). An open, multicentre, randomised, comparative, endoscopy-blind parallel group study included 201 patients with nabumetone and 193 patients with diclofenac retard suffering from moderate to severe OA of the knee or hip joint. Twelve clinical efficacy variables were assessed and a portion of the population underwent gastroduodenoscopy. All patients exhibited significant improvement in pain severity and pain relief (p < 0.001 and p < 0.0001, respectively) but there were no differences between the groups for all the efficacy variables. Eleven per cent of patients on nabumetone and 19% on diclofenac experienced GIT side-effects. Sixty-nine patients with nabumetone and 61 with diclofenac underwent gastroduodenoscopy. The differences in the mucosal grade for the oesophagus, stomach and duodenum at baseline were not significant. In the oesophagus there were significantly less changes after treatment with nabumetone (p = 0.007) than with diclofenac; there were similar findings in the stomach (p < 0.001) but the difference in the duodenum was not significant. This study indicates that nabumetone and diclofenac retard have similar efficacy in the treatment of OA, but nabumetone has significantly fewer GIT side-effects.

Adolescent↗

PubMed1999

Role of reactive oxygen species and poly-ADP-ribose polymerase in the development of AZT-induced cardiomyopathy in rat.

The short term cardiac side-effects of AZT (3'-azido-3'-deoxythymidine, zidovudine) was studied in rats to understand the biochemical events contributing to the development of AZT-induced cardiomyopathy. Developing rats were treated with AZT (50 mg/kg/day) for 2 wk and the structural and functional changes were monitored in the cardiac muscle. AZT treatment provoked a surprisingly fast appearance of cardiac malfunctions in developing animals characterized by prolonged RR, PR and QT intervals and J point depression. Electron microscopy showed abnormal mitochondrial structure but the cardiomyocyte had normal myofibers. The AZT treatment of rats significantly increased ROS and peroxynitrite formation in heart tissues as determined by the oxidation of nonfluorescent dihydrorhodamine123 and dichlorodihydro-fluorescein diacetate (H2DCFDA) to fluorescent dyes, and induced single-strand DNA breaks. Lipid peroxidation and oxidation of cellular proteins determined from protein carbonyl content were increased as a consequence of AZT treatment. Activation of the nuclear poly-ADP-ribose polymerase and the accelerated NAD+ catabolism were also observed in AZT-treated animals. Western blot analysis showed that mono-ADP-ribosylation of glucose regulated protein (GRP78/BIP) was enhanced by AZT treatment, that process inactivates GRP78. In this way moderate decrease in the activity of respiratory complexes was detected in the heart of AZT-treated animals indicating a damaged mitochondrial energy production. There was a significant decrease in creatine phosphate concentration resulting in a decrease in creatine phosphate/creatine ratio from 2.08 to 0.58. ATP level remained close to normal but the total extractable ADP increased with 45%. The calculated free ATP/ADP ratio decreased from 340 to 94 in the heart of AZT-treated rats as a consequence of increased free ADP concentration. It was assumed that the increased free ADP in AZT-treated cardiomyocyte may help cells to compensate the defective ATP production in damaged mitochondria by activating the ATP synthesis in undamaged mitochondria. Southern blot analysis did not show decreased quantity of mtDNA deriving from AZT-treated rat hearts indicating that under our experimental conditions AZT-induced heart abnormalities are not the direct consequence of the mtDNA depletion. These data show that ROS-mediated oxidative damages, activated ADP-ribosylation reactions and accelerated NAD+ catabolism play basic roles in the development of AZT-induced cardiomyopathy in our animal model and indicated that these ROS-mediated processes can be important factors in the development of myopathy and cardiomyopathy in zidovudine-treated AIDS patients.

ADP Ribose Transferases↗

PubMed1999

Immune responses to adenoviruses: viral evasion mechanisms and their implications for the clinic.

Adenoviruses encode proteins that block responses to interferons, intrinsic cellular apoptosis, killing by CD8(+) cytotoxic T lymphocytes and killing by the death ligands TNF, Fas ligand and TRAIL. The viral proteins are believed to prolong acute and persistent adenovirus infections. The proteins may prove useful in protecting adenovirus gene therapy vectors and transplanted cells from the immune system.

Adenoviridae↗

PubMed1999

Hemorheological and hemodynamic parameters in patients with essential hypertension and their modification by alpha-1 inhibitor drug treatment.

Hemorheological factors play an important role in the pathogenesis of different cardiovascular diseases. The hemorheological and hemodynamic parameters in essential hypertension and their possible modification by antihypertensive treatment were examined in the following two studies. In the first study the fundus appearance and hemorheological parameters (plasma and whole blood viscosity (WBV), fibrinogen level) of 33 hypertensive patients (mean age: 55 years) were examined. The fundus appearance showed retinopathy in all the cases between stages I-III. All the measured hemorheological parameters of the examined patients were in the pathological range (WBV at 90 s(-1): 5.18 mPa s) and were significantly (p < 0.01) higher than in healthy controls (WBV at 90 s(-1): 4.18 mPa s). The hemorheological factors showed a parallel deterioration with the fundus appearance, namely their values were significantly (p < 0.01) higher in patients with a fundus appearance stage III (WBV at 90 s(-1): 6.02 mPa s) than stage I (WBV at 90 s(-1): 4.51 mPa s). These results show that there is a correlation between hemorheological parameters and fundus appearance in hypertensives, and this suggests that hemorheological factors may play a role in the development of hypertensive retinopathy. In the second study the hemorheological and hemodynamical effects of Doxazosin, a selective alpha-1-adrenoreceptor blocker agent, was examined in twenty patients (mean age: 54 years) with essential hypertension. Hemorheologic (hematocrit, fibrinogen, plasma and whole blood viscosity) and hemodynamic (cardiac output and index, total peripheral resistance) parameters and plasma lipids were determined. The measurements were carried out before the beginning of the treatment, after 1 week and after 12 weeks treatment periods. Besides significant reduction of blood pressure and total peripheral resistance (p < 0.001), a decrease in cholesterol (p < 0.001) and triglycerides (p < 0.01) levels and a beneficial effect on hemorheological parameters was detected. Fibrinogen and plasma viscosity decreased significantly (p < 0.01). Hematocrit value was also lower after one week (p < 0.001), then an increase could be seen. Whole blood viscosity showed similar changes as hematocrit, but the degree of its final increase was slighter, which was supported by the significantly lower value of corrected blood viscosity (p < 0.05). All these findings indicate that hemorheological factors may play a role in the pathogenesis and in the development of organ damages in hypertension.

Adrenergic alpha-Antagonists↗

PubMed1999

Effects of doxazosin on hemorheological, hemodynamic and lipid parameters in patients with essential hypertension.

It is known from previous studies that hemorheological parameters are altered in patients with essential hypertension. The hemorheological and hemodynamical effects of doxazosin, a selective alpha-1-adrenoreceptor blocker agent, was examined in twenty patients (mean age: 54+/-10 years) with essential hypertension. Hemorheologic (hematocrit, fibrinogen, plasma and whole blood viscosity) and hemodynamic (cardiac output and index, total peripheral resistance) parameters and plasma lipids were determined. The measurements were carried out before the beginning of the treatment, after 1 week and after 12 weeks treatment periods. Besides significant reduction of blood pressure and total peripheral resistance (p < 0.001), a decrease in cholesterol (p < 0.001) and triglyceride (p < 0.01) levels and a beneficial effect on hemorheological parameters was detected. Fibrinogen and plasma viscosity decreased significantly (p < 0.01). Hematocrit value was also lower after one week (p < 0.001), then an increase could be seen. Whole blood viscosity showed similar changes as hematocrit, but the degree of its final increase was slighter, which was supported by the significantly lower value of corrected blood viscosity (p < 0.05).

Adult↗

PubMed1998

Forced degradation of Fas inhibits apoptosis in adenovirus-infected cells.

DNA viruses have evolved elaborate mechanisms to overcome host antiviral defences. In adenovirus-infected cells, programmed cell death (apoptosis) induced by the cytokine tumour necrosis factor (TNF) is inhibited by several adenovirus-encoded proteins. Occupation of the cell-surface receptor Fas, a member of the TNF-receptor superfamily that is expressed on most cell types, triggers apoptosis of that cell. Here we show that the adenovirus RID (for receptor internalization and degradation) protein complex, which is an inhibitor of TNF-induced apoptosis, mediates internalization of cell-surface Fas and its destruction inside lysosomes within the cell. Fas has not previously been shown to be internalized and then degraded. RID also mediates internalization of the receptor for epidermal growth factor, but it does not affect the transferrin receptor or class I antigens of the major histocompatibility complex. Removal of Fas from the surface of adenovirus-infected cells expressing RID may allow infected cells to resist Fas-mediated cell death and thus promote their survival.

Adenoviridae↗

PubMed1998

An adult case of Kawasaki disease with multiplex coronary aneurysms and myocardial infarction: the role of transesophageal echocardiography.

Kawasaki disease (mucocutaneous lymph node syndrome) is an acute inflammatory disease that primarily affects infants and young children. In spite of proper therapy, coronary aneurysms develop in 10 to 25% of cases. Adult diagnosis of coronary aneurysm, presumably caused by Kawasaki disease, is rare. A 37-year-old male patient with previous inferior wall myocardial infarction (MI) was admitted with an acute anterior wall MI. Coronary angiography, performed 2 weeks after successful thrombolytic therapy, showed right coronary artery occlusion and multiplex (left main, left anterior descending, left circumflex, right coronary artery) giant coronary aneurysms. Transthoracic echocardiography was unable to detect the aneurysms. Transesophageal echocardiography (TEE) visualized a large left main coronary aneurysm with an occlusive thrombus and measured low flow velocity (0.2 m/s) in the proximal left anterior descending artery. At 4 weeks control, TEE showed marked regression of the thrombus, and it was not detectable after 6 months of oral anticoagulation with acenocumarol (International Normalized Ratio: 3-3.5) and standard postinfarction therapy. After 2 years of follow-up, the patient has no symptoms, and myocardial ischemia could not be provoked by stress tests [treadmill, dipyridamole single-photon emission computed tomography (SPECT)]. We conclude that, for diagnosis and follow-up of adult Kawasaki disease, transesophageal echocardiography is indicated. The importance and efficacy of long-term anticoagulant treatment should be emphasized in this disease.

Adult↗

PubMed1998

New analogs of human growth hormone-releasing hormone (1-29) with high and prolonged antagonistic activity.

Based on our previous results, in conjunction with various structural considerations, 19 new analogs of the GHRH antagonist [PhAc-Tyr1,D-Arg2,Phe(pCl)6,Abu15,Nle27,Agm29]++ +hGHRH(1-29) (MZ-5-156) were synthesized by the solid-phase method. These compounds were designed to develop further analogs of this class with increased receptor-binding affinity. All analogs had Abu15 and Nle27 modifications and were acylated with phenylacetic acid at the N-terminus. Most of the analogs had D-Arg2 and Phe(pCl)6 substituents and Agm29 or Arg29-NH2 at the C-terminus. Additional single substitutions consisted of the incorporation of D- or L-Tic1, D-Tic2, Tic6 or Phe(pNO2)6 and Arg29-NH2. The Arg29-NH2 analog of MZ-5-156 (KT-48) was further modified by single substitutions using Pal1; D-Tpi2; D- or L-Phe4; Phe(pX)6 X = F, Cl, I; Tyr7; Aib8; Tyr(Me)10 or Phe(pCl)10. Four peptides had multiple substitutions. All the analogs were evaluated for their ability to inhibit GH release induced by hGHRH(1-29)NH2 in vitro and some were also tested in vivo. Peptides [PhAc-Tyr1,D-Arg2,Phe(pI)6,Abu15,Nle27]hGHRH(1-2 9)NH2 (KT-30), [PhAc-Tyr1,D-Arg2,Phe(pCl)6,Aib8,Abu15,Nle27] hGHRH(1-29)NH2 (KT-50) and [PhAc-Tyr1,D-Arg2,Phe(pCl)6,Tyr(Me)10,Abu15,Nle27]h GHRH(1-29)NH2 (KT-40) with Phe(pI)6, Aib8 or Tyr(Me)10 modifications, respectively, showed high and prolonged inhibitory effect in superfused rat pituitary system. Analog KT-50 also exhibited a strong and long-term inhibitory activity in vivo in rats. Most of the new analogs showed high binding affinities to rat pituitary GHRH receptors.

Amino Acid Sequence↗

PubMed1998

Hemorheological parameters in coronary artery disease.

Hemorheological parameters are primary risk factors in ischemic heart disease (IHD). In the present study the relation of these parameters to the severity of coronary artery disease (CAD) was examined. The data of 109 patients (mean age: 55+/-9 years) undergoing coronary angiography and 59 healthy controls (mean age:35+/-10 years) were analyzed. Hemorheological parameters (hematocrit, fibrinogen level, plasma viscosity (PV) and apparent whole blood viscosity (WBV)) were determined and the circulatory index (CRI) was calculated. Patients were classified into three groups according to their coronary vessel state based on the coronary angiogram: Group 1 (n = 19, mean age: 53+/-8 years) without significant CAD, Group 2 (n = 19, mean age: 51+/-11 years) with single vessel disease, Group 3 (n = 71, mean age: 57+/-8 years) with multivessel disease. All the measured hemorheological parameters of IHD patients were significantly higher than those of controls. Fibrinogen and PV were significantly elevated in Groups 2 and 3 compared with Group 1 (p < 0.05 and 0.01). Hematocrit and WBV were significantly increased in Group 3 compared with Groups 1 and 2 (p < 0.05). CRI was significantly decreased in IHD patients, and it was also lower in Group 3 than in Group 2 (p < 0.05). These results indicate that hemorheological parameters may play a role in the pathogenesis and development of CAD.

Adult↗