Biomedical subjects
J Horváth
Publications and source records attributed to J Horváth.
[Questions about scientometry].
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Heck reactions of steroidal alkenyl iodides.
Heck reactions of some steroid derivatives possessing iodo-alkenyl moiety (17-iodo-androst-16-ene, 1, 17-iodo-4-aza-4-methyl-androst-16-en-3-one, 2, 17-iodo-4-aza-androst-16-en-3-one, 3) were carried out in the presence of palladium catalysts using various olefins (methyl acrylate, ethyl methacrylate, allyl alcohol and allyl acetate) as coupling partners. With methyl acrylate, a side reaction was observed: the coupling product underwent a Diels-Alder reaction with the excess of methyl acrylate resulting in a six-membered carbocyclic E-ring. Reaction conditions of the synthesis of the Heck-product were optimized. Although the coupling with allyl alcohol led to the formation of 21-formyl-16-pregnene derivatives, the synthesis of the corresponding steroidal unsaturated alcohol could be achieved only via hydrolysis of the coupling product of the alkenyl iodide with allyl acetate.
Phage restriction and the presence of small plasmids in Salmonella enteritidis.
Between 1990-1994, a total of 16,505 S. enteritidis strains of human, animal and food origin were phage-typed, using the Hungarian scheme and the changes of incidence of the dominant phage types were monitored. The incidence of PT1 (corresponding to Ward's PT1 was very high between 1990 and 1992 (67.9-71.0% of the total S. enteritidis isolates), later, it decreased. The prevalence of PT6 (corresponding to Ward's PT4) was rare until 1992, then it gradually increased. The phage type and plasmid content of 78 Salmonella enteritidis strains were determined. Small plasmids were present in 59% of the isolates, together with a serotype-specific (38 MDa) plasmid. A correlation was found between the presence of the small plasmid and phage restriction to two phages used for subdividing the Hungarian phage types 1 (PT1) and 6 (PT6) of S. enteritidis (corresponding to PT1 and PT4 in Ward's typing scheme, respectively).
Effect of etoposide on the pharmacokinetics of methotrexate in vivo.
The effect of etoposide on the pharmakokinetics of methotrexate (MTX) was examined in vivo. High-dose (5g/m2/24 h) MTX therapy was combined with two etoposide (100mg/m2/ 1 h) infusions as a part of the medulloblastoma protocol developed in our department. Vepesid therapy was administered in two different schedules. The first group of patients received etoposide immediately before and at the end (24 h) of MTX treatment. The second group was treated with etoposide at 24 and at 48 h after starting MTX infusion. In this latter group both treatment-related grade III and grade IV toxicity developed more frequently than in the first group (58.6 versus 29.2%, for grade 3 toxicity p=0.019, for grade 4 toxic signs p=0.040, respectively). We observed that after the second dose of etoposide given at 48 h (second group) both total and unbound serum MTX levels (determined by high-performance liquid chromatography) were elevated by 53-109 and 26-65%, respectively, by the third hour after completion of Vepesid infusion. This effect was detectable for 6 h. All the liver and kidney functions of the patients were within the normal range. These results suggest the possibility of partial recirculation of extra/intracellular MTX into the blood after etoposide administration. Based on these results, the therapeutic protocol has been modified, and Vepesid is given prior to and at the end (24 h) of high-dose MTX treatment. Under these conditions only a slight decrease of MTX elimination has been detected between 25 and 28 h. These results emphasize the role of possible schedule-dependent interactions of cytostatic drugs.
Direct anticancer activity of gonadotropin-releasing hormone-III.
In previous studies GnRH-III, a variant of the hypothalamic neurohormone GnRH, was isolated from the brain of the sea lamprey and structurally characterized. GnRH-III is a hypothalamic neurohormone in both female and male sea lampreys. In the present work biological activities of GnRH-III in mammalian systems were examined. In superfused rat pituitary cells, GnRH-III at 1 nM to 100 nM neither induced LH-secretion nor inhibited the LH-secretion elicited by native GnRH and elicited LH release only at 1 microM. At high dose (500 microg/day) in vivo, GnRH-III behaved as a GnRH agonist, though, it was 1000-fold less active than ovurelin. The in vitro and in vivo results were in good agreement in showing that GnRH-III is only a weak agonist of the endocrine activity of GnRH. GnRH-III specifically bound to receptors on cancer cells and recognized not only the high-, but also the low-affinity binding sites. GnRH-III significantly suppressed growth of human cancer cells which have GnRH receptors. The inhibitory effect of GnRH-III on growth of cancer cells was specific and direct since the peptide did not have endocrine activity in the concentration range found to be effective in anticancer assays. GnRH-III inhibited equally the growth of ER-positive and -negative breast and TeR-positive and negative prostate cells.
[In vivo effect of etoposide on the pharmacokinetics of methotrexate].
High dose (5 g/m2/24 h) methotrexate therapy was combined two times with etoposide (100 mg/m2/1h) infusions as a part of the Medulloblastoma protocol developed in our Department Vepesid therapy was administered in two different schedules. The first group of the patients have received etoposide immediately before and at the end (24th h) of methotrexate treatment. The second group was treated with etoposide at 24 h and at 48 hour after starting methotrexate infusion. In this latter group treatment related grade 3-4 toxicity developed more frequently than in the first group (58.6% vs 33.3%). The authors observed that after the second dose of etoposide given at 48 h (second group) both total and unbound serum methotrexate levels (determined by high performance liquid chromatography) were elevated by 53.14-109.19%, and 25.86-64.95%, respectively by the third hour after completion of Vepesid infusion. This effect was detectable for 6 hours. All the liver and kidney functions of the patients were in the normal range. These results suggest the possibility of partial recirculation of extra/intracellular methotrexate into the blood after etoposide administration. Based on these results the therapeutic protocol has been modified and Vepesid is given prior to and at the end (24 h) of high dose methotrexate treatment. Under these conditions only a slight decrease of methotrexate elimination has been detected between the 25-28th h. These results emphasize the role of possible schedule dependent interactions of cytostatic drugs.
Anti-inflammatory and antinociceptive effect of different somatostatin-analogs.
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[Soy formula in the feeding of infants with milk allergy].
Authors administered soy formula to 16 infants and toddlers with clinically diagnosed cow's milk allergy. During 3 months of soy feeding it was not observed signs indicating soy allergy. The patients showed normal length and weight development. Their protein, carbohydrate and fat metabolism was normal. It is an advantageous feature of the soy feeding that the serum cholesterin level significantly decreased. Authors conclude that the advantageous features of soy formulas make their widespread use justified in infant nutrition and they are especially useful in the treatment of cow's milk allergy.
Homogeneous catalytic dehalodimerization of 17-iodo-delta 16 steroids.
17-Iodo-delta 16 steroids undergo selective dimerization and carbonylative dimerization in the presence of palladium catalysts in dimethylformamide which result in 16-17'-coupled dienes and 17-carboxylic anhydrides, respectively. Moderate to good yields have been obtained for both types of dimers.
Steroidal alkenylphosphonates via palladium-catalyzed coupling reactions.
The palladium-catalyzed coupling of various 17-iodo-delta 16 steroids (17-iodo-androst-16-ene, 17-iodo-4-methyl-4-aza-androst-16-en-3-one, and 17-iodo-4-aza-androst-16-en-3-one) with dialkyl phosphites (dimethyl phosphite, diethyl phosphite, and diisopropyl phosphite) was examined in detail. The only successful condition for homogeneous coupling involved carrying out the reaction in the absence of any solvents. A large excess of dialkyl phosphite was used, which means that the phosphite itself acted as a solvent. Eight new androst-16-ene derivatives with phosphonate groups at C-17 were synthesized and characterized. These steroids are of pharmacological interest as potential 5 alpha-reductase inhibitors. Under the same conditions, methylation of lactam NH was observed using dimethyl phosphite.
Palladium-catalyzed homogeneous coupling reactions of steroids with organostannanes.
Direct and carbonylative coupling reactions of various steroid derivatives possessing iodo- and bromo-alkenyl moiety (17-iodo-androst-16-ene, 1, 17-bromoandrost-2,16-diene, 2, 17-iodo-4-aza-4-methylandrost-16-en-3-one, 3, 17-iodo-4-azaandrost-16-en-3-one, 4) with vinyltributylstannane and ethynyltributylstannane were carried out in the presence of various palladium catalysts. While carbonylation took place only with vinyltributylstannane, 17-vinyl-, and 17-ethynyl-delta 16 steroids were produced via direct coupling with vinyltributylstannane and ethynyltributylstannane, respectively. Activities of some catalysts based on Pd(0) and Pd(II) precursors were compared, and Pd(PPh3)4 was found to be superior to other complexes in most cases. In the coupling of 17-iodoandrost-16-ene with organostannanes Pd2(dba)3 + 8 AsPh3 in situ catalyst was found to be even more effective.
Effect of operational variables on the separation of proteins by capillary sodium dodecyl sulfate-gel electrophoresis.
Capillary sodium dodecyl sulfate (SDS)-gel electrophoresis, for fast and high-resolution separations of protein molecules based on their molecular masses was investigated, employing a polymeric sieving network of polyethylene oxide (PEO). A standard mixture of five proteins ranging from 14.2-66.0 kDa in molecular mass was used to evaluate the sieving matrix. A general migration velocity equation was derived for capillary SDS-gel electrophoresis of proteins and supported by the experimental data. This equation gives a better understanding of SDS-protein separations via capillary gel electrophoresis. Results are presented regarding the effects of different operational variables such as gel concentration, electric field strength, molecular mass, and temperature on the electrophoretic migration properties of the different size protein molecules.
LH-RH analogue carrying a cytotoxic radical is internalized by rat pituitary cells in vitro.
The binding and internalization of a cytotoxic analogue of luteinizing hormone-releasing hormone (LH-RH), T-98 (agonist [D-Lys6]LH-RH linked to glutaryl-2-(hydroxymethyl)anthraquinone), by rat anterior pituitary cells was investigated. Analogue T-98 was bound to pituitary membrane binding sites for LH-RH with a high affinity (Kd = 1.2 nM) and was 17 times more potent in releasing luteinizing hormone (LH) from superfused rat pituitary cells than LH-RH. The labeling of this cytotoxic LH-RH analogue was carried out both with radioactive (125I) and nonradioactive iodine. Monoiodination of the Tyr5 residue of T-98 did not significantly affect its binding affinity but greatly decreased its LH-releasing activity to about 3% of the original value. Di-iodination in the same position lowered binding affinity twenty-threefold and further diminished LH-releasing potency. [125I]T-98 was found to bind very strongly to polystyrene, which precluded the use of regular tissue culture plasticware in our experiments. In pituitary cells cultured in glass vials, binding and internalization of [125I]T-98 were observed, which were time and temperature dependent, and which could be inhibited by excess unlabeled analogue. No enzymatic degradation of labeled T-98 was detected in the culture medium during the incubation. Our results indicate that T-98 is internalized by pituitary gonadotropes through receptor-mediated endocytosis. Because this new class of compounds was designed as anticancer drugs, our findings also suggest that this cytotoxic LH-RH agonist may also be internalized by LH-RH receptors present in breast, prostate, ovarian, and other tumors.
Autologous activated lymphocyte therapy in a community hospital.
In the authors' institution patients suffering from metastatic melanoma, renal cell carcinoma or mesothelioma, resistant to conventional therapeutic modilities, are treated with adoptive immunotherapy. Tumour infiltrating lymphocytes (TIL) are prepared from surgical samples and expanded ex vivo in the presence of recombinant interleukin-2 (rIL-2). When sufficient amount of cells are available (5 x 10(9)-10(10)) they are being reinfused. The patients also receive rIL-2 subcutaneously to support the activity and proliferation of reinfused TIL, and to avoid side effects caused by bolus or continuous intravenous administration. Leukapheresed lymphocytes activated by conditioned medium from OKT3 stimulated autologous lymphocytes and rIL-2 (autologous activated lymphocytes, AAL) are used as an alternative when TIL is not available or until it can be produced in sufficient amount. Subcutaneous IL-2 and oral cimetidine are also administered to support the reinfused AAL and to inhibit activation of CD8+ suppressor cells, respectively. Expression of activation markers CD25 and HLA-DR are monitored by flow cytometry as well as cytotoxicity is measured against K562 (NK specific target), HeLa (AALT specific) and against allogeneic or autologous tumour cell targets with a non-radioactive test. Methods are discussed by which the therapeutic efficiency of infused lymphocyte preparations can be improved.
Suppressed phagocytosis but promoted bacterial growth upon the effect of virus free supernatants of infected lymphocytes.
The pathomechanism of suppressed phagocytosis and bacterial superinfections which follow viral diseases is not completely understood. Both polymorphonuclear leukocytes (PMNL) and mononuclear phagocytes (MNPh) as well as bacterial growth are controlled by several cytokines produced by other immune cells. The effect of disturbed production of cytokines on phagocytes and microbes have not been studied yet. Peripheral T lymphocytes were infected with human adenoviruses (Ad) and herpes simplex virus type 1 (HSV-1) or were activated by phytohaemagglutinin (PHA), then culture supernatants containing no infectious virus were mixed to phagocytes swallowing viable Staphylococcus aureus. Influence of supernatants on eukaryotic and bacterial cell growth was compared to cytokine assays. Supernatant mediators, different from interferon (IFN) and tumour necrosis factor (TNF), induced by oncogenic Ad-12 or HSV-1 diminished phagocytosis of both PMNL and MNPh in a dose dependent manner, promoted bacterial growth free and inside MNPh, while those of latent Ad-5 and nononcogenic Ad-8 exerted moderate effects. Plating efficiency of HEp-2 cells was decreased by all of them. Supernatants of PHA treated lymphocytes containing IFN-gamma enhanced both phagocytosis and bacterial replication free and inside MNPh, while it suppressed HEp-2 plating. Neither viruses nor PHA affected phagocytic process directly. Staphylococci inside PMNL were not affected. Presumably, production of a single mediator by infected T lymphocytes is responsible for the multiple effects. Relationship with another soluble factors is discussed.
Novel somatostatin analogs with tyrosine kinase inhibitory and antitumor activity.
A series of new somatostatin analogs have been developed and tested for antitumor activity. Some analogs strongly inhibited tyrosine kinase activity of human colon tumor cells and this activity correlated well with their antiproliferative effect, but did not correlate with GH release inhibition. The best analogs strongly inhibited the metastasis formation in the Lewis lung metastasis model in mice. On the basis of these in vitro and in vivo data we were able to select one analog with strong tyrosine kinase inhibitory and antitumor activity, without inhibiting growth hormone release.
New Gaba-containing analogues of human growth hormone-releasing hormone (1-30)-amide: I. Synthesis and in vitro biological activity.
Analogues of human growth hormone-releasing hormone (1-30)-amide have been developed. All analogues have been modified in position 27 with Nle and with Gaba in position 30. Additional D-amino-acids have been inserted in the GHRH(1-30)-NH2 sequence: A-1741: Nle27,Gaba30-GH-RH(1-30)-NH2 A-495: D-Ala2,Nle27,Gaba30-GH-RH(1-30)-NH2 A-515: D Ala2,Leu15,Nle27,Gaba30-GH-RH(1-30)-NH2 A-527: D-Ala2,D-Arg11,Leu15,Nle27,Gaba30-GH-RH(1-30)-NH2. Our analogues were synthesized by solid phase peptide synthesis and were tested is two different in vitro systems and in rat pituitary cell cultures. A-495 and A-1741 were found to be the most active in releasing GH, however they showed different activities in the two different test systems. A-495 exhibited higher potency in the superfusion system (1.63 fold potency of the GHRH (1-29)-amide), while A-1741 evoked higher GH release from cultured pituitary cells (1.5-2.5 times higher than the GH-RH(1-44)-amide). The other analogues (A-515 and A-527) were found to be equipotent to the standard molecule. We can conclude that Nle27 and Gaba30 substitutions appeared to be a good modification in in vitro test systems, and Gaba30 substitution served as a good spacer during the synthesis, since it made the coupling of the C-terminal amino acids easier and produced quantitative coupling. In addition to the advantageous properties in the synthesis these modifications with or without D-Ala at the N-terminus increased the in vitro biological activity to 1.5-2.5 fold of the GHRH molecule.(ABSTRACT TRUNCATED AT 250 WORDS)