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Biomedical subjects

I Toth

Publications and source records attributed to I Toth.

At least 55 records · Page 3Linked to original sources
PubMed1994

A novel chemical approach to drug delivery: lipidic amino acid conjugates.

A novel infinity-amino acid based oligopeptide system has been designed, which combines structural features of lipids with those of amino acids and peptides. Because of their bifunctional nature, the fatty amino acids and peptides have the capacity to be chemically conjugated to drugs and peptides with a wide variety of functional groups. The linkage between drug and lipidic unit may either be biologically stable (ie. a new drug is formed) or exhibit biological or chemical instability (ie. the conjugate is a pro-drug). In either case, the resulting conjugates would be expected to possess a high degree of membrane-like character, which may be sufficient to facilitate their passage across membranes. The long alkyl side chains may also have the additional effect of protecting a labile parent drug from enzymatic attack. The lipidic system has been conjugated to a wide variety of different compounds, including (i) alkaloids (ii) beta-lactam antibiotics, (iii) anticancer compounds (iv) CNS drugs and (v) peptides. The biological examination of the conjugates showed that an increase in lipophilicity caused an increase in the in vitro cellular and in vivo oral uptake, as well as passage through the blood-brain-barrier, suggesting that conjugation to lipidic amino acids and peptides is a useful approach to improve the absorption of poorly-absorbed drugs. Lipidic conjugates of peptides (TRH, LHRH) resulted in higher enzymatic stability of the conjugates, proving that the long alkyl side chains also have the additional effect of protecting a labile parent drug or peptide in a biological environment. A novel Lipid-Core-Peptide (LCP) system has also been synthesised by incorporating lipidic amino acids to a lysine based polyamino acid system to enhance lipophilicity and membrane binding effects and the metabolic stability of the compound. The LCP system as a combined adjuvant-carrier-vaccine greatly increased the immunogenicity of synthetic peptides.

Absorption↗
PubMed1993

Immunogenicity evaluation of a lipidic amino acid-based synthetic peptide vaccine for Chlamydia trachomatis.

Lipidic amino acid-based synthetic peptides derived from the variable domains (VD) of Chlamydia trachomatis outer membrane protein 1 were evaluated as potential candidate sequences in a vaccine. A peptide sequence designated P2 from the VD IV of serovar B contained a B cell epitope capable of eliciting antibodies binding to serovar B elementary bodies (EB) and a T helper site capable of presentation by multiple H-2 alleles. Polymerization of the P2 into polylysine to form lipid core peptides (LCP) significantly enhanced immunogenicity compared with P2 monomer alone. The LCP system incorporates lipidic amino acids into the polylysine system and enhances lipophobicity and membrane binding effects of the peptide. A second peptide sequence derived from the VD I of serovar C was cosynthesized with P2 into lipidic polylysine LCP and was designated LCP-H1. Antibodies to this construct reacted at high titer with EB of the three major trachoma causing C. trachomatis serovars A, B, and C. LCP-H1 was immunogenic among four of five murine H-2 alleles. Pepscan analysis showed that the fine specificity of antibodies generated to LCP-H1 were directed to the predetermined neutralizing epitope sequences. An in vitro HAK cell neutralization assay showed that LCP-H1 elicited neutralizing antibodies to serovars A, B, and C, but these were of low titer. Because LCP-H1 antibodies bound to the peptide sequence with 10-100-fold higher titer than to EB, the low neutralization titers most likely result from conformational differences between the synthetic peptide and antigenic sites on the native organism. Modification of LCP-H1 to incorporate a predefined conformation may result in improved antigenic properties.

Adjuvants, Immunologic↗
PubMed1992

Synthesis and spectroscopy of membrane receptor proteins. The gamma subunit of the IgE receptor.

The high-affinity receptor for IgE is a tetrameric complex of subunits of the type alpha beta gamma 2. We report here conformational studies of the intact gamma subunit in trifluoroethanol and water/liposomes by circular dichroism and Fourier-transform infrared (FTIR) spectroscopy. In trifluoroethanol, the FTIR amide I' frequencies were consistent with two predominant conformational components, the beta-turn and alpha-helix, whilst in liposomes consisting of D2O and dimyristoylglycerophosphocholine (Myr2GroPCho), three components were observed. The third component present may contain some left-handed extended helix. Spectral simulation was carried out to demonstrate that the CD spectra were consistent with the component conformations identified from FTIR spectroscopy. The stimulated CD spectra were in excellent agreement with the experimental spectra. The intact gamma subunit conformation in trifluoroethanol was shown to possess 72% alpha-helical and 28% beta-turn conformations. In water/Myr2GroPCho liposomes the percentage of each conformational component present is 37%, 38% and 25% for the alpha-helix, beta-turn and extended structures, respectively. Assuming that the transmembrane fragment was alpha-helical, an excellent correlation was found between this derived alpha-helical content in water/liposomes (37%) and from hydrophobicity plots where the percentage of amino acids in the transmembrane domain is predicted by others to be 34%. It is suggested that the beta-turn detected by CD and FTIR was attributable to a 3(10) helix rather than a type I or type III reverse turn.

Antigens, Differentiation, B-Lymphocyte↗
PubMed1992

Lipidic peptides. V: Penicillin and cephalosporin acid conjugates with increased lipophilic character.

Lipophilic, double-ester derivatives of beta-lactam antibiotics with methylene, ethylene, and propylene spacers were prepared by crown-ether-assisted coupling of halogenoalkyl esters of 2-(tert-butoxycarbonylamino)decanoic acid to either penicillin G or cefuroxime. The hydroxyethyl ester of penicillin G and the tert-butoxypropyl ester of cefuroxime were also prepared. The lipophilic, double-ester conjugates, the hydroxyethyl ester of penicillin G, and the tert-butoxypropyl ester of cefuroxime showed weak or no antibiotic activity in vitro, as expected. The lipophilic penicillin G conjugates and the tert-butoxypropyl ester of cefuroxime were active in vivo against a nonpenicillinase-producing strain of Staphylococcus aureus after subcutaneous administration. The penicillin G double ester with propylene spacer and the tert-butoxypropyl ester of cefuroxime were inactive in vitro, a fact indicating that both compounds were hydrolyzed in vivo, as desired. After oral administration, the lipophilic, double-ester conjugate of penicillin G with methylene spacer and the tert-butoxypropyl ester of cefuroxime were active.

Administration, Oral↗
PubMed1991

Lipidic peptides. III: Lipidic amino acid and oligomer conjugates of morphine.

A series of lipidic morphine esters 1b-1f with enhanced membrane-like character were synthesized by coupling the lipidic amino acids 2a-2e to the phenolic hydroxyl group of the opioid analgesic morphine (1a). The antinocioceptive activity of the esters 1b-1f was determined in vivo following both iv and oral dosing. After iv administration, four of the conjugates, 1b, 1c, 1d, and 1f, exhibited antinocioceptive activity in the mouse abdominal constriction test, with a potency similar to that of the parent compound 1a. Conjugate 1b showed activity following oral administration.

Administration, Oral↗
PubMed1991

Enzyme-linked immunosorbent assay for products of the 60-megadalton plasmid of Escherichia coli serotype O157:H7.

Eighty strains of pathogenic Escherichia coli, representing each of the major diarrheal disease-causing groups, were examined by direct enzyme-linked immunosorbent assay (ELISA) for the presence of proteins associated with a 60-MDa plasmid from E. coli serotype O157:H7. Antiserum specific for plasmid-encoded proteins was prepared by immunizing a rabbit with a wild-type E. coli O157:H7 strain (strain 7785) and absorbing the serum with a plasmid-cured derivative (strain 2-45). Use of this antiserum in Western immunoblot analysis detected two proteins of 82 and 92 kDa in strain 7785 but not in strain 2-45. All 16 wild-type E. coli O157:H7 strains and all 10 Shiga-like toxin (SLT)-producing E. coli strains of serotypes other than O157 were ELISA positive. Thirteen of 14 enterotoxigenic and all of 24 enteroinvasive E. coli strains were ELISA negative, as were all of 16 E. coli strains isolated from healthy persons. Of 16 traditional enteropathogenic E. coli (EPEC) serotypes, 10 were ELISA positive, including 10 of 12 strains carrying the EPEC adherence factor gene. Absorption of the serum with an EPEC adherence factor-positive EPEC eliminated EPEC reactivity. This study demonstrates that two plasmid-mediated proteins are common to E. coli O157:H7 strains and to SLT-producing strains of other serotypes. Detection of these proteins by ELISA provides a sensitive and specific screening test for identifying SLT-producing E. coli of both O157 and non-O157 serotypes. Identification of the cross-reactive proteins found in EPEC could provide the basis for a single assay to detect both EPEC and SLT-producing E. coli.

Bacterial Adhesion↗
PubMed1991

Rosai-Dorfman disease involving the premaxilla.

Sinus histiocytosis with massive lymphadenopathy (SHML), introduced in 1969 by Rosai and Dorfman, is a benign and self-limited (albeit often relapsing) pseudolymphomatous entity with characteristic histopathologic features. Although the presence of massive cervical lymphadenopathy often aids in the diagnosis of SHML, the disease may present in the absence of detectable nodal involvement (Rosai-Dorfman disease). Therefore, the physician must be aware of such extranodal presentations. A recent review of the 365 cases in the SHML registry has revealed a preponderance of eyelid and/or orbital involvement; only 26 cases were found with subcutaneous or soft tissue involvement in areas other than the eyelid and/or orbit. This is a case report of one such atypical presentation of SHML without clinically apparent lymphadenopathy or eyelid or orbital involvement.

Adult↗
PubMed1990

Hodgkin's disease after non-Hodgkin's malignant lymphoma in acquired immune deficiency syndrome.

Hodgkin's disease (HD) after treatment of non-Hodgkin's lymphoma (NHL) has been reported but is extremely rare, and to the authors' knowledge has not been reported in patients with acquired immune deficiency syndrome (AIDS). The authors present a case of an AIDS patient who developed mixed cellularity type HD 2.5 years after chemotherapy and radiotherapy for Stage II NHL. The patient died of infectious causes 1.5 years after interferon therapy for the HD. Autopsy revealed Stage IV HD, mixed cellularity type.

Acquired Immunodeficiency Syndrome↗
PubMed1990

Influence of the 60-megadalton plasmid on adherence of Escherichia coli O157:H7 and genetic derivatives.

The adherence of enterohemorrhagic Escherichia coli serotype O157:H7 and various genetic derivatives to Henle 407 intestinal and HEp-2 epithelial cell lines was examined by light and electron microscopy. The parent outbreak strain, 7785, harbors a 60-megadalton serotype-specific plasmid designated pO157 and adhered to both cell lines, as determined by light microscopy. A plasmidless derivative, 2-45, showed reduced adherence to both cell lines. After being labeled with Tn801, pO157 was transformed into E. coli C600, E. coli HB101, and E. coli GH42, and back into 2-45. Both E. coli C600 and HB101 transformants adhered weakly; full adherence was restored to the 2-45(pO157::Tn801) transformant. Transmission electron microscopy (EM) demonstrated the intimate attachment of HB101(pO157::Tn801) to Henle 407 cells which formed cuplike structures and areas of possible actin polymerization adjacent to adhering bacterial cells; scanning EM further extended these observations. EM studies of E. coli O157:H7 strains were hampered by extensive intestinal cell damage, presumably due to the action of Shiga-like toxins. EM also demonstrated that 7785 and its plasmidless derivative 2-45 were piliated and that no pili were apparent on HB101(pO157::Tn801) or GH42//(pO157::Tn801). The plasmid pO157 appears to modify the eucaryotic cell adherence of E. coli O157:H7 and to confer that adherence on E. coli HB101 through surface structures other than pili. These findings, when compared with other published reports, also suggest similarities between enterohemorrhagic and enteropathogenic E. coli adherence properties.

Bacterial Adhesion↗
PubMed1989

Coregulation of dihydrofolate reductase and thymidylate synthase in overproducer cell lines of wild carrot.

Dihydrofolate reductase (DHFR) and thymidylate synthase (TS) activities are associated with a 285,000 molecular weight enzyme complex in carrot (Daucus carota L.). Selection for methotrexate (MTX) resistance by stepwise increase of the concentration of MTX results in a high frequency adaptation to MTX with little or no significant increase in DHFR activity. However, when as a second step following MTX selection a specific inhibitor of TS, 5-fluoro-2-deoxyuridine was used, DHFR overproducer lines were obtained. The overproduction phenotype of the lines was almost completely lost after 8 weeks of growth in the absence of selection pressure. Although DHFR and TS are independent gene products, their activities increase in proportion ( approximately 20-fold) in the overproducer lines. This strongly suggests that DHFR and TS are not only functionally and physically linked in the same enzyme complex, but also are coregulated. These cell lines resemble the MTX-induced DHFR overproducer amplified cell lines of mammalian origin in their mode of selection, high frequency of appearance, elevated enzyme activity, and increased specific mRNA levels.

Journal Article↗
PubMed1987

Purification and immunochemical characterization of a dihydrofolate reductase-thymidylate synthase enzyme complex from wild-carrot cells.

An enzyme complex with dihydrofolate reductase (DHFR, E.C.1.5.1.3.) activity was purified to apparent homogenity from wild-carrot cells. The complex has a mol. wt of 286 kd and contains five polypeptide chains of 95, 70, 50, 45 and 26 kd. The DHFR enzyme activity and methotrexate-binding site are on the 45-kd subunit. Folate analogs (methotrexate, aminopterin and formylaminopterin) as well as SH-group inhibitors [p-hydroxymercuribenzoate, 5,5' -dithiobis(2-nitrobenzoic acid), or N-ethylmaleimide] inhibit DHFR. Thymidylate synthase (TS, E.C.2.1.1.45) activity co-purified with the enzyme complex through each of seven steps and co-eluted from gel filtration columns with the DHFR activity at the mol. wt of the enzyme complex. Further identification of TS within the complex was achieved using a Leishmania DHFR-TS antisera which specifically inhibited the carrot TS, although it immunoprecipitated both TS and DHFR. Polyclonal antisera, raised against and specific for the complex as judged by Ouchterlony double diffusion tests and Western blot analysis, inhibited and immunoprecipitated both DHFR and TS. The Leishmania antisera also identified the 70-kd polypeptide within the purified complex as TS in a Western blot experiment. The functions of the other three polypeptides have not yet been established.

Journal Article↗
PubMed1987

Berbanes: a new class of selective alpha 2-adrenoceptor antagonists.

The alpha-adrenoceptor blocking properties of some berbanes have been studied and compared with those of idazoxan, yohimbine, phentolamine, and prazosin. Their effects on presynaptic alpha 2-adrenoceptors were studied on chemical neurotransmission of isolated rat vas deferens and longitudinal muscle strip of guinea pig ileum; xylazine or norepinephrine was employed as agonist. The alpha 1-adrenoceptor blocking activities of the berbanes were tested on isolated rat vas deferens and rabbit pulmonary artery by using phenylephrine or norepinephrine as agonist. The antagonistic activity of the berbanes and the reference compounds on alpha 2- and alpha 1-adrenoceptors was characterized by the apparent pA2 values. Of the compounds studied, [8aS*-(8a alpha,12a alpha,13a alpha)]-11 alpha-hydroxy-5,6,8a,9,10,11,12a,13,13,a-decahydro-8H-benzo[g]-1,3 -benzodioxolo[5,6-a]quinoli zine, 6d, proved to be the most selective antagonist at the presynaptic alpha 2-adrenoceptors (alpha 1:alpha 2 ratio = 1659). Since blockade of alpha 2-adrenoceptors located on noradrenergic axon terminals leads to an increase of norepinephrine release, this compound could have potential as an antidepressant agent.

Adrenergic alpha-Antagonists↗
PubMed1978

Cryoglobulinemia and amyloidosis associated with intestinal lymphoma.

A case of lymphocytic lymphoma of the small intestine was associated with cryoglobulinemia and amyloidosis. The neoplastic lymphoid cell demonstrated surface IgG membrane markers by immunofluorescence and immunoelectron microscopy. The cryoglobulins were characterized as monoclonal IgG3 proteins with lambda light chains. Amyloidosis of the small intestine and regional lymph nodes was found in association with lymphatic infiltration of these organs, suggesting the production of amyloid in situ.

Aged↗