Search PubMed⌕ Search

Biomedical subjects

B Mehlis

Publications and source records attributed to B Mehlis.

12 recordsLinked to original sources
PubMed1991

Gonadotropin-releasing hormone (GnRH) analogs: relationship between their structure, proteolytic inactivation and pharmacokinetics in rats.

There are two types of superactive agonists of gonadotropin-releasing hormone (GnRHa-I: (D-amino acid)6-GnRH and GnRHa-II: (D-amino acid)6-(desGly)10-GnRH- ethylamide) the high hormonal activity of which is understood to be due to their higher receptor affinity and their higher proteolytic stability as compared with the native GnRH sequence. Using the soluble fractions of various rat tissues in studies on the inactivation of GnRH peptides, we confirmed the higher proteolytic resistance of GnRHa-II, but not of D-Phe6-GnRH (GnRHa-I) and of another analog, D-Trp3-D-Phe6-GnRH, as compared with GnRH. The exact behaviour of the peptides during degradation was found to be dependent on the peptide concentrations used, showing the importance of using conditions as near to the physiological ones a possible. Towards the membrane fractions, however, the order of degradability was found to be GnRH much greater than D-Phe6-GnRH much greater than D-Trp3-D-Phe6-GnRH. The pharmacokinetic consequences of the different proteolytic degradabilities of the GnRH peptides, observed in rats, were a moderate increase in the biological half-life of D-Phe6-GnRH by 2.5-fold, as compared with GnRH, and a small increase in half-life of D-Trp3-D-Phe6-GnRH by 1.4-fold when compared with D-Phe6-GnRH. Whereas no intact GnRH was recovered in rat urine, small amounts of D-Phe6-GnRH (about 1% of dose) and high amounts of D-Trp3-D-Phe6-GnRH (25.5%) were excreted into urine. Combining the biochemical and pharmacokinetic data, it is concluded that proteolytic stability of GnRH analogs in pharmacological terms means stability towards membrane enzymes (pharmacologically-related stability) and that designing analogs with further increased proteolytic stability will be of only limited consequences with respect to their biological half-lives, the glomerular filtration rate of the kidney becoming the determining factor in the peptide clearance.

Amino Acid Sequence↗
PubMed1991

In-vivo release of a GnRH agonist from a slow-release poly(lactide-glycolide) copolymer preparation: comparison in rat, rabbit and guinea-pig.

Different batches of 50:50 poly((+-)-lactide-glycolide) copolymer (PLG) were used as biodegradable carriers for D-Phe6-gonadotropin-releasing hormone (GnRHa) in the form of injectable long-acting implants loaded with 10% GnRHa and tracer amounts of [125I]GnRHa. After their injection subcutaneously into rats, rabbits, and guinea-pigs, the release kinetics of the peptide were determined by counting the radioactivity remaining in the implants (i) after recovery from the rats after death or (ii) directly on the skin above the injection site of rabbits and guinea-pigs in-vivo. No significant differences in the release pattern of the peptide amongst the three species whether the release process was controlled by diffusion or by degradation of the polymeric matrix were found. It is concluded that the results of in-vivo release tests using laboratory animals are valid for man and that enzymes are not involved in the degradation of the polymeric matrix. The results may be of general importance for the use of long-term release PLG formulations of highly active drugs, especially peptides and proteins.

Animals↗
PubMed1990

Insulin aggregation in solution.

The process of insulin aggregation in neutral solutions was studied by dynamic light scattering. Solutions of different concentrations were subjected to thermal and mechanical stress (37 degrees, rotation) for a period of 4 weeks. The starting solutions contained exclusively one particle distribution of insulin in the association equilibrium with hexamers as the largest structures. After a lag period of about 8 days the solutions showed continuously increasing scattering intensities but did not evolve perceptible turbidity within the experimental period. A more rapid increase in scattering intensity was observed in diluted than in concentrated solutions. The analysis of scattering data unexpectedly revealed that insulin species did not grow continuously. After the lag period one additional relatively restricted size distribution with particles of a mean radius of about 100 nm was found, the amount of which increased continuously with time. The occurrence of these particles seems to be related to adsorption phenomena of insulin to the solid interface. We assume the 100 nm-class of aggregates to be a transient state in the physical destabilization process of insulin solutions.

Humans↗
PubMed1988

Gonadotropin-releasing hormone (GnRH) pharmacokinetics: peptide hormone pharmacokinetics needs clarification.

The plasma level curves of the peptide hormone gonadotropin-releasing hormone (GnRH) after its intravenous, intramuscular, and intraperitoneal administration into rats were fitted according to a two- (i.v.) and one-compartment model (i.m., i.p.), respectively. From the pharmacokinetic parameters it is concluded that urinary excretion and proteolytic degradation by kidney and liver are not sufficient to fully account for the clearance of the hormone and that, therefore, proteolytic degradation by tissues may play a role for the elimination of GnRH. This may be generally true with other short peptide hormones. The GnRH pharmacokinetics is shown as an example to underline that there presently exist problems of interpreting pharmacokinetic data of peptide hormones and that there is a need for a close interplay between biochemical and pharmacokinetic studies on peptide hormones for their pharmacokinetic behaviour to be understood.

Absorption↗
PubMed1986

[The purification and characterization of Cordemcura].

3-Amino-5-(4-pyridinyl)-1,2-dihydro-pyrid-2-one (1) is an amphoteric compound and forms one crystalline sodium salt and two hydrochlorides. Physicochemical properties UV, NMR and MS are described. TLC has been used mainly and is the most sensitive method for estimation of 1-byproducts. Coloured byproducts, generated by hypochlorite or air oxidation during synthesis and handling in solution, are monitored by vis-spectra, diminished by sulfite addition and removed by alkaline precipitation. The purification procedure is able to produce 1 with only 0.1% of precursors or byproducts.

Aminopyridines↗
PubMed1985

[Synthesis of cyclic and non-cyclic tachykinin partial sequences. 2. Synthesis of the homocyclic substance P(6-11) hexapeptide].

The authors describe the synthesis of Gln-Phe-Phe-Gly-Leu-Met by cyclization of H-Leu-Met-Gln-Phe-Phe-Gly using three different methods. The linear sequence was obtained by a (2+4)-segment condensation. The resulting cyclopeptide showed only a small kinin activity on isolated guinea pig ileum compared to substance P, but it is a full agonist.

Amino Acid Sequence↗
PubMed1985

[The influence of viscosity-increasing pharmaceutic aids on the liberation of the peptide gonadotropin releasing hormone (GnRH) in solution].

The in vitro liberation of the peptide hormone GnRH from polymer solutions was studied as a function of the viscosity of the polymer solutions. The liberation experiments were performed with a flow through dialysis apparatus. From solutions of dextran, carboxymethylcellulose, hydroxyethylcellulose, and polyvinylpyrrolidone the release of GnRH is prolonged whereas the release of GnRH from highly viscous solutions of methylcellulose and polyacrylic acid is not. The delivery process was found to be diffusion-controlled in solutions of dextran, carboxymethylcellulose, and hydroxyethylcellulose. In solutions of polyvinylpyrrolidone the diffusion-controlled prolongation of the GnRH release is additionally influenced by binding of the peptide to the polymer. The results imply that in these polymer solutions the diffusion coefficient of GnRH does not obey the classical relation D approximately 1/eta which is often used to predict liberation from viscous solutions. Thus, the measured macroscopic viscosity of the polymer solutions is not relevant for the diffusion-controlled prolongation of the in vitro release of GnRH. This phenomenon can be explained by the obstruction effect and the microviscosity of the polymer solutions. The described rapid and simple method can be applied for the quantitative determination of the prolonged release in polymer solutions based on diffusion-controlled processes and is useful in the comparison of the efficacy of various polymeric additives. Furthermore the method allows the quantitative proof of the decrease of diffusion in viscous low-molecular solutions and the proof of prolongations of delivery due to the binding of the investigated drug to the polymer.

Diffusion↗
PubMed1975

[Studies on the mechanism of action of peptides attacking smooth muscles. III. The effect of N-azylation on the activity of C-terminal partial sequences of eledoisin, physalaemin and substance P on the guinea pig ileum].

C-terminal pentapeptides of eledoisin, physalaemin, and the substance P, when N-substituted with acetyl, halogenacetyl and other acyl residues, are increased in their action more than 100fold, reaching the activity of acylated hexa- and heptapeptides. The effect found with a number of compounds is interpreted as the influence of predominantly hydrophobic substituents upon the peptide sequence essential for the action. Polar groups in the acylic residue seem to cause additional increase in action.

Animals↗
PubMedDate not supplied

Proteolytic inactivation of luteinizing hormone-releasing hormone (LHRH) by the whole rat ovary in vitro.

Using 3H-labeled luteinizing hormone-releasing hormone (LHRH) at low concentrations, the in vitro proteolytic inactivation of the peptide hormone by whole rat ovaries was studied and compared with that by the soluble and particulate rat ovarian fraction. Whole rat ovaries were found to express the three proteolytic activities that were, according to their properties, also observed in rat ovarian homogenates: (1) soluble intracellular activity which was released into the medium, (2) released activity of membrane-bound origin, and (3) firmly membrane-bound activity. It is suggested that in vivo LHRH is largely inactivated extracellularly at least by enzymes that are located in the plasma membrane although the membrane-bound activity comprises only about 1% of the whole LHRH-inactivating capacity of the ovary.

Animals↗