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Biomedical subjects

J C Jamoulle

Publications and source records attributed to J C Jamoulle.

At least 19 recordsLinked to original sources
PubMed1992

Influence of formulation, receptor fluid, and occlusion, on in vitro drug release from topical dosage forms, using an automated flow-through diffusion cell.

An automated flow-through diffusion cell apparatus was used for comparing the release rates of a naphthoic acid derivative, CD 271, from different topical formulations. The influence of the following parameters on CD 271 release from the formulations was investigated: receptor fluid composition, occlusion, weight of tested formulation, and dosage form type. The amount of tested formulation was shown to have no significant effect on the apparent release constant and lag time for an anionic oil-in-water emulsion and an aqueous gel. Occlusion affected drug release from the different dosage forms. Thus, occlusion increased CD 271 pharmaceutical availability for a lotion and a hydroalcoholic gel containing 0.1% of solubilized drug. The release profile of CD 271 from the formulations was highly dependent on the receptor fluid composition. Drug release was dramatically enhanced with n-octanol as compared to an aqueous solution of surfactant. Using occlusive or nonocclusive procedures, CD 271 apparent release constant and lag time were found to be highly dependent on the type of tested formulation. The flow-through diffusion cell proposed in the present study allows an accurate comparison of drug release characteristics from prototype topical formulations and therefore represents a valuable tool for formulation research or quality control process.

Adapalene↗
PubMed1990

Reconstituted epidermis: a novel model for the study of drug metabolism in human epidermis.

The metabolic capacity of reconstituted epidermis from the outer root sheath cells of human hair follicles was determined. It was found that this epidermis possesses enzymes involved in both phase I (oxidation) and phase II (conjugation) reactions for drug biotransformation. The use of model substrates allowed the characterization of several isoenzymes. The homogenate fraction contained membrane-bound mixed-function oxydases (cytochrome P-450 dependent) involved in the O-dealkylation of 7-ethoxy-, 7-pentoxy-, and 7-benzoxyresorufin, NADPH cytochrome c (P-450) reductase, testosterone 5 alpha-reductase, and UDP-glucuronosyltransferases, which conjugate 1-naphthol and bilirubin. One isoform of each glutathione S-transferase, steroid-, and arylsulfatases, acting on estrone- and 4-methylumbelliferone sulfates, was detected. Additionally, the activity of two distinct forms of epoxide hydrolases, which hydrate cis- and trans-stilbene oxides, could be measured. The presence of these drug metabolizing enzymes in the reconstituted epidermis indicates that it has a potential to serve as a model to study epidermal drug metabolism in vitro.

Arylsulfatases↗
PubMed1987

Respective role of each of the purine N7 nitrogens of 5'-O-triphosphoadenylyl(2'----5')adenylyl(2'----5')adenosine in binding to and activation of the RNase L of mouse cells.

Through a combination of chemical and enzymatic approaches a series of sequence-specific tubercidin-substituted ppp5'A2'p(5'A2'p)n5'A (n = 1 to about 10; 2-5A) analogues were generated. In addition to the previously developed methodology of Imai and Torrence [Imai, J., & Torrence, P.F. (1985) J. Org. Chem. 50, 1418-1420], a new approach to synthesis of 2',5'-linked oligonucleotides utilized adenosine in 3',5' linkage as a precursor to the targeted 5'-terminus of the desired product. For instance, A3'p5'A could be condensed under conditions of lead ion catalysis with tubercidin 5'-phosphate to give A3'p5'A2'p5'(c7A). Treatment with the 3',5'-specific nuclease P1 led to p5'A2'p5'(c7A). The combined use of the above procedures led to the synthesis of p5'(c7A)2'p5'A2'p5'A, p5'A2'p5'(c7A)2'p5'A, p5'A2'p5'A2'p5'(c7A), and p5'A2p5'(c7A)2'p5'(c7A), which were converted to their corresponding 5'-triphosphates by the usual methods. Evaluation of these analogues for their ability to bind to and activate the 2-5A-dependent endonuclease (RNase L) of mouse L cells showed that there were small changes (less than or equal to 10-fold) in the ability of the four tubercidin analogues to bind to RNase L. However, whenever the first and/or third adenosine nucleotide units were replaced by tubercidin, a dramatic decrease in ability to activate RNase L occurred. Only the second (from the 5'-terminus) adenosine residue could be replaced by tubercidin without any effect on RNase L activation ability.

Adenine Nucleotides↗
PubMed1985

Sequence-specific 2'5'-oligonucleotides in the molecular dissection of the biological activity of 2-5A.

Recently developed chemical synthetic methodology for facile preparation of sequence-specific 2'5'-oligonucleotides has allowed more exacting questions to be asked regarding the biological role of each of the nucleotide residues of 2-5A. We have found, employing analogs in which each adenosine residue has been sequentially replaced by adenosine (viz, ppp5'I2'p5'A2'p5'I, ppp5'A2'p5'I2'p5'A, ppp5'A2'p5'A2'p5'I) that the N6 amino group of the first (or 5'-terminal) adenosine residue of 2-5A trimer is critical in RNase L binding whereas the N6 amino moiety of the third (or 2'-terminal) adenosine residue of 2-5A is crucial for the activation of RNase L. The second or middle adenosine unit of 2-5A does not seem to be critical for either binding or activation. Similarly, in studies on sequence-specific tubercidin analogs of 2-5A, activation of but not binding to mouse RNase L was dependent on the presence of the purine N7 atoms of the first and third adenosine residues of 2-5A, but, as with the N6 amino group, the N7 moiety of the second adenosine residue of 2-5A was not essential for either binding to or activation of the 2-5A-dependent endonuclease. Finally, sequence-specific purine 8-bromination provided analogs of dramatically varying biological properties, and provided a 5'-monophosphate, p5'A2'p5'(br8A)2'p5'(br8A), which possessed 8% of the translational inhibitory action of 2-5A itself. This latter result may represent an important impetus toward obtaining a 2-5A derivative with biological activity in an intact cell.

Adenine Nucleotides↗
PubMed1984

Synthesis and biological activity of tubercidin analogues of ppp5'A2'p(5'A2'p)n5'A.

A series of tubercidin (7-deazaadenosine) analogues of 2-5A of the general formula p5'(c7A)2'p[5'(c7A)-2'p]n5'(c7A) (n = 0-5) were prepared by lead ion catalyzed polymerization of the 5'-phosphoroimidazolidate of tubercidin. Through the corresponding imidazolidates, these oligonucleotide 5'-monophosphates were converted to the 5'-triphosphates. All reported structures were corroborated by enzyme digestion and 1H or 31P nuclear magnetic resonance. When evaluated for its ability to bind to the 2-5 A-dependent endonuclease of mouse L cells, the tubercidin analogue of trimeric 2-5A, namely, ppp5'(c7A)2'p5'(c7A)2'p5'(c7A), and the corresponding tetramer were bound as effectively as 2-5A itself; nonetheless, it and the corresponding tetramer, ppp5'-(c7A)2'p5'(c7A)2'p5'(c7A)2'p5'(c7A), failed to stimulate the 2-5A-dependent endonuclease as judged by its inability to inhibit translation in extracts of mouse L cells programmed with encephalomyocarditis virus RNA and to give rise to ribosomal RNA cleavage in the same cell system under conditions where 2-5A showed activity at 10(-9) M. The trimer, ppp5'(c7A)2'p5'(c7A)2'p5'(c7A), was an antagonist of 2-5A action in the L cell extract. In the lysed rabbit reticulocyte system, both the trimeric and tetrameric tubercidin 2-5A analogues were bound to the 2-5A-dependent endonuclease as well as 2-5A, but in this case, the tetramer triphosphate, ppp5'(c7A)2'p5'(c7A)2'p5'(c7A)2'p5'(c7A), was just as potent an inhibitor of translation as 2-5A tetramer triphosphate. Moreover, this inhibition was prevented by the established 2-5A antagonist p5'A2'p5'A2'p5'A.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenine Nucleotides↗
PubMed1984

Active-site-directed inactivators of the Zn2+-containing D-alanyl-D-alanine-cleaving carboxypeptidase of Streptomyces albus G.

Several types of active-site-directed inactivators (inhibitors) of the Zn2+-containing D-alanyl-D-alanine-cleaving carboxypeptidase were tested. (i) Among the heavy-atom-containing compounds examined, K2Pt(C2O4)2 inactivates the enzyme with a second-order rate constant of about 6 X 10(-2)M-1 X S-1 and has only one binding site located close to the Zn2+ cofactor within the enzyme active site. (ii) Several compounds possessing both a C-terminal carboxylate function and, at the other end of the molecule, a thiol, hydroxamate or carboxylate function were also examined. 3-Mercaptopropionate (racemic) and 3-mercaptoisobutyrate (L-isomer) inhibit the enzyme competitively with a Ki value of 5 X 10 X 10(-9)M. (iii) Classical beta-lactam compounds have a very weak inhibitory potency. Depending on the structure of the compounds, enzyme inhibition may be competitive (and binding occurs to the active site) or non-competitive (and binding causes disruption of the protein crystal lattice). (iv) 6-beta-Iodopenicillanate inactivates the enzyme in a complex way. At high beta-lactam concentrations, the pseudo-first-order rate constant of enzyme inactivation has a limit value of 7 X 10(-4)S-1 X 6-beta-Iodopenicillanate binds to the active site just in front of the Zn2+ cofactor and superimposes histidine-190, suggesting that permanent enzyme inactivation is by reaction with this latter residue.

Binding Sites↗
PubMed1984

Oligonucleotide structural parameters that influence binding of 5'-O-triphosphoadenylyl-(2'----5')-adenylyl-(2'----5')-adenosine to the 5'-O-triphosphoadenylyl-(2'----5')-adenylyl-(2'----5')-adenosine dependent endoribonuclease: chain length, phosphorylation state, and heterocyclic base.

A number of 2',5'-linked oligoadenylates and their analogues were prepared and evaluated for their ability to interact with the 5'-O- triphosphoadenylyl -(2'----5')-adenylyl-(2'----5')-adenosine (2-5A) dependent endoribonuclease of mouse L cells. The oligonucleotides were assayed for their ability to antagonize the action of 2-5A, to displace a radiolabeled probe from the 2-5A-dependent nuclease, or to inhibit translation in a cell-free system. These experiments demonstrated the following: (1) Three AMP residues in a 5'-phosphorylated oligonucleotide were needed for maximum interaction with the endonuclease, and higher oligomers (greater than or equal to 4 AMP residues) did not show significantly higher binding. (2) The third (2'-terminal) adenosine residue was required for optimal binding activity. (3) 5'-Phosphorylation of the oligonucleotide was necessary for maximum binding to the endonuclease, but the first (from the 5' terminus) internucleotide phosphate of higher unphosphorylated or core oligomers, such as A2'p5'A2'p5'A2'p5'A, may partly replace the requirement for a 5'-monophosphate moiety; in agreement with this, the 5'-methyl ester of 5'pA2'p5'A2'p5'A, i.e., Me-p5'A2'p5'A2'p5'A, was bound to the endonuclease as well as or better than the higher core oligomers but approximately 100 times more effectively than the trimer core, A2'p5'A2'p5'A. (4) Base-modified analogues, such as p5'C2'p5'C2'p5'C, p5'U2'p5'U2'p5'U, or p5'I2'p5'I2'p5'I, were at least 2000 times less effectively bound to the endonuclease than p5'A2'p5'A2'p5'A. (5) The triphosphate ppp5 'I2'p5'I2'p5'I was 10 000 times less active than 2-5A as an inhibitor of translation. These latter two points implied the critical role of the adenine N1-nitrogen and/or exocyclic amino group in the binding of 2-5A to the endonuclease.

Adenine Nucleotides↗