Biomedical subjects

R A Rajewski

Publications and source records attributed to R A Rajewski.

22 records · Page 2Linked to original sources

PubMed1996

The interaction of charged and uncharged drugs with neutral (HP-beta-CD) and anionically charged (SBE7-beta-CD) beta-cyclodextrins.

PURPOSE: The objective of this work was to determine the role that charge might play in the interaction of charged and uncharged drugs with neutral (2-hydroxypropyl-beta-cyclodextrin, HP-beta-CD) and anionically charged (SBE7-beta-CD) modified beta-cyclodextrins. SBE7-beta-CD is a sulfobutyl ether, sodium salt, derivative variably substituted on the 2-, 3- and the 6-positions of beta-cyclodextrin. The number seven refers to the average degree of substitution. METHODS: The binding of the acidic drugs, indomethacin, naproxen and warfarin and the basic drugs, papaverine, thiabendazole, miconazole and cinnarizine with the two cyclodextrins was determined at 25 degrees C as a function of pH and cyclodextrin concentration by the phase-solubility method. RESULTS: Except for miconazole and cinnarizine (Ap-type diagrams), all other materials studied displayed AL-type diagrams. By comparing the binding constants of both the charged and uncharged forms of the same drugs to both HP-beta-CD and SBE7-beta-CD, the following conclusions could be drawn. The binding constants for the neutral forms of the drugs were always greater with SBE7-beta-CD than with HP-beta-CD. For the anionic agents, the binding constants between SBE7-beta-CD and HP-beta-CD were similar while the binding constants for the cationic agents with SBE7-beta-CD were superior to those of HP-beta-CD, especially when compared with the neutral form of the same drug. CONCLUSIONS: A clear charge effect on complexation, attraction in the case of cationic drugs and perhaps inhibition in the case of anionic drugs, was seen with the SBE7-beta-CD.

2-Hydroxypropyl-beta-cyclodextrin↗

PubMed1995

Preliminary safety evaluation of parenterally administered sulfoalkyl ether beta-cyclodextrin derivatives.

Parenteral administration of beta-cyclodextrin (beta-CD) results in renal and/or local toxicity dependent on the mode of administration. In an attempt to alleviate these properties, a series of anionically charged sulfoalkyl ether cyclodextrin (SAE-beta-CD) derivatives have been developed. The parenteral safety of these derivatives was determined by survival of male mice after intraperitoneal (ip) injection, kidney histopathology, plasma urea nitrogen levels of mice determined 24 h after injection, relative in vitro hemolytic potential and activated partial thromboplastin times (APTT). In addition, the 24-h renal excretion behavior of the derivatives was measured. Where appropriate, the results obtained with these cyclodextrin derivatives were compared with results obtained for beta-CD and (hydroxypropyl)-beta-cyclodextrin (HP-beta-CD). The SAE-beta-CD derivatives did not produce mortality in mice following ip injection at doses exceeding 5.45 mmol/kg. No significant histological lesions were observed in the kidney tissue of mice receiving the cyclodextrin derivatives. The SAE-beta-CD derivatives were excreted faster and to a greater extent than beta-CD and at rates comparable to HP-beta-CD. The hemolytic potential of these derivatives was less than that of beta-CD and comparable to or better than that of HP-beta-CD. The SAE-beta-CD derivatives did not increase APTT clotting times indicating that these derivatives have no significant anticoagulant activity. The toxicological profile of these derivatives suggests that these molecules may have application as biologically safe beta-CD derivatives.

Animals↗

PubMed1995

Stereo-specific analysis of a novel protein kinase C inhibitor.

SPC-100270 drug substance ((2S,3S)-2-aminooctadecane-1,3-diol) is a synthetic sphingosine analogue possessing limited ultraviolet absorbance (UV) and two chiral centres. Analytical methodology employing derivatization of SPC-100270 with o-phthaldialdehyde (OPA) and a chiral thiol, N-acetyl-D-penicillamine, was developed to assess the isomeric purity of SPC-100270 in the presence of two of its three stereoisomers. Separation of the isoindole derivatives was achieved with isocratic reversed-phase column chromatography with detection at 330 nm. Under the conditions studied, the derivatization was complete within 3 h at 50 degrees C. The standard and derivatized solutions were stable for 7 days under refrigerated conditions. The limit of detection was 0.036 micrograms SPC-100270 per ml and the limit of quantitation was 0.237 micrograms SPC-100270 per ml. The assay response was linear over a concentration range of 4.7-376 micrograms SPC-100270 per ml with a coefficient of determination of greater than 0.9999. The precision, ruggedness and specificity of the assay were acceptable for determination of SPC-100270 in the presence of its stereoisomers and under forced degradation conditions. The method has been applied successfully in two independent laboratories for quality control release and stability assessment of SPC-100270 drug substance for early clinical studies.

Chromatography, High Pressure Liquid↗

PubMed1992

Characterization of sulphoalkyl ether derivatives of beta-cyclodextrin by capillary electrophoresis with indirect UV detection.

A capillary electrophoresis method which characterizes the degrees of substitution of heterogeneous sulphoalkyl ether beta-cyclodextrin derivatives is described. The separation is based on the different electrophoretic mobilities observed from changes in the overall charge of the molecule as a result of substitution. Individual peaks of the electropherogram then provide a measure of each degree of substitution of the present beta-cyclodextrin. Detection of these beta-cyclodextrin derivatives is performed by indirect UV detection.

Benzoates↗