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Biomedical subjects

C Hendrix

Publications and source records attributed to C Hendrix.

At least 19 recordsLinked to original sources
PubMed2001

A straightforward stereoselective synthesis of D- and L-5-hydroxy-4-hydroxymethyl-2-cyclohexenylguanine.

A novel and facile synthesis of 5-hydroxy-4-hydroxymethyl-2-cyclohexenylguanine 1 is described. The key steps involve a Diels-Alder reaction of ethyl (2E)-3-acetyloxy-2-propenoate 2 as dienophile with Danishefsky's diene 3 to build up the six-membered ring skeleton, a Fraser-Reid reductive rearrangement of the adduct using LiAlH(4), and base-moiety introduction using a Mitsunobu reaction. Optically pure D- and L-1 were obtained via resolution of intermediate 7 with (R)-(-)-methylmandelic acid. The synthetic procedure toward racemic 1 consists of only five steps and has proven to be highly efficient toward the synthesis of cyclohexenyl nucleosides.

Aluminum Compounds↗
PubMed2000

Enzymatic incorporation in DNA of 1,5-anhydrohexitol nucleotides.

The ability of several DNA polymerases to catalyze the template-directed synthesis of duplex oligonucleotides containing a base pair between a nucleotide with anhydrohexitol ring and its natural complement has been investigated. All DNA polymerases were able to accept the chemically synthesized anhydrohexitol triphosphate as substrate and to catalyze the incorporation of one anhydrohexitol nucleotide. However, only family B DNA polymerases succeeded in elongating the primer after the incorporation of an anhydrohexitol nucleotide. In this family, Vent (exo(-)) DNA polymerase is the most successful one and was therefore selected for further investigation. Results revealed that at high enzyme concentrations six hATPs could be incorporated; however, a selective incorporation proved only feasible under experimental conditions where no more than two analogues could be inserted. Also the synthesis of a mixed HNA-DNA sequence was examined. Kinetic parameters for incorporation of one anhydrohexitol adenine nucleoside were similar to those of its natural analogue.

Chromatography, High Pressure Liquid↗
PubMed2000

Platelet GP IIIa Pl(A) polymorphisms display different sensitivities to agonists.

BACKGROUND: Both inherited predisposition and platelet hyperreactivity have been associated with ischemic coronary events, but mechanisms that support genetic differences among platelets from different subjects are generally lacking. Associations between the platelet Pl(A2) polymorphism of GP IIIa and coronary syndromes raise the question as to whether this inherited variation may contribute to platelet hyperreactivity. METHODS AND RESULTS: In this study, we characterized functional parameters in platelets from healthy donors with the Pl(A) (HPA-1) polymorphism, a Leu (Pl(A1)) to Pro (Pl(A2)) substitution at position 33 of the GP IIIa subunit of the platelet GP IIb/IIIa receptor (integrin alpha(IIb)beta(3)). We studied 56 normal donors (20 Pl(A1,A1), 20 Pl(A1,A2), and 16 Pl(A2,A2)). Compared with Pl(A1,A1) platelets, Pl(A2)-positive platelets showed a gene dosage effect for significantly greater surface-expressed P-selectin, GP IIb/IIIa-bound fibrinogen, and activated GP IIb/IIIa in response to low-dose ADP. Surface expression of GP IIb/IIIa was similar in resting platelets of all 3 genotypes but was significantly greater on Pl(A2,A2) platelets after ADP stimulation (P=0.003 versus Pl(A1,A1); P=0.03 versus Pl(A1,A2)). Pl(A1,A2) platelets were more sensitive to inhibition of aggregation by pharmacologically relevant concentrations of aspirin and abciximab. CONCLUSIONS: Pl(A2)-positive platelets displayed a lower threshold for activation, and platelets heterozygous for Pl(A) alleles showed increased sensitivity to 2 antiplatelet drugs. These in vitro platelet studies may have relevance for in vivo thrombotic conditions.

Abciximab↗
PubMed2000

The cyclohexene ring system as a furanose mimic: synthesis and antiviral activity of both enantiomers of cyclohexenylguanine.

Both enantiomers of cyclohexenylguanine were synthesized in a stereospecific way starting from the same starting material: R-(-)-carvone. Both compounds showed potent and selective anti-herpesvirus activity (HSV-1, HSV-2, VZV, CMV). The binding of both cyclohexene nucleosides in the active site of HSV-1 thymidine kinase was investigated, and a model for the binding of both enantiomers is proposed. The amino acids involved in binding of the optical antipodes are the same, but the interaction energy of both enantiomers is slightly different. This may be attributed to the interaction of the secondary hydroxyl function of the nucleoside analogues with Glu-225. Structural analysis has demonstrated the flexibility of the cyclohexenyl system, and this may be considered as an important conformational characteristic explaining the potent antiviral activity.

Animals↗
PubMed1999

Laser resurfacing complication.

A 43 year-old woman had full facial laser resurfacing for treatment of multiple actinic keratoses and aging skin. Healing was uneventful on most of the areas treated except the forehead, where a progressive nonhealing wound developed. After seeking numerous consultations around the Southeast, the patient came to our facility, 6 months after the initial laser treatment, with exuberant granulation tissue of the forehead and temples and a painful wound. Many topical treatments had been previously tried. Debridement and split-thickness skin grafting were done using general anesthesia. Pathologic analysis revealed hyperplastic granulation tissue and epidermal appendages. The wound healed with an improved aesthetic result. This case illustrates that seemingly impossible laser complications can be handled by a basic approach to wound healing.

Adult↗
PubMed1997

alpha-Amino acids derived from ornithine as building blocks for peptide synthesis.

Recently great interest has arisen in the synthesis of combinatorial libraries, and this technology provides a significant partner to contemporary strategies in rational design and lead discovery. By simple combination of a given set of building blocks, high numbers of different molecules are produced simultaneously, increasing the possibility of discovery of a lead compound in a limited time. One direction of research in this field focuses on the synthesis of libraries composed of modified amino acids. Here, the synthesis and characteristics of some building blocks derived from ornithine are described. The synthesis is based on the acylation/sulfonation of the copper complex of ornithine by aroyl and arylsulfonyl chlorides exemplified by 2-thiophenecarbonyl chloride, p-toluenesulfonyl chloride and 8-quinolinesulfonyl chloride. To evaluate the potential use of these modified alpha-amino acids as component in an oligopeptide library, all three derivatives were incorporated in a hexapeptide with a random sequence using a standard coupling procedure (DIC/HOBt/DIEA). Depending upon the acidity of the amido hydrogen on the delta-nitrogen, competition between intramolecular cyclization and peptide bond formation was observed. The higher the acidity, the more pronounced is this side reaction. Coupling conditions for peptide formation were optimized so that the newly described amino acid based building blocks are suitable for incorporation into libraries consisting of unnatural amino acids. The outlined procedures open up a broad avenue of possibilities for creation of diversity into peptidic libraries.

Amino Acids↗
PubMed1996

Selection of hammerhead ribozymes for optimum cleavage of interleukin 6 mRNA.

Four GUC triplets in the coding region of the MRNA of interleukin 6 (IL-6) were examined for their suitabilty to serve as a target for hammerhead ribozome-mediated cleavage. This selection procedure was performed with the intention to downregulate IL-6 production as a potential treatment of those diseases in which IL-6 overexpression is involved. Hammerhead ribozymes and their respective short synthetic substrates (19-mers) were synthesized for these four GUC triplets. Notwithstanding the identical catalytic core sequences, the difference in base composition of the helices involved in substrate binding caused substantial variation in cleavage activity. The cleavage reactions on the 1035 nucleotide IL-6 mRNA transcript revealed that two ribozymes were able to cleave this substrate, showing a decrease in catalytic efficiency to 1/30 and 1/300 of the short substrate. This study indicates that the GUC triplet located at nucleotide 510 of the mRNA of IL-6 is the best site for hammerhead ribozyme-mediated cleavage. We suggest that in future targeting of chemically modified hammerhead ribosomes for cleavage of IL-6 RNA should be directed at this location.

Base Sequence↗
PubMed1995

In vitro NCp7 enhancement of ribozyme-mediated cleavage of full-length human IL-6 mRNA.

We have previously shown that a ribozyme directed against human interleukin-6 (IL-6) mRNA is efficient in vivo, despite its poor activity in vitro on full-length IL-6 mRNA. We compared the effect of the nucleocapsid protein of HIV-1 (NCp7) on the ribozyme cleavage reaction of a long (1041 nt) and a short (19 nt) substrate IL-6 RNA in vitro. At a one to five molar ratio of the long substrate to ribozyme, almost no cleavage is observed after 30 min at 37 degrees C. The NCp7 protein significantly increases the catalytic activity of the ribozyme on this substrate (from 0 to 53% after 7 min at 37 degrees C), but not on the short one. A kinetic analysis of single turnover reactions performed with ribozyme in at least fivefold molar excess over substrate also lead to a stimulation (70-fold) of the reaction rate with long substrate, but not with the shorter one. Preferential increases of the catalytic activity on the long substrate suggests that the NCp7 protein prevents misfolding of RNAs.

Base Sequence↗
PubMed1995

Catalytic activity and stability of hammerhead ribozymes containing 2'-acetamido-2'-deoxyribonucleosides.

Hammerhead ribozymes may be of great therapeutic importance, since they can, in theory, be developed to cleave any undesired target RNA. In order to design ribozymes which are stable against endogenous RNases, we incorporated 2'-acetamido-2'-deoxynucleosides in the catalytic core of a hammerhead ribozyme. The 2'-acetamido function has, like the hydroxyl group, both proton donor and proton acceptor capacities, which seem to be crucial for efficient catalytic activity. However, the presence of 2'-acetamido-2'-deoxypyrimidine residues in the catalytic core caused a considerable drop in cleavage rate. Replacement of the purine residues led to complete loss of the catalytic activity. Surprisingly, these 2'-modifications showed no beneficial influence on the stability of the ribozymes against RNases present in cell culture supernatant containing 10% fetal calf serum.

Acetamides↗
PubMed1995

Incorporation of 2'-amido-nucleosides in oligodeoxynucleotides and oligoribonucleotides as a model for 2'-linked conjugates.

The functionalisation of oligodeoxynucleotides and oligoribonucleotides by incorporation of 2'-amido-2'-deoxyribonucleosides, possibly containing a reporter group via the 2'-amido bond, was examined. Therefore 2'-acetamido-ribonucleosides containing a small methyl group at the 2'-amido bond were synthesized as model compounds. In order to evaluate the influence of this 2'-modification on the hybridization capacities, 2'-acetamido-2'-deoxyuridine was incorporated in both RNA and DNA strands. The suitability of phosphoramidite chemistry for the introduction of this modified nucleoside was proven using laser desorption mass spectrometry of the final oligonucleotide. The presence of the 2'-modification destabilised both RNA-RNA, DNA-DNA and mixed duplexes. Therefore, it can be concluded that the 2'-acetamido group is not a good linker for attachment of reporter groups to oligonucleotides.

Base Sequence↗
PubMed1995

Spatial performance with perspective displays as a function of computer graphics eyepoint elevation and geometric field of view.

The purpose of this study was to investigate the effect of varying the elevation of the computer graphics eyepoint and the geometric field of view on judgements of spatial information using a stereoscopic perspective display. Twelve subjects judged the elevation and azimuth angle separating two computer-generated objects viewed using an eyepoint elevation that ranged between -15 degrees and 45 degrees and a geometric field of view that ranged between 40 degrees and 80 degrees. The results of the study indicated that judgements of elevation were affected by the compression of the vertical axis resulting from the raised eyepoint elevation. Furthermore, azimuth judgements were influenced by both the eyepoint elevation and the geometric field of view. Implications of the results for the design of displays and for spatial performance using stereoscopic displays are discussed.

Journal Article↗
PubMed1995

Obstructive sleep apnea in patients with human immunodeficiency virus (HIV) disease.

Adenotonsillar hypertrophy has been identified as an early manifestation of human immunodeficiency virus (HIV) disease. Three patients with HIV disease were identified with obstructive sleep apnea (OSA) due to adenotonsillar hypertrophy. In order to examine the relationship between HIV-induced adenotonsillar hypertrophy and OSA, 134 patients with asymptomatic HIV disease were screened with a self-administered sleep survey designed to detect OSA and excessive daytime somnolence. Patients meeting trigger score criteria were studied with overnight polysomnography and nine additional patients were identified with OSA. The only consistent risk factor for OSA in this young and primarily nonobese population was the presence of adenotonsillar hypertrophy, found in 11 of 12 patients with OSA. Three patients had tonsillar biopsy or tonsillectomy and all displayed benign follicular lymphoid hyperplasia. Scores on the Epworth Sleepiness Scale (ESS) were significantly higher for patients with OSA, indicating a greater degree of hypersomnolence (mean ESS scores: OSA+ = 11.4 +/- 3.6, OSA- = 7.8 +/- 4.6, p = 0.012). In our population, patients with HIV disease had a prevalence of OSA of 7%. HIV-induced adenotonsillar hypertrophy is a risk factor for the development of OSA. HIV patients with complaints of excessive daytime sleepiness and snoring who are found to have adenotonsillar hypertrophy on exam should undergo a sleep evaluation to rule out the presence of OSA.

Adult↗
PubMed1994

Isolation and structural elucidation of an impurity of cefradine.

An impurity of unknown identity was isolated from commercial cefradine by liquid chromatography on poly (styrene-divinylbenzene) with HOAc (0.01 M)-CH3CN (94:6, v/v) as the mobile phase. The structure was elucidated as 4',5'-dihydrocefradine using nuclear magnetic resonance spectroscopy (NMR) and mass spectrometry (MS). The structure was confirmed by comparison with the chromatographic retention characteristics and photodiode-array detected ultraviolet spectrum of the synthetic compound and with its infrared, NMR and MS spectra. The presence of 4',5'-dihydrocefradine in cefradine has not been described previously.

Cephalexin↗
PubMed1993

Hybridization specificity, enzymatic activity and biological (Ha-ras) activity of oligonucleotides containing 2,4-dideoxy-beta-D-erythro-hexopyranosyl nucleosides.

Antisense oligonucleotides with a 2,4-dideoxyhexopyranosyl nucleoside incorporated at the 3'-end and at a mutation site of the Ha-ras oncogene mRNA were synthesized. Melting temperature studies revealed that an A*-G mismatch is more stable than an A*-T mismatch with these hexopyranosyl nucleosides incorporated at the mutation site. The oligonucleotides are stable against enzymatic degradation. RNase H mediated cleavage studies revealed selective cleavage of mutated Ha-ras mRNA. The oligonucleotide containing two pyranose nucleosides at the penultimate position activates RNase H more strongly than natural oligonucleotides. No correlation, however, was found between DNA - DNA or RNA - DNA melting temperatures and RNase H mediated cleavage capacity. Although the A*-G mismatch gives more stable hybridization than the A*-T base pairing, only the oligonucleotides containing an A*-T base pair are recognized by RNase H. This modification is situated 3 base pairs upstream to the cleavage site. Finally, the double pyranose modified oligonucleotide was able to reduce the growth of T24 cells (bladder carcinoma) while the unmodified antisense oligonucleotide was not.

Base Composition↗
PubMed1993

A comparative study of LC methods for analysis of cefradine.

A comparative study of two isocratic liquid chromatographic methods for the analysis of cefradine is described. The first method is prescribed by the European Pharmacopoeia for the assay of cefradine, using classical alkyl bonded phase (C18) as the stationary phase. Poor reproducibility of the selectivity towards cefradine and its related substances was observed when this method was used and none of the C18 columns examined was able to separate cefradine completely from its potential related substances under the prescribed LC conditions. On the other hand, the second method, which uses poly(styrene-divinylbenzene) as the stationary phase, shows good selectivity even when using columns from different manufacturers and of different age. Four bulk samples of cefradine were analysed following both methods and the results were compared.

Cephalexin↗
PubMed1993

Quantitative analysis of cefradine by liquid chromatography on poly(styrene-divinylbenzene).

A method is described for isocratic analysis of cefradine by liquid chromatography on a poly(styrene-divinylbenzene) column (PLRP-S, 250 x 4.6 mm i.d.) at 50 degrees C. Cefradine is separated from its related substances using a mobile phase of acetonitrile-0.02 M sodium 1-octanesulphonate-0.2 M phosphoric acid-water (14.5:10:5:up to 100, v/v/v/v). The flow rate was 1.0 ml min-1 and UV-detection was performed at 254 nm. The method was employed for the quantitative analysis of reference substances, bulk samples and pharmaceutical dosage forms.

Acetonitriles↗