PubMed Health⌕ Search

Biomedical subjects

C D Thompson

Publications and source records attributed to C D Thompson.

At least 19 recordsLinked to original sources
PubMed2006

Rotationally resolved infrared spectrum of the Li+-D2 cation complex.

The infrared spectrum of mass selected Li(+)-D(2) cations is recorded in the D-D stretch region (2860-2950 cm(-1)) in a tandem mass spectrometer by monitoring Li(+) photofragments. The D-D stretch vibration of Li(+)-D(2) is shifted by -79 cm(-1) from that of the free D(2) molecule indicating that the vibrational excitation of the D(2) subunit strengthens the effective Li(+)cdots, three dots, centeredD(2) intermolecular interaction. Around 100 rovibrational transitions, belonging to parallel K(a)=0-0, 1-1, and 2-2 subbands, are fitted to a Watson A-reduced Hamiltonian to yield effective molecular parameters. The infrared spectrum shows that the complex consists of a Li(+) ion attached to a slightly perturbed D(2) molecule with a T-shaped equilibrium configuration and a 2.035 A vibrationally averaged intermolecular separation. Comparisons are made between the spectroscopic data and data obtained from rovibrational calculations using a recent three dimensional Li(+)-D(2) potential energy surface [R. Martinazzo, G. Tantardini, E. Bodo, and F. Gianturco, J. Chem. Phys. 119, 11241 (2003)].

Journal Article↗
PubMed2005

Infrared spectra of the Cl- -C2H4 and Br- -C2H4 anion dimers.

Infrared spectra of mass-selected Cl- -C2H4 and Br- -C2H4 complexes are recorded in the vicinity of the ethylene CH stretching vibrations (2700-3300 cm(-1) using vibrational predissociation spectroscopy. Spectra of both complexes exhibit 6 prominent peaks in the CH stretch region. Comparison with calculated frequencies reveal that the 4 higher frequency bands are associated with CH stretching modes of the C2H4 subunit, while the 2 weaker bands are assigned as overtone or combinations bands gaining intensity through interaction with the CH stretches. Ab initio calculations at the MP2/aug-cc-pVDZ level suggest that C2H4 preferentially forms a single linear H-bond with Cl- and Br- although a planar bifurcated configuration lies only slightly higher in energy (by 110 and 16 cm(-1), respectively). One-dimensional potential energy curves describing the in-plane intermolecular bending motion are developed which are used to determine the corresponding vibrational energies and wavefunctions. Experimental and theoretical results suggest that in their ground vibrational state the Cl- -C2H4 and Br- -C2H4 complexes are localized in the single H-bonded configuration, but that with the addition of modest amounts of internal energy, the in-plane bending wavefunction also has significant amplitude in the bifurcated structure.

Journal Article↗
PubMed2001

Medical internet ethics: a field in evolution.

As in any new field, the merger of medicine, e-commerce and the Internet raises many questions pertaining to ethical conduct. Key issues include defining the essence of the patient-provider relationship, establishing guidelines and training for practicing online medicine and therapy, setting standards for ethical online research, determining guidelines for providing quality healthcare information and requiring ethical conduct for medical and health websites. Physicians who follow their professional code of ethics are obligated not to exploit the relationship they have with patients, nor allow anyone else working with them to do so. Physicians and therapists are obligated to serve those who place trust in them for treatment, whether in face-to-face or online Internet encounters with patients or clients. This ethical responsibility to patients and clients is often in direct conflict with the business model of generating profits. Healthcare professionals involved in Medical Internet Ethics need to define the scope of competent medical and healthcare on the Internet. The emerging ethical issues facing medicine on the Internet, the current state of medical ethics on the Internet and questions for future directions of study in this evolving field are reviewed in this paper.

Confidentiality↗
PubMed2000

Constitutive activation of STAT3 is associated with the acquisition of an interleukin 6-independent phenotype by murine plasmacytomas and hybridomas.

Interleukin 6 (IL-6), the major growth factor for myeloma cells, signals through the activation of signal transducers and activators of transcription (STAT) proteins. An important step in the malignant progression of murine plasmacytomas is the transition from dependence on IL-6 to a state of IL-6 independence. To elucidate the mechanism whereby IL-6 independence occurs, intracellular signaling events elicited by IL-6 in both IL-6-dependent and -independent plasmacytomas and hybridomas were compared. It was found that STAT3, a key molecule involved in IL-6 signaling, was constitutively activated and phosphorylated in IL-6-independent cell lines compared to the IL-6-dependent cells. Further comparison of upstream signaling pathways revealed that JAK-1 was constitutively present in anti-phosphotyrosine immunoprecipitates of IL-6-independent cells; gp130 was constitutively phosphorylated in a subset of IL-6-independent plasmacytomas, whereas other IL-6-independent lines showed no detectable gp130 phosphorylation in the absence of exogenous IL-6. Secretion of a factor capable of supporting the growth of IL-6-dependent cells was observed in one of the IL-6-independent plasmacytomas, but not in others, making an autocrine mechanism an unlikely explanation for IL-6 independence. These findings provide evidence that the constitutive activation of STAT3, either in the absence of detectable receptor-proximal events or associated with the concomitant activation of gp130, can contribute to the process of IL-6 independence.

Animals↗
PubMed2000

The synthesis, in vitro reactivity, and evidence for formation in humans of 5-phenyl-1,3-oxazinane-2,4-dione, a metabolite of felbamate.

Previously we have proposed and provided evidence for a metabolic scheme leading to 3-carbamoyl-2-phenylpropionaldehyde from the antiepileptic drug felbamate. This aldehyde was found to undergo reversible cyclization to form the more stable cyclic carbamate 4-hydroxy-5-phenyl-tetrahydro-1,3-oxazin-2-one or undergo elimination to form 2-phenylpropenal. The cyclic carbamate bears structural similarity to 4-hydroxycyclophosphamide and there is an intriguing parallelism between the pathway from the cyclic carbamate to 2-phenylpropenal and the known pathway from 4-hydroxycyclophosphamide to acrolein. The similarity of these transformations led us to consider 5-phenyl-1,3-oxazinane-2,4-dione, which could arise from an oxidation of the cyclic carbamate, as a potential metabolite of felbamate. As the formation of this dione species may have both potential pharmacologic and toxicologic implications for felbamate therapy, we wished to study its reactivity. We have developed a synthesis of 5-phenyl-1, 3-oxazinane-2,4-dione and evaluated its reactivity in vitro. This dione was found to undergo base-catalyzed decomposition to three products, one of which is the major human metabolite of felbamate, 3-carbamoyl-2-phenylpropionic acid. Furthermore, we have found evidence for the presence of the dione in human urine after felbamate treatment through the identification of its major in vitro decomposition product, 2-phenylacrylamide 11.

Anticonvulsants↗
PubMed1999

The synthesis and evaluation of temperature sensitive tubulin toxins.

The synthesis of several potent inhibitors of tubulin polymerization that exert their activities through interaction at the colchicine binding site is described. These agents were evaluated for their abilities to inhibit the polymerization of tubulin and the growth of neoplastic cell cultures. Additionally, the inhibition of tubulin polymerization activity of these agents was assessed over a temperature range of 30-45 degrees C to ascertain the effect of temperature on this activity. Several of the compounds possess significant inhibition of tubulin polymerization activity, and select compounds exhibit this activity in a temperature dependent manner.

Binding Sites↗
PubMed1999

Quantification in patient urine samples of felbamate and three metabolites: acid carbamate and two mercapturic acids.

PURPOSE: Previously we proposed and provided evidence for the metabolic pathway of felbamate (FBM), which leads to the reactive metabolite, 3-carbamoyl-2-phenylpropion-aldehyde. This aldehyde carbamate was suggested to be the reactive intermediate in the oxidation of 2-phenyl-1,3-propanediol monocarbamate to the major human metabolite 3-carbamoyl-2-phenylpropionic acid. In addition, the aldehyde carbamate was found to undergo spontaneous elimination to 2-phenylpropenal, commonly known as atropaldehyde. Moreover, atropaldehyde was proposed to play a role in the development of toxicity during FBM therapy. Evidence for atropaldehyde formation in vivo was reported with the identification of modified N-acetyl-cysteine conjugates of atropaldehyde in both human and rat urine after FBM administration. Identification of the atropaldehyde-derived mercapturic acids in urine after FBM administration is consistent with the hypothesis that atropaldehyde is formed in vivo and that it reacts with thiol nucleophiles. Based on the hypothesis that the potential for toxicity will correlate to the amount of atropaldehyde formed, we sought to develop an analytic method that would quantify the amount of relevant metabolites excreted in patient urine. METHODS: We summarize the results of an LC/MS method used to quantify FBM, 3-carbamoyl-2-phenylpropionic acid and two atropaldehyde-derived mercapturic acids in the patient population. RESULTS: Analysis was performed on 31 patients undergoing FBM therapy. The absolute quantities of FBM and three metabolites were measured. CONCLUSIONS: This method demonstrated sufficient precision for the identification of patients exhibiting "abnormal" levels of atropaldehyde conjugates and may hold potential for patient monitoring.

Acetylcysteine↗
PubMed1999

Evaluation of methods for transient transfection of a murine macrophage cell line, RAW 264.7.

Monocyte/macrophage cell lines are fastidious cells commonly used in transient transfection experiments. In the course of a study of gene regulation by lipopolysaccharide (LPS), we have compared several methods for DNA-mediated cell transfection to determine which would be optimally applicable to the macrophage line, RAW 264.7. Both the response level (LPS inducibility) and the degree of inter-assay variation were evaluated for each transfection technique. The following methods were compared: Lipofectin, LipofectAMINE, LipofectAMINE PLUS, SuperFect, Ca3(PO4)2 DNA co-precipitation, DEAE dextran-mediated transfection and electroporation. The transfected plasmid DNA included a luciferase reporter construct containing the junB minimal promoter under the control of an LPS-inducible 1300-bp regulatory fragment downstream of junB 5'-flanking sequence, as well as a beta-galactosidase reporter construct under the adenovirus promoter and enhancer used as an internal control. Electroporation, followed by a resting period of 16-24 h before stimulation with LPS, had the highest inducibility of all methods. DEAE dextran and Ca3(PO4)2 precipitation showed the least and the greatest inter-assay variation, respectively. For all other methods, inter-assay variability fell within this range. The results presented may serve as both a general reference and a guide for reporter gene studies in this or other macrophage cell lines.

Adenoviridae↗
PubMed1998

The synthesis and evaluation of benzannelated-azatoxins: the benzazatoxins.

The synthesis and evaluation of azatoxin congeners possessing annealed aromatic frameworks are described. The compounds were evaluated for their abilities to affect topoisomerase II inhibition through the stabilization of "cleavable complex" and for the inhibition of tubulin polymerization using purified bovine brain tubulin.

Animals↗
PubMed1998

Potentially reactive cyclic carbamate metabolite of the antiepileptic drug felbamate produced by human liver tissue in vitro.

Felbamate (FBM) is a novel antiepileptic drug that was approved in 1993 for treatment of several forms of epilepsy. After its introduction, toxic reactions (aplastic anemia and hepatotoxicity) associated with its use were reported. It is unknown whether FBM or one of its metabolites is responsible for these idiosyncratic adverse reactions. Although the metabolism of FBM has not been fully characterized, three primary metabolites of FBM have been identified, i.e. 2-hydroxy, p-hydroxy, and monocarbamate metabolites. In addition, the monocarbamate metabolite leads to a carboxylic acid, which is the major metabolite of FBM in humans. Formation of the hydroxylated products of FBM involves cytochrome P450 enzymes, but the enzymes involved in the formation and further metabolism of the monocarbamate have not yet been elucidated. Recently, mercapturate metabolites of FBM have been identified in human urine, and a metabolic scheme involving reactive aldehyde metabolite formation from the monocarbamate metabolite has been proposed. The present study confirmed the formation of the proposed metabolites using human liver tissue in vitro. The aldehyde intermediates were trapped as oxime derivatives, and the cyclic equilibrium product (proposed as a storage and transport form for the aldehydes) was monitored directly by HPLC or GC/MS. Formation of putative toxic aldehyde intermediates and the major carboxylic acid metabolite of FBM was differentially effected with the cofactors NADP+ and NAD+. It is possible that the cofactors may influence the relative metabolism via activation and inactivation pathways.

Anticonvulsants↗
PubMed1997

Synthesis and structure-activity profiles of A-homoestranes, the estratropones.

2-Methoxyestradiol, a mammalian metabolite of estradiol, has reported antiangiogenic activity which has been proposed to be mediated through interaction at the colchicine binding site on the tubulin monomer. Subsequent structure-activity studies of 2-methoxyestradiol have yielded highly potent steroidal inhibitors of tubulin polymerization. In an effort to probe the scope of binding at the colchicine binding site and the nature of the relationship between 2-methoxyestradiol and colchicine, a series of colchicine/2-methoxyestradiol hybrids was synthesized. These A-homoestrane hybrid systems, collectively termed estratropones, possessed an A-ring tropone system with the keto functionality at either the C-2, C-3, or C-4 position of the steroid nucleus. The estratropones were evaluated for their ability to inhibit the polymerization of tubulin using an in vitro purified bovine brain assay. Most of these hybrids inhibit polymerization with greater potency than either of the natural products. The most potent of these congeners possessed an approximate 5-fold enhancement of the activity of colchicine for the inhibition of tubulin polymerization. alpha-Substituents on the tropone ring showed varied effects on the activities for the two classes of estratropones studied in this regard, the C-3 oxo and the C-4 oxo species. The 3-substituted 4-oxoestratropones exhibited antitubulin activity according to Cl approximately Br > OCH3, whereas the 4-substituted 3-oxoestratropones exhibited activity according to OCH3 > Br approximately Cl. It is unclear if these substituent factors are purely electronic or steric effects or if the substituent operates indirectly by altering the conformation of the nonplanar troponoid ring. The estratropones represent a new class of tubulin binding agents with potential antiangiogenic utility.

2-Methoxyestradiol↗
PubMed1997

Mechanisms of adrenergic agonist induced allergy bioactivation and antigen formation.

Reduction of elevated intraocular pressure with alpha 2 agonists has proved to be an exciting new therapeutic approach for the treatment of glaucoma. We have studied the chemical reactivities of several alpha 2 agonists and known allergens to elucidate the origin of the observed ocular allergic response to the alpha 2 agonist apraclonidine. The oxidation potentials of clonidine, apraclonidine, brimonidine, and two known allergens, amodiaquine, and epinephrine, were measured vs. a standard calomel electrode.. Agents that were oxidatively labile were treated with both chemical and enzymatic oxidants. Clonidine and brimonidine proved to be oxidatively stable in sharp contrast to apraclonidine which had an oxidation potential similar to that observed with epinephrine and amodiaquine, two known allergy-inducing agents. In addition, two glutathione-apraclonidine conjugates formed by the in-situ reaction of glutathione with an enzymatically oxidized apraclonidine intermediate were isolated and their structures determined using spectroscopic methods. The structures were shown to be analogous to those obtained with amodiaquine and epinephrine. Apraclonidine, like amodiaquine and epinephrine, possesses a hydroquinone-like subunit and can be readily oxidized and conjugated with thiols modeling well known hapten-forming reactions. Brimonidine, like clonidine, lacks the hydroquinone subunit and does not undergo the thiol conjugation reactions.

Adrenergic alpha-Agonists↗
PubMed1997

Identification of modified atropaldehyde mercapturic acids in rat and human urine after felbamate administration.

3-Carbamoyl-2-phenylpropionaldehyde has recently been proposed [Thompson et al. (1996) Chem. Res. Toxicol. 9, 1225-1229] as a potential reactive metabolite of the anti-epileptic drug felbamate. This aldehyde was found to undergo rapid elimination to generate 2-phenylpropenal and reversible cyclization to generate 4-hydroxy-5-phenyltetrahydro-1,3-oxazin-2-one at physiological pH. 2-Phenylpropenal, an alpha,beta-unsaturated aldehyde commonly termed atropaldehyde, is a potent electrophile and undergoes rapid conjugation with glutathione. We sought to demonstrate the formation of atropaldehyde in vivo through the identification of mercapturic acids in rat and human urine after felbamate administration. In this paper, we describe the identification of both the reduced (N-acetyl-S-(2-phenylpropan-3-ol)-L-cysteine) and oxidized (N-acetyl-S-(2-phenyl-3-propanoic acid)-L-cysteine) mercapturic acids of atropaldehyde in rat and human urine. The reduced species was the more abundant in human (approximately 2:1) and rat (approximately 6:1) urine. These findings establish the possibility that atropaldehyde is formed from felbamate in vivo, undergoes glutathione conjugation, and is ultimately excreted in urine in the form of mercapturic acids. Thus, the proposed pathway of felbamate biotransformation, if confirmed in patients, could contribute to our understanding of the toxicities observed during felbamate treatment.

Acetylcysteine↗
PubMed1997

A proposed mechanism for p-aminoclonidine allergenicity based on its relative oxidative lability.

p-Aminoclonidine (apraclonidine) is a selective alpha 2 adrenergic agonist used to reduce intraocular pressure in the treatment of glaucoma. Use of apraclonidine is frequently associated with severe local allergic effects which warrant discontinuation of the drug in affected patients. We have assessed the oxidative lability of apraclonidine relative to a panel of adrenergic agonists and/or known allergens; amodiaquine, epinephrine, clonidine, and brimonidine. These compounds were compared by their electrochemical potentials as well as their oxidative lability in the presence of several oxidative enzyme systems (i.e., horseradish peroxidase, lactoperoxidase, myeloperoxidase, and diamine oxidase). The half-lives for enzymatic oxidation of these compounds were found to parallel the electrochemical oxidation potentials in the order: amodiaquine approximately epinephrine < apraclonidine << clonidine approximately brimonidine. The production of a reactive electrophilic intermediate of apraclonidine was demonstrated through the formation of two glutathione apraclonidine adducts from the horseradish peroxidase/H2O2-mediated oxidation of apraclonidine in the presence of glutathione. A mechanism for apraclonidine allergenicity in vivo is proposed wherein apraclonidine is bioactivated through oxidation to the bis-iminoquinone followed by protein conjugation to form an apraclonidine-protein hapten that elicits the immune response.

Adrenergic alpha-Agonists↗
PubMed1996

Synthesis and in vitro reactivity of 3-carbamoyl-2-phenylpropionaldehyde and 2-phenylpropenal: putative reactive metabolites of felbamate.

We propose that 3-carbamoyl-2-phenylpropionaldehyde is an intermediate in the metabolism of felbamate, an anti-epileptic drug with a unique profile of the therapeutic activity, and undergoes a cascade of chemical reactions responsible for the toxic properties of the parent drug. To test this hypothesis, we have synthesized 3-carbamoyl-2-phenylpropionaldehyde and evaluated its in vitro reactivity. This molecule was found to be highly unstable at physiological pH (t1/2 < or = 30 s) and to undergo facile elimination to 2-phenylpropenal, an alpha, beta-unsaturated aldehyde commonly termed atropaldehyde. However, the predominant reaction pathway for 3-carbamoyl-2-phenylpropionaldehyde was reversible cyclization to generate 4-hydroxy-5-phenyltetrahydro-1,3-oxazin-2-one, a urethane that has a considerably longer half-life at physiological pH (t1/2 > or = 5 h) and may serve as a stable reservoir of the reactive aldehyde both in vitro and in vivo. Atropaldehyde is a potent electrophile and was found to exhibit cytotoxicity to cultured fibroblasts (50% growth inhibition (GI50) = 4.1 +/- 1.1 microM) comparable to the known unsaturated aldehyde toxins, 4-hydroxy-2-nonenal and acrolein. 3-Carbamoyl-2-phenylpropionaldehyde also exhibited significant cytotoxicity (GI50 = 53 +/- 8 microM), whereas 2-phenyl-1,3-propanediol monocarbamate (GI50 > 500 microM) and 3-carbamoyl-2-phenylpropionic acid (GI50 > 500 microM) were nontoxic. We have additionally demonstrated the formation of a glutathione-atropaldehyde conjugate from the in vitro incubation of 3-carbamoyl-2-phenylpropionaldehyde with glutathione. Thus, the potent cytotoxicity and potential allergenicity of atropaldehyde implicate this unsaturated aldehyde as a possible causative agent in the toxicities observed with felbamate treatment.

Aldehydes↗
PubMed1995

Use of GnRH agonist before hysterectomy: a cost simulation.

OBJECTIVE: To evaluate the potential savings in cost of care derived from performing vaginal hysterectomies instead of abdominal hysterectomies in selected women with fibroid uteri equivalent in size to a 14-18 week gestation. METHODS: Women 35-46 years of age undergoing hysterectomy for fibroid uteri were selected to allow application of conversion rates gained in a separate randomized study using leuprolide acetate depot 3.75 mg. Statewide public data for North Carolina's hospital discharges provided relative rates of hospital charges and leiomyomas for all hysterectomies, by age. Professional charges were omitted from the analysis. Estimated savings were projected to the national level. RESULTS: During 1992 in North Carolina, 18,110 inpatient hysterectomies were performed for women of all ages; 28.1% of these were for uterine leiomyomas. For women 35-46 years old (12.7% of all hysterectomies), there were 1904 abdominal and 390 vaginal hysterectomies; the mean total charge for abdominal hysterectomy was $5590, and $4732 for the vaginal alternative. These statewide data provide missing elements to allow a national estimate of the potential savings of using GnRH agonist preoperatively. The projected national savings, if 1987 utilization data are used, was $4.6 million, nearly 1.4% of the inpatient charges. The 1992 value of these savings is $6.7 million. CONCLUSION: The use of preoperative GnRH agonist therapy before hysterectomy for patients with a uterine size equivalent to a 14-18 week gestation represents a significant cost-saving alternative, increasing the use of vaginal hysterectomy and resulting in potential savings in direct inpatient medical care charges.

Adult↗
PubMed1975

Quantitation of cell-mediated immunity: responses to dinitrochlorobenzene and ubiquitous antigens.

T-lymphocyte immune capacity in man was assessed semiquantitatively by two in vivo procedures: the primary type of response to dinitrochlorobenzene and the secondary type of response, representing memory, to a group of five uniquitous antigens. Controlling for degree of illness proved important in assessing immune capacity in specific diseases; thus, the number of responders and mean score of semiquantitated responses was significantly lower in groups of patients with cancer and multisystem autoimmune disease when comparisons were made with healthy persons, but less so when comparisons were made with a group of subjects with other incapacitating diseases. A notable finding was the lack of correlation in the results of tests of cell-mediated immunity between the two procedures described. Depressed cell-mediated immunity shown in multisystem autoimmune disease is relevant to both predisposition to infection and the postulated role of thymic dysfunction in the pathogenesis of autoimmunity.

Adolescent↗