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Biomedical subjects

W R Wilson

Publications and source records attributed to W R Wilson.

At least 37 records · Page 2Linked to original sources
PubMed2000

Ross procedure for complex left ventricular outflow tract obstruction.

BACKGROUND: Complex left ventricular outflow tract (LVOT) obstruction in children continues to pose a significant therapeutic challenge to cardiac surgeons. The Ross procedure, in combination with resection of subaortic stenosis or a Konno type septal incision, is an important option for these difficult patients. METHODS: Recently two children aged 14 and 5 years with LVOT obstruction involving combined subaortic and valvar stenosis underwent surgical correction using the pulmonary autograft. Clinical presentation, operative technique, outcome and intermediate follow-up are detailed. RESULTS: One patient had resection of an isolated subaortic membrane in combination with a pulmonary autograft and the second a Ross Konno procedure. Postoperative hospital stays were without complication. Both patients were discharged at 5 days and have no significant obstruction nor semilunar valve insufficiency at 3 years' follow-up. CONCLUSIONS: Pulmonary autografts can be used in combination with resection of subaortic tissue or a septal incision for reconstruction of complex left ventricular outflow tract obstruction. This technique renders excellent short term valve function, relief of obstruction, avoids anticoagulation and provides potential for future growth.

Adolescent↗
PubMed1999

Nitrobenzyl carbamate prodrugs of enediynes for nitroreductase gene-directed enzyme prodrug therapy (GDEPT).

The synthesis and evaluation of the 4-nitrobenzylcarbamate enediyne 6 and related compounds as prodrugs activated by a nitroreductase enzyme (NTR) from E. coli B is described. Expression of NTR in three different cell lines gives increases in cytotoxicity of 21- to 135-fold for 6 (IC50 values 13-24 nM in the NTR-expressing lines), indicating its potential as a prodrug for NTR-mediated Gene-Directed Enzyme Prodrug Therapy. The cytotoxicity of 6 and related enediynes is shown to be oxygen-dependent, especially in nucleotide excision repair-proficient cells, which might limit activity in hypoxic regions of tumours.

Animals↗
PubMed1999

5-Amino-1-(chloromethyl)-1,2-dihydro-3H-benz[e]indoles: relationships between structure and cytotoxicity for analogues bearing different DNA minor groove binding subunits.

A series of 5-amino-seco-CBI compounds, designed for use as effectors for prodrugs, were prepared to study structure-activity relationships for the cytotoxicity of side chain analogues. Compounds were prepared by coupling 1-(chloromethyl)-5-nitro-1, 2-dihydro-3H-benz[e]indole to appropriate carboxylic acids, followed by nitro group reduction, or by coupling suitable 5-amino-protected indolines to alpha,beta-unsaturated acids, followed by deblocking. These AT-specific DNA alkylating agents were evaluated for cytotoxicity in a series of tumor cell lines (AA8, UV4, EMT6, SKOV3). For those analogues bearing an indolecarbonyl side chain, the 5'-methoxy derivative was the most cytotoxic (IC(50) 1.3 nM in AA8 cells, 4 h exposure), comparable to that of the parent CBI-TMI (5', 6',7'-trimethoxyindole) derivative (IC(50) 0.46 nM in the above assay). A subset of solubilized derivatives bearing O(CH(2))(2)NMe(2) substituents were about 10-fold less potent. For compounds containing an acryloyl linker in the side chain, the 4'-methoxycinnamoyl derivative proved the most cytotoxic (IC(50) 0. 09 nM in the above assay). A number of these 5-amino-seco-CBI-TMI analogues (including the solubilized compounds) are of interest both as cytotoxins and as components of amine-based prodrugs designed for tumor-specific activation.

Animals↗
PubMed1999

A 2-nitroimidazole carbamate prodrug of 5-amimo-1-(chloromethyl)-3-[(5,6,7-trimethoxyindol-2-yl)carbony l]-1,2-dihydro-3H--benz[E]indole (amino-seco-CBI-TMI) for use with ADEPT and GDEPT.

The synthesis of a 2-nitroimidazol-5-ylmethyl carbamate prodrug 10 of the potent minor groove alkylating agent amino-seco-CBI-TMI 3 is described. Chemical, radiolytic, and enzymic reductions of a model 2-nitroimidazol-5-yl carbamate 8 show release of the amine effector upon reduction. Prodrug 10 gives a ten fold increase in cytotoxicity against human ovarian carcinoma SKOV3 cells in the presence of E. coli B nitroreductase (NTR) and a 21-fold increase in cytotoxicity against a SKOV3 cell line (SC3.2) transfected with the gene for NTR. The cytotoxicity of 10 increased 15- to 40-fold under hypoxia. Prodrug 10 has significant potential as a prodrug for use in ADEPT and GDEPT applications, and as a hypoxia-selective cytotoxin.

Alkylating Agents↗
PubMed1999

Synthesis of 1-substituted 3-(chloromethyl)-6-aminoindoline (6-amino-seco-CI) DNA minor groove alkylating agents and structure-activity relationships for their cytotoxicity.

A series of racemic 6-amino-seco-cyclopropylindole (seco-CI) compounds was prepared by coupling 1-(tert-butyloxycarbonyl)-3-(chloromethyl)-6-nitroindoline with appropriate acids, followed by nitro group reduction, and evaluated for cytotoxicity in AA8, UV4, EMT6, and SKOV3 cell lines. These compounds are of interest due to their close structural relationship to known AT-specific alkylating agents and cytotoxins and also for the possible construction of stable amine-based prodrugs designed for tumor-specific release. Variations included indole or furan side chains with different substituents, sulfonamide or carboxamide linkers, extension of the minor groove binding side chain to two subunits, and the use of a pyrroylacryloyl unit previously reported to give extremely potent analogues. The parent compound, with a trimethoxyindole side chain, was a moderately potent cytotoxin (IC50 = 0.34 microM in AA8 cells, 4 h exposure). A single 5-methoxy group on the indole minor groove binding unit was sufficient to maintain potency, and a series of dimethylaminoethoxy-substituted analogues retained the cytotoxicity of the parent compound, while providing increased aqueous solubility.

Animals↗
PubMed1999

N-Substituted 2-(2,6-dinitrophenylamino)propanamides: novel prodrugs that release a primary amine via nitroreduction and intramolecular cyclization.

A series of N-dinitrophenylamino acid amides [(4-CONHZ-2, 6-diNO2Ph)N(R)C(X,Y)CONHPhOMe] were prepared as potential bioreductive prodrugs and reduced radiolytically to study their rates of subsequent intramolecular cyclization. Compounds bearing a free NH group (R = H) underwent rapid cyclization in neutral aqueous buffers (t1/2 < 1 min) following 4-electron reduction, with the generation of a N-hydroxydihydroquinoxalinone and concomitant release of 4-methoxyaniline. Amine release from analogous N-methyl analogues (R = Me) was relatively slow. These results are consistent with intramolecular cyclization of a monohydroxylamine intermediate. The high rates of cyclization/extrusion by these very electron-deficient hydroxylamines suggest that the process is greatly accelerated by the presence of an H-bonding "conformational lock" between the anilino NH group and the adjacent o-nitro group (Kirk and Cohen, 1972). Changes in the phenylcarboxamide side chain or in C-methylation in the linking chain had little effect on the rate of cyclization. The model compounds had 1-electron reduction potentials in the range appropriate for cellular reduction (-373 mV for a measured example) and appeared suitable for development as prodrugs that release amine-based effectors following enzymic or radiolytic reduction. Prodrug examples containing 4-aminoaniline mustard and 5-amino-1-(chloromethyl)benz[e]indoline alkylating units were evaluated but were not activated efficiently by cellular nitroreductases. However, cell killing by the radiation-induced reduction of the latter prodrug was demonstrated.

Amides↗
PubMed1999

Radiosensitization of advanced squamous cell carcinoma of the head and neck with cisplatin during concomitant radiation therapy.

Treatment regimens for advanced squamous cell carcinoma of the head and neck require both attention to local tumor burden as well as contingencies for control of disseminated disease. Relatively new protocols utilizing cisplatin for radiosensitization of tumor cells during concomitant radiotherapy have shown progress in providing effective tumor control. Cisplatin as a chemotherapeutic agent induces DNA changes in malignant cells that may be mutagenic or lethal. Additionally, when used concurrently with radiation therapy, cisplatin acts as a radiosensitizer, increasing damage to malignant nuclear DNA to enhance the anti-neoplastic capability of radiotherapy. The mechanisms by which this radiosensitization occurs remain controversial, although one leading theory involves cisplatin's ability to inhibit sublethal damage repair in radiated tumor cells. Recent investigations utilizing cisplatin with concurrent radiation for treatment of advanced squamous cell carcinomas of the head and neck are reviewed. The variations in protocols presented include route of administration, dosing, scheduling, timing with surgery, and combination therapy with 5-fluorouracil and radiation. Higher response rates, prolonged mean survival, increased survival rates, longer local recurrence-free survival rates, and considerable organ preservation with the use of concurrent cisplatin and radiation have been demonstrated by these studies. Further investigation of concurrent cisplatin and radiotherapy in patients with advanced disease is justified.

Carcinoma, Squamous Cell↗
PubMed1999

Cytotoxicity and DNA interaction of the enantiomers of 6-amino-3-(chloromethyl)-1-[(5,6,7-trimethoxyindol-2-yl)carbonyl]indo- line (amino-seco-CI-TMI).

The enantiomers of the previously reported racemic 6-amino-3-(chloromethyl)-1-[(5,6,7-trimethoxyindol-2-yl)carbonyl] indoline (amino-seco-CI-TMI) were prepared via resolution of a precursor by chiral HPLC. The only detectable product isolated from reaction of the racemic compound with calf thymus DNA, followed by thermal cleavage, was shown by mass spectrometry and two-dimensional NMR spectroscopy to be the adenine N3 adduct. Polyacrylamide gel electrophoresis assays with the racemate and with each enantiomer also showed adenine to be the only site of alkylation. While the racemic amino compound exhibited sequence selectivity identical to that of the previously characterized phenol analogue, the enantiomers exhibited distinctly different sequence selectivities, allowing the (+) enantiomer to be assigned the "natural" S configuration. The (+)-(S) enantiomer is 3-fold more cytotoxic than the (-)-(R) enantiomer (IC(50) values of 240 and 700 nM, respectively, in AA8 cells, after exposure for 4 h).

Alkylation↗
PubMed1999

G-protein-coupled inwardly rectifying potassium channels are targets of alcohol action.

G-protein-coupled inwardly rectifying potassium channels (GIRKs) are important for regulation of synaptic transmission and neuronal firing rates. Because of their key role in brain function, we asked if these potassium channels are targets of alcohol action. Ethanol enhanced function of cerebellar granule cell GIRKs coupled to GABAB receptors. Enhancement of GIRK function by ethanol was studied in detail using Xenopus oocytes expressing homomeric or heteromeric channels. Function of all GIRK channels was enhanced by intoxicating concentrations of ethanol, but other, related inwardly rectifying potassium channels were not affected. GIRK2/IRK1 chimeras and GIRK2 truncation mutants were used to identify a region of 43 amino acids in the carboxyl (C) terminus that is critical for the action of ethanol on these channels.

Alcohols↗
PubMed1999

Transcutaneous monitoring of carbon dioxide tension after cardiothoracic surgery in infants and children.

UNLABELLED: In this prospective investigation, we evaluated the efficacy and accuracy of transcutaneous monitoring of CO2 (TC-CO2) in infants and children after cardiothoracic surgery. Cardiothoracic surgery patients whose ETCO2 and arterial CO2 values did not correlate (gradient > or = 5 mm Hg) during the first postoperative hour underwent placement of the TC electrode (30 of 33 patients). If the TC-CO2 to arterial difference was > or = 5 mm Hg, the TC-CO2 electrode was recalibrated and reapplied on another site. If the discrepancy was still > or =5 mm Hg, the case was considered a clinical failure and no further data were collected (3 of 30 patients). If the arterial to TC gradient was <5 mm Hg, the patient was included in the data collection (27 of 30 patients). One to five sample sets (TC and arterial CO2) were collected from these patients. Statistical analysis included linear regression analysis and Bland-Altman analysis. The cohort for the study included 27 patients ranging in age from 2 days to 9 yr and in weight from 3.2 to 25 kg. A total of 101 sample sets were analyzed. The mean +/- SD absolute difference between the TC-CO2 and arterial CO2 was 1.7 +/- 1.4 mm Hg (range 0-9 mm Hg). The TC-CO2 to arterial CO2 difference was 0-2 mm Hg in 82 of 101 values (81%), 35 mm Hg in 18 of 101 values (18%), and >6 mm Hg in 1 of 101 values (1%). Linear regression analysis revealed a slope of 0.90, an r value of 0.9410, and an r2 value of 0.8854 (P < 0.0001). Bland-Altman analysis revealed a bias of 0.58 mm Hg with a precision of +/- 2.1 mm Hg when comparing the TC-CO2 with the arterial CO2. IMPLICATIONS: We conclude that, with certain caveats in mind, including the need to correlate the transcutaneous CO2 with an initial arterial CO2 value, transcutaneous CO2 monitoring can be used to estimate arterial CO2 in most neonates and children after cardiothoracic surgery.

Blood Gas Monitoring, Transcutaneous↗
PubMed1999

Exploring endoscopic neck surgery in a porcine model.

OBJECTIVES: This study uses a porcine model to establish the feasibility of performing endoscopic procedures in the neck using standard techniques currently being employed in preperitoneal endoscopy in the abdomen. STUDY DESIGN: It is a pilot study presented as a case series. METHODS: Ten animals were subjected to anterior deep cervical fascia dissection using standard endoscopic instrumentation. RESULTS: Balloon dissection and CO2 insufflation poses a number of problems: CO2 gas dissection into the chest, CO2 gas embolism into the venous circulation, carotid artery occlusion, and limited visualization causing increased risk of injury to adjacent structures. CONCLUSION: These issues need to be dealt with before such a method could be employed safely in humans. However, with further research and development, endoscopic neck surgery may someday become a reality.

Animals↗
PubMed1999

Amiodarone in the treatment of junctional ectopic tachycardia after cardiac surgery in children: report of two cases and review of the literature.

Junctional ectopic tachycardia (JET) occurs most frequently after operative repair of congenital heart defects. The mechanism is thought to involve direct trauma to the atrioventricular node and His bundle resulting in an ectopic focus. Several therapeutic methods have been described in the pediatric literature with varying degrees of success and complication rates. Because heart rates may exceed 200 to 300 beats per minute, there may be inadequate time for ventricular filling. Ventricular filling can be further compromised because of the asynchrony between the atria and the ventricles. These factors can lead to significant compromise of cardiovascular function in the postoperative patient. We describe our experience with amiodarone in two patients who developed postoperative JET after repair of congenital heart defects. Dosing regimens and previous experience with amiodarone in patients with JET are reviewed.

Adolescent↗
PubMed1999

Ketolide treatment of Haemophilus influenzae experimental pneumonia.

The MICs of HMR 3004 and HMR 3647 at which 90% of beta-lactamase-producing Haemophilus influenzae isolates were inhibited were 4 and 2 micrograms/ml, respectively. Both HMR 3004 and HMR 3647 were active against beta-lactamase-producing H. influenzae in a murine model of experimental pneumonia. As assessed by pulmonary clearance of H. influenzae, HMR 3004 was more effective (P < 0.05) than was azithromycin, ciprofloxacin, clarithromycin, erythromycin A, pristinamycin, or HMR 3647 in this model.

Animals↗
PubMed1999

Pericardial tamponade and massive pleural effusion complicating orthotopic heart transplantation.

Pericardial and pleural effusions occur commonly after open cardiac procedures. However, the combination of tamponade and massive pleural effusion is not often observed. We present a case of such a patient who received an orthotopic heart transplant in a setting of previously diagnosed systemic sarcoidosis. Treatment ultimately required the creation of a pericardial window and chemical pleurodesis.

Anti-Bacterial Agents↗
PubMed1999

Giant ameloblastoma: report of an extreme case and a description of its treatment.

Ameloblastoma is an odontogenic tumor that usually occurs in the mandible. It is an aggressive but benign tumor of epithelial origin that is rarely metastatic. We report the case of a 53-year-old woman who had a massive ameloblastoma of the mandible. The tumor measured 15.2 x 11.4 x 12.0 cm. The patient had oral bleeding that required a transfusion. The workup included three-dimensional imaging, arteriography, and embolization to control bleeding. Surgical management entailed the resection of the entire left mandible and right symphysis, followed by reconstruction with a free fibular flap. To our knowledge, this is the largest reported ameloblastoma managed with three-dimensional imaging, radical resection, and free-flap reconstruction. This article also reviews aspects of the differential diagnosis, pathology, and management of jaw tumors.

Ameloblastoma↗
PubMed1999

The design of cobalt(III) complexes of phenazine-1-carboxamides as prointercalators and potential hypoxia-selective cytotoxins.

A series of cobalt (III) complexes, [Co(Racac)2(L)]+, have been prepared as potential hypoxia-selective prointercalator forms of the ligands L, where L is the cytotoxic DNA mono-intercalating ligands N-[2-[(aminoethyl)amino]ethyl]-phenazine-1-carboxamide and N-[5-[(aminoethyl)amino]pentyl]-phenazine-1-carboxamide or the potentially bis(intercalating) ligand bis[2-(phenazine-1-carboxamido)ethyl]-1,2-diaminoethane. The cobalt(III) complexes of the monointercalating ligands have significantly lower DNA binding affinity and cytotoxicity than the ligands themselves, indicating the potential utility of this prodrug approach for deactivation (and release under hypoxic conditions). However, the complexes showed only low hypoxic selectivity. The complex of the bis(intercalating) ligand also showed significantly lower DNA binding affinity than the free ligand, but in this case there was no attenuation of cytotoxicity.

Animals↗
PubMed1999

Nitracrine N-oxides: effects of variations in the nature of the side chain N-oxide on hypoxia-selective cytotoxicity.

The tertiary amine N-oxide (nitracrine-N-oxide, 1b) of the 1-nitroacridine nitracrine is a bis-bioreductive agent showing very high hypoxic selectivity (approximately 1000-fold) against tumour cells in culture, but only modest activity against the hypoxic subfraction of tumours in vivo. Because the hypoxic selectivity of 1b was considered to depend significantly on the rate of enzyme-mediated reduction of the N-oxide group, this paper reports the preparation and evaluation of a series of analogues in which the environment of this group was modified. Three analogues contained more weakly basic N-oxides, while two others had varying degrees of steric bulk around the N-oxide. In all but one case (an aromatic N-oxide), the N-oxides were much less cytotoxic (10- to 300-fold) than the corresponding tertiary amines towards AA8 Chinese hamster cells under aerobic conditions. Both the N-oxides and the corresponding amines were more cytotoxic to an ERCC-1 mutant defective in nucleotide excision repair, indicating that DNA alkylation was the cytotoxic event. However, there was no apparent correlation of these parameters with structure. All of the aliphatic N-oxides, with the exception of the aromatic N-oxide example, showed substantial (70- to 800-fold) hypoxic selectivity against AA8 cells in a clonogenic assay. While the weakly basic derivatives were the least selective, there was no apparent relationship between hypoxic selectivity and the steric environment of the N-oxide. Selectivity for hypoxic cells in culture is shown to depend on the hypoxic selectivity of the corresponding tertiary amine (reflecting O2-inhibitable reduction of the 1-nitro group) and the differential in aerobic toxicity between amine and N-oxide (a measure of the potential toxicity increase achievable by reducing the N-oxide). Four analogues whose structures fairly represented the range of steric and electronic modifications of the N-oxide site were evaluated against the hypoxic subfraction of cells in KHT tumours in vivo, but were inactive. These results suggest that either such modifications do not exert significant effects on N-oxide reduction, or that the rate of such reduction is not a factor limiting the in vivo activity of the parent analogue 1b.

Animals↗