Search PubMed⌕ Search

Biomedical subjects

J M Collins

Publications and source records attributed to J M Collins.

At least 19 recordsLinked to original sources
PubMed2003

Contribution of indirect computed tomography venography to computed tomography angiography of the chest for the diagnosis of thromboembolic disease in two United States emergency departments.

Recent reports suggest that physicians in non-ambulatory settings can use indirect CT venography (CTV) of the lower extremities immediately following spiral CT angiography (CTA) of the chest to identify patients with a negative CTA who have thromboembolic disease identified on CTV. We sought to determine the frequency of isolated deep venous thrombosis (DVT) discovered on CTV in emergency department (ED) patients with complaints suggestive of pulmonary embolism (PE) yet having a negative CTA. This study was conducted in a suburban and urban ED where patients with symptoms suspicious for PE were primarily evaluated with CTA and CTV. A total of 800 patients were studied, including 360 from the suburban ED and 440 from the urban ED. 88 (11%) patients were diagnosed with thromboembolic disease by CTA, or CTV, or both. Seventy-three patients had a CTA of the chest that was positive for PE, 42 (5.2%) of whom had evidence of both PE on CTA and DVT on CTV. Fifteen patients (2%, 95% CI = 1-3%) had a negative CTA and were subsequently found to have isolated DVT on CTV, all of whom received anticoagulation therapy. These data suggest that indirect CT venography of immediately following CT angiography of the chest significantly increased the frequency of diagnosed thromboembolic disease requiring anticoagulation in ED patients with suspected PE.

Adult↗
PubMed2001

Inter-species differences in drug properties.

There has been a clear trend towards decreased reliance upon animal studies and increased emphasis upon experiments with human-derived tissues. Nonetheless, we continue to need investigations of interspecies differences for two principal reasons: (1) to prospectively design experiments so that the animal species most similar to humans can be chosen, on a case-by-case basis, for each drug; (2) to properly evaluate and interpret data obtained from the experiments ("risk assessment"). Four core examples derived from the work in our FDA laboratory are used to illustrate these points. For paclitaxel, different metabolites were formed in humans and rats, which makes metabolic drug-drug interaction studies in rats irrelevant. For zidovudine (AZT), rapid glucuronidation in humans produced a much shorter half-life than expected from studies in animals, which have negligible glucuronidation. The toxicology and efficacy of both parent drug and metabolite need to be assessed in cases such as iododeoxydoxorubicin, in which the parent molecule is the dominant circulating species in mice, but patients have more than 10-fold greater exposure to the metabolite compared with the parent. While rats have highly-active arylamine N-acetyltransferases, dogs totally lack this enzyme family, and humans have intermediate amounts. For some situations, we've suggested that it can be desirable to inhibit NAT to make the human exposure more similar to dogs. In conclusion, although the ratio of animal:human data is decreasing, our ability to use animal data effectively for drug development has actually increased. Continued focus should be placed upon the application of comparative interspecies data for prospective design of animal experiments and retrospective interpretation of animal findings in terms of the potential for human risk and benefit.

Animals↗
PubMed2001

Thymidine phosphorylase as a target for imaging and therapy with thymine analogs.

PURPOSE: Thymidine phosphorylase (TPase; platelet-derived endothelial cell growth factor) is an attractive target for imaging and therapy because of the strong relationship between its expression in tumor biopsies and clinical outcome in many tumor types. Although the mechanism has yet to be explained, expression of TPase is highly associated with angiogenesis. METHODS: Tumor cells were phenotyped for TPase activity, and incubated with thymine or its analogs (5-X-Ura). After intracellular conversion to thymidine analogs via the reverse reaction for TPase, these molecules were phosphorylated and incorporated into DNA. RESULTS: Preferential localization was found in cells with high TPase, e.g. U937. Incorporation was enhanced in cells with high TPase by coincubation with modulators such as deoxyuridine. CONCLUSIONS: 5-X-Ura molecules can be readily labeled with positron emitters, and this finding provides support for further evaluation in vivo of their potential as probes for noninvasive external imaging of TPase, both at the time of diagnosis and during maneuvers intended to manipulate TPase. If the 5-X-Ura molecules were labeled with a therapeutic isotope, e.g. 125I or 211At, selective cytotoxicity would be expected in cells with high TPase expression. However, direct evaluation of the safety in vivo of the therapeutic approach is required. The 5-X-Ura compounds constitute a novel approach to both imaging and therapy directed towards TPase. Further, there are distinct advantages to using the imaging mode to identify tumors likely to benefit from therapy with the same set of molecules.

DNA↗
PubMed2001

In vitro human tissue models in risk assessment: report of a consensus-building workshop.

Advances in the technology of human cell and tissue culture and the increasing availability of human tissue for laboratory studies have led to the increased use of in vitro human tissue models in toxicology and pharmacodynamics studies and in quantitative modeling of metabolism, pharmacokinetic behavior, and transport. In recognition of the potential importance of such models in toxicological risk assessment, the Society of Toxicology sponsored a workshop to evaluate the current status of human cell and tissue models and to develop consensus recommendations on the use of such models to improve the scientific basis of risk assessment. This report summarizes the evaluation by invited experts and workshop attendees of the current status of such models for prediction of human metabolism and identification of drug-drug interactions, prediction of human toxicities, and quantitative modeling of pharmacokinetic and pharmaco-toxicodynamic behavior. Consensus recommendations for the application and improvement of current models are presented.

Cell Culture Techniques↗
PubMed2001

Metabolism of vanoxerine, 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine, by human cytochrome P450 enzymes.

Vanoxerine (1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine; GBR12909) is a promising agent for the treatment of cocaine dependence. Knowledge of the major pathway for GBR12909 metabolism is important for prediction of the likelihood of drug-drug interactions, which may affect the therapeutic clinical outcome, when this agent is used in cocaine-dependent individuals receiving multiple drug therapy. We studied biotransformation of GBR12909 in human liver microsomes (n = 4), human hepatocytes, and microsomes containing cDNA-expressed human P450 isoforms with GBR12909 concentrations within the range of steady-state plasma concentrations detected in healthy volunteers. A high-pressure liquid chromatography assay was used to measure parent GBR12909 and its primary metabolite. GBR12909 was metabolized by human liver microsomes, hepatocytes, and cDNA-expressed human P450s to a single metabolite. Ketoconazole, a selective inhibitor of CYP3A, reduced GBR12909 biotransformation in human liver microsomes and primary hepatocytes by 92 +/- 2 and 92.4 +/- 0.4%, respectively. Quercetin (an inhibitor of CYP2C8/3A4) was a less effective inhibitor producing 62 +/- 22% inhibition in human liver microsomes and 54 +/- 35% in hepatocytes. Other P450 selective inhibitors did not decrease GBR12909 biotransformation more than 29% in either human liver microsomes or hepatocytes with the exception of chlorzoxazone (CYP2E1), which inhibited GBR12909 biotransformation by 71.4 +/- 18.5% in primary human hepatocytes. Ciprofloxacin (CYP1A2), sulfaphenazole (CYP2C9), quinidine (CYP2D6), chlorzoxazone (CYP2E1), and mephenytoin (CYP2C19) did not demonstrate statistically significant inhibition (p > 0.05) of GBR12909 biotransformation in liver microsomes. cDNA-expressed P450 3A4 metabolized GBR12909 to a greater extent than 2C8 and 2E1. These data suggest the possibility that multiple P450 isoforms may be involved in human GBR12909 metabolism but that CYP3A appears to be the major enzyme responsible for human GBR12909 biotransformation.

Biotransformation↗
PubMed1999

Quality-of-service improvements from coupling a digital chest unit with integrated speech recognition, information, and picture archiving and communications systems.

Speech recognition reporting for chest examinations was introduced and tightly integrated with a Radiology Information System (RIS) and a Picture Archiving and Communications System (PACS). A feature of this integration was the unique one-to-one coupling of the workstation displayed case and the reporting via speech recognition for that and only that particular examination and patient. The utility of the resulting, wholly integrated electronic environment was then compared with that of the previous analog chest unit and dedicated wet processor, with reporting of hard copy examinations by direct dictation to a typist. Improvements in quality of service in comparison to the previous work environment include (1) immediate release of the patient, (2) decreased rate of repeat radiographs, (3) improved image quality, (4) decreased time for the examination to be available for interpretation, (5) automatic hanging of current and previous images, (6) ad-hoc availability of images, (7) capability of the radiologist to immediately review and correct the transcribed report, (8) decreased time for clinicians to view results, and (9) increased capacity of examinations per room.

Humans↗
PubMed1999

Salvage brachytherapy for localized prostate cancer after radiotherapy failure.

OBJECTIVES: To evaluate the effectiveness and morbidity of salvage brachytherapy for locally recurrent or persistent prostate cancer after radiotherapy failure. METHODS: In this retrospective study, 49 patients of median age 73.3 years (range 52.9 to 86.9) with biopsy-proven localized prostate cancer underwent interactive transperineal fluoroscopic-guided and biplane ultrasound-guided brachytherapy with either iodine 125 or palladium 103 after prior radiotherapy failure. Post-treatment follow-up was conducted for a median of 64.1 months (range 26.6 to 96.8) and included clinical assessment of disease status, assays of serum prostate-specific antigen (PSA) levels, and documentation of treatment-related symptoms and complications. Determination of biochemical treatment failure was based on two successive rising PSA values above the post-treatment PSA nadir value. RESULTS: The actuarial rate of local prostate cancer control was 98% (95% confidence interval [CI] 94% to 99%). Actuarial disease-specific survival at 3 and 5 years was 89% (95% CI 73% to 96%) and 79% (95% CI 58% to 91%), respectively. At 3 and 5 years, actuarial biochemical disease-free survival was 48% (95% CI 32% to 63%) and 34% (95% CI 17% to 51%), respectively. Post-treatment PSA nadir was found to be a significant predictor of biochemical disease-free survival. Actuarial biochemical disease-free survival of patients who achieved a PSA nadir less than 0.5 ng/mL was 77% (95% CI 53% to 90%) and 56% (95% CI 25% to 78%) at 3 and 5 years, respectively. Of 49 patients, 23 (47%) achieved a post-treatment PSA nadir less than 0.5 ng/mL. The incidence of serious complications after salvage brachytherapy, such as incontinence and rectal complications, was lower than that reported after other types of salvage procedures. CONCLUSIONS: Interactive transperineal fluoroscopic-guided and biplane ultrasound-guided brachytherapy is a novel, potentially curative salvage modality for patients in whom prior radiotherapy failed. In a population of patients with poor prognosis, this modality was associated with a high rate of local prostate cancer control and a 34% actuarial rate of biochemical disease-free survival at 5 years. The incidence of major complications after salvage brachytherapy appears to be lower than that after other potentially curative salvage procedures, such as radical prostatectomy and cryoablation. Salvage brachytherapy warrants further investigation.

Actuarial Analysis↗
PubMed1999

Effects of cytochrome P450 inducers on 17alpha-ethinyloestradiol (EE2) conjugation by primary human hepatocytes.

AIMS: Our objective was to elucidate further the underlying mechanism responsible for therapeutic failures observed with concomitant administration of the oral contraceptive 17alpha-ethinyloestradiol (EE2 ) and rifampicin. METHODS: We investigated both oxidative and direct conjugative [3H]-EE2 metabolism by human liver S9 fraction and the effect of known enzyme-inducing drugs using a human hepatocyte induction model in vitro. RESULTS: Cofactor dependent [3H]-EE2 metabolism by human liver S9 fraction produced 2-hydroxy-[3H]-EE2, 2-methoxy-[3H]-EE2, and direct [3H]-EE2 sulphate and glucuronide conjugates. Only two detectable metabolites of [3H]-EE2 were produced by the S9 fraction in the presence of all cofactors: [3H]-EE2-3-sulphate (75.7+/-7.6% s. d.) and 2-methoxy-3H-EE2 (2.6%+/-0.5% s.d.). Human hepatocytes extensively metabolized [3H]-EE2 to its glucuronide and sulphate conjugates. Small amounts of a 2-methoxy-[3H]-EE2 3-conjugate, < or = 10%, was observed but no. 2-hydroxy-[3H]-EE2 was detected. An unexpected finding in our study was increased [3H]-EE2-3-sulphate production (1.5-3.3 fold, n=3 donor livers) by hepatocytes pretreated with rifampicin compared to control hepatocytes. No statistically significant increase in [3H]-EE2-3-sulphation was observed in hepatocytes pretreated with 3-methylcholanthrene, phenobarbitone, dexamethasone, or omeprazole over nontreated hepatocytes. To our knowledge, this is the first observation of sulphotransferase induction by rifampicin in human hepatocytes in vitro resulting in increased [3H]-EE2 sulphation. CONCLUSIONS: Our data indicate that the major EE2 metabolic products formed by human hepatocytes in vitro are direct EE2 conjugates with EE2 oxidation representing minor pathways. Further studies are required to establish the mechanism of sulphotransferase induction and the clinical relevance of our findings.

Adolescent↗
PubMed1999

Prehospital discharge defibrillation testing in ICD recipients: a prospective study based on cost analysis.

Prehospital discharge defibrillation testing is often performed to verify the function of newly implanted cardioverter defibrillators (ICDs). To determine whether elimination of predischarge testing could reduce costs without placing patients at additional risk, 31 patients were randomized in this prospective clinical evaluation to either receive or not receive a predischarge ICD defibrillation test. Expenses associated with postimplant care was the primary endpoint. All patients underwent induction of ventricular fibrillation after 6 months to evaluate ICD function. The groups were well matched in terms of patient characteristics, initial lead implant parameters, and defibrillation thresholds. Elimination of prehospital discharge testing resulted in a savings of $1,800/patient after 6 months, with no difference between groups in terms of ICD complication rates or unanticipated hospital admissions. Further studies are needed to better define the most appropriate time to assess defibrillation thresholds in the first year after implantation.

Aged↗
PubMed1999

Testing the equivalence of the socialization factor structure for criminals and noncriminals.

Considerable evidence supports the criterion-related validity of the Socialization (So) scale of the California Psychological Inventory (Gough, 1948, 1994, 1996) for the prediction of antisocial and prosocial behavior. However, no research has examined the similarity of the So construct for the two populations. Meaningful interpretation of So scores is possible if the factor structure is equivalent for antisocial and prosocial groups.

Antisocial Personality Disorder↗
PubMed1999

Suicide prodrugs activated by thymidylate synthase: rationale for treatment and noninvasive imaging of tumors with deoxyuridine analogues.

Most tumors are resistant to therapy by thymidylate synthase (TS) inhibitors due to their high levels of TS. Instead of inhibiting TS, we hypothesized that it was possible to use this enzyme to activate suicide prodrugs (deoxyuridine analogues) to more toxic species (thymidine analogues). Tumors with high levels of TS could be particularly sensitive to deoxyuridine analogues because they would be more efficient in producing the toxic methylated species. Furthermore, the accumulation of methylated species within tumors could be visualized externally if a tracer dose of the deoxyuridine analogue was tagged with an isotope, preferably a positron emitter, such as 18F. Higher accumulation of isotope indicates higher activity of TS and lower sensitivity of the tumor to TS inhibitors, but perhaps more sensitivity to therapy with deoxyuridine analogues as suicide prodrugs. 2'-F-ara-deoxyuridine (FAU) was used as a prototype to demonstrate these concepts experimentally. FAU readily entered cells and was phosphorylated, methylated, and subsequently incorporated into cellular DNA. Among different cell lines, FAU produced varying degrees of growth inhibition. Greater DNA incorporation (e.g., for CEM and U-937 cells) was reflected as increased toxicity. FAU produced less DNA incorporation in Raji or L1210 cells, and growth rate was minimally decreased. As the first demonstration that cells with high levels of TS activity can be more vulnerable to therapy than cells with low TS activity, this preliminary work suggests a new therapeutic approach for common human tumors that were previously resistant. Furthermore, it appears that the TS activity of tumors could be noninvasively imaged in situ by tracer doses of [18F]FAU and that this phenotypic information could guide patient therapy.

Animals↗
PubMed1998

Actuarial disease-free survival after prostate cancer brachytherapy using interactive techniques with biplane ultrasound and fluoroscopic guidance.

PURPOSE: To evaluate the effectiveness and safety of interactive transperineal brachytherapy under biplane ultrasound and fluoroscopic guidance in patients with localized prostate cancer. METHODS AND MATERIALS: Brachytherapy using 125I or 103Pd radioactive seeds either alone or in combination with adjunctive external beam radiotherapy (XRT) was administered to 490 patients at a single institution. Post-treatment follow-up included clinical assessment of disease status, assays of serum prostate-specific antigen (PSA) levels and documentation of treatment-related symptoms and complications. RESULTS: Actuarial disease-free survival at 5 yr was 79% (95% CI, 71-85%), and the 5-yr actuarial rate of local control was 98% (95% CI, 94-99%). Post-treatment PSA nadir and pretreatment PSA level were found to be significant predictors of disease-free survival. In patients with a PSA nadir < 0.5 ng/ml, 5-yr disease-free survival was 93% (95% CI, 84-97%), compared with 25% (95% CI, 5-53%) in patients whose PSA nadir was 0.5-1.0 ng/ml and 15% (95% CI, 3-38) in patients with a PSA nadir > 1.0 ng/ml. Brachytherapy was well tolerated with few post-treatment complications. CONCLUSION: A broad range of patients with localized prostate cancer can benefit from transperineal brachytherapy with minimal morbidity. A post-treatment PSA nadir below 0.5 ng/ml provides a useful prognostic indicator of favorable long-term outcome.

Aged↗
PubMed1998

Physiologic cardiac pacing in patients with contemporary implantable cardioverter-defibrillators.

Contemporary implantable cardioverter-defibrillators (ICD) incorporate single-chamber ventricular pacing capability. However, because poor ventricular function and/or congestive heart failure is common in the ICD population, the provision of more "physiologic" pacing modes has been receiving increased attention. To evaluate the potential impact of ICDs with physiologic pacing features, we assessed the frequency with which atrial-based pacing modes with or without rate responsiveness are currently used in ICD recipients. Further, we characterized those clinical variables at initial ICD implant that tended to be associated with subsequent need for physiologic pacing. Clinical findings were reviewed in 250 consecutive patients who received ICDs with VVI pacing capability at the University of Minnesota Cardiac Arrhythmia Center between January 1991 and February 1997. Adjunctive physiologic pacing was undertaken in 35 patients (14%): 13 before or at the same time as their ICD, and 22 within a mean of 2.5 years after initial ICD surgery. A history of atrial tachyarrhythmia before ICD implantation (p <0.0001) and treatment with antiarrhythmic drugs at the time of ICD surgery (p <0.05) were predictors of subsequent need for physiologic pacing. The type of presenting ventricular tachyarrhythmia and electrophysiologic parameters (such as the HV interval and the shortest atrial pacing cycle length associated with 1:1 anterograde atrioventricular conduction) were not associated with a subsequent decision to implant a physiologic pacing system. Thus, we conclude that despite the need to implant a second device, physiologic pacing is currently used in an important subset of ICD recipients. Further, certain clinical features at time of ICD implant appear to characterize these patients and may prove helpful in patient selection for the next generation "dual-chamber" ICD.

Adolescent↗