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Biomedical subjects

J Perkins

Publications and source records attributed to J Perkins.

At least 19 recordsLinked to original sources
PubMed2002

Differences in the absorption, metabolism and biliary excretion of a diastereomeric pair of alphavbeta3-antagonists in rat: limited role of P-glycoprotein.

1. The study investigated mechanisms underlying the pharmacokinetic differences of two zwitterionic diastereomers ((3S)-3-[(3R or 3S)-2-oxo-3-[3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)propyl]pyrrolidin-1-yl]-3-quinolin-3-ylpropanoic acid) with different lipophilicities using a combination of in vivo and in vitro approaches. 2. In rat, both isomers possessed comparable plasma clearances (CL). However, the more lipophilic diastereomer I exhibited a higher metabolic clearance (>2-fold higher than II), whereas the hydrophilic zwitterion II exhibited a higher biliary clearance (approximately 5-fold higher than I). Following oral administration, the bioavailability (F) of I (17%) was much higher than that of II (1%). 3. Consistent with these in vivo observations and the expectation based on their lipophilicity differences, the metabolism in rat liver microsomes was faster and the permeability in Caco-2 and LLC-PK1 cells and in situ rat intestinal loop was better for I than for II. 4. Only the absorption of the more lipophilic diastereomer I was subjected to an efflux system in the Caco-2 and in situ rat intestinal loop models. I was a good substrate for P-glycoprotein (P-gp) in both the human MDR1 and mouse mdr1a transfected cell lines, and in the wild-type mdr1a (-/-) mouse when compared with the P-gp-deficient mdr1a (-/-) mouse. Concomitant administration of I with verapamil in rat caused significant increases in oral AUC, F and Cmax of I without affecting its CL, further supporting the effect of P-gp in limiting the intestinal absorption of I in vivo in this animal model. 5. Since the findings that the lipophilic diastereomer I, but not II, was a good P-gp substrate were not in line with the observations that I was excreted to bile much slower than II and that I was absorbed better than II, the results suggested that P-gp played a minor role to the observed differences in the biliary excretion and intestinal absorption of the diastereomers I and II in rat.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2001

Molecular-based electronically switchable tunnel junction devices.

Solid-state tunnel junction devices were fabricated from Langmuir Blodgett molecular monolayers of a bistable [2]catenane, a bistable [2]pseudorotaxane, and a single-station [2]rotaxane. All devices exhibited a (noncapacitive) hysteretic current-voltage response that switched the device between high- and low-conductivity states, although control devices exhibited no such response. Correlations between the structure and solution-phase dynamics of the molecular and supramolecular systems, the crystallographic domain structure of the monolayer film, and the room-temperature device performance characteristics are reported.

Journal Article↗
PubMed2001

A supramolecular system for quantifying aromatic stacking interactions.

A supramolecular complex for investigating the thermodynamic properties of intermolecular aromatic stacking interactions has been developed. The conformation of the complex is locked in a single well-defined conformation by an array of H-bonding interactions that force two aromatic rings on one end of the complex into a stacked geometry. Chemical double-mutant cycles have been used to measure an anthracene-aniline interaction (+0.6 +/- 0.8 kJ mol(-1)) and a pentafluorophenyl-aniline interaction (-0.4 +/- 0.9 kJ mol(-1)) in this system. Although the interactions are very weak, the pentafluorophenyl interaction is attractive, whereas the anthracene interaction is repulsive: this is consistent with the dominance of pi-electron electrostatic interactions. The nitropyrrole subunits used to control the conformation of these complexes lead to problems of aggregation and multiple conformational equilibria. The implications for the thermodynamic analysis are examined in detail, and the double-mutant-cycle approach is found to be remarkably robust with respect to such effects, since systematic errors in individual experiments are removed in a pair-wise fashion when the cycle is constructed.

Journal Article↗
PubMed2001

The mechanism of action of bacimethrin, a naturally occurring thiamin antimetabolite.

The mechanism of bacimethrin (2) toxicity has been determined. This compound is converted to 2'-methoxy-thiamin pyrophosphate (10) by the thiamin biosynthetic enzymes. Of the seven thiamin pyrophosphate utilizing enzymes in Escherichia coli, 2'-methoxy-thiamin pyrophosphate inhibits alpha-ketoglutarate dehydrogenase, transketolase, and deoxy-D-xylulose-5-phosphate synthase. Bacimethrin does not cause repression of the genes coding for the thiamin biosynthetic enzymes.

Antimetabolites↗
PubMed2001

Effect of a community action intervention on cervical cancer screening rates in rural Australian towns: the CART project.

BACKGROUND: The effect of community action on cervical cancer screening rates was explored in 20 rural Australian towns. METHODS: Town quarterly Pap test counts, from the Australian Health Insurance Commission, were converted to town rates using Census populations. Pap test rates for 12 quarters before and after mobilization were examined. RESULTS: Wilcoxon-Mann-Whitney tests demonstrated significantly higher per capita Pap test rates pre- to postmobilization for intervention towns compared to matched control towns for women whose last Pap test was more than 2 years ago (P=0.008). Maximum efficiency robust tests examining the equality of mean differences (intervention-control) of per capita rates between pre- and post-mobilization periods also found significant differences for Pap tests where last procedure was between 1 and 2 years ago (R = 13.9, P = 0.039) and near significance for Pap tests where last procedure was less than one year ago (R = 10.6, P = 0.087). CONCLUSIONS: It appeared that underscreened women were more likely and overscreened women were less likely to have a Pap test in response to the intervention. The results indicate that a community action program can positively impact cervical cancer screening rates.

Adult↗
PubMed2001

Effect of a community action program on adult quit smoking rates in rural australian towns: the CART project.

BACKGROUND: This article describes one outcome of a randomized controlled trial of community action for cancer prevention. The aims of this article were to (a) explore the effectiveness of a community action program in decreasing community smoking rates in rural Australian towns and (b) describe the relationship between adult smoking quit and uptake rates and demographic variables. METHODS: In 1992, 20 towns were selected for randomization. Community action involved formation of community committees and utilization of access point networks to initiate and maintain intervention strategies. At post-test, outcomes were proportion of "quitters" from a cohort of self-described smokers, proportion of "uptakers" from a cohort of self-described nonsmokers, and "net effect." RESULTS: Differences in quit rate, uptake rate, and net effect for intervention compared to control condition favored the intervention in all cases, although mainly nonsignificant. Significantly more male smokers quit in intervention towns than in control towns [7.0% (95% CI: 0.6, 13.5)]. CONCLUSIONS: Given that CART utilized and improved upon strategies argued as effective in the literature, the limited success of the project in reducing adult smoking, considered in combination with COMMIT findings, suggests the need for further innovation in the field.

Adolescent↗
PubMed2001

The effect of a community action intervention on adolescent smoking rates in rural australian towns: the CART project. Cancer Action in Rural Towns.

BACKGROUND: This paper describes one outcome of a randomized controlled trial of community action for cancer prevention, Cancer Action in Rural Towns. The aims are to [1] explore the effectiveness of community action in decreasing adolescent smoking in rural Australian towns; and [2] describe the relationship between adolescent smoking rates and demographic variables. METHODS: In 1992, 20 rural Australian towns were selected. Community action involved formation of community committees and utilization of access-point networks to initiate and maintain intervention strategies. Cross-sectional surveys of smoking behaviors for all Year 9 and Year 10 students (13-16 years) in each town were conducted pre- and posttest. The main outcome measure was self-reported smoking in the past 4 weeks. SUDAAN software was used to look at differences between treatment. RESULTS: The results showed strong secular trends toward increased adolescent smoking, regardless of treatment group, particularly for females. There was no significant intervention effect. CONCLUSIONS: Increasing adolescent smoking rates found in this and other studies highlight that the definitive strategy to stem the adolescent smoking epidemic has not been found. Hope may remain for recent legislative strategies, but rigorous evaluation is essential, and compliance with legislation should be carefully monitored.

Adolescent↗
PubMed2001

Ocular complications of thermal injury: a 3-year retrospective.

BACKGROUND: Diagnosis and treatment of thermal ocular injuries are often delayed because facial burns are usually associated with life-threatening injuries requiring immediate intervention. The purpose of the present study is to review the diagnosis and management of ocular complications associated with thermal burns in a tertiary care burn unit. METHODS: In this retrospective study, the charts of patients admitted to the Loyola University Medical Center Burn Unit between January 1993 and January 1996 were reviewed. RESULTS: Of the 1,461 patients who were admitted to the burn unit during that period, 155 (10.6%) required ophthalmic consultation. Sixty-one patients (4.2%) had ocular injury, the most common type being periorbital burn and edema followed by corneal involvement. Thirty-one of the 61 patients (51%) received consultation on the day of admission. Six of the 61 patients (10%) required surgical intervention. There was no correlation between number of days to consultation and need for surgical intervention. Patients requiring surgery were more likely to have suffered third-degree burns. CONCLUSION: Because it is difficult to predict which patients suffering from thermal burns involving the eyes will require surgical intervention, ophthalmic consultation should be sought early.

Adolescent↗
PubMed2001

RNA expression analysis using an antisense Bacillus subtilis genome array.

We have developed an antisense oligonucleotide microarray for the study of gene expression and regulation in Bacillus subtilis by using Affymetrix technology. Quality control tests of the B. subtilis GeneChip were performed to ascertain the quality of the array. These tests included optimization of the labeling and hybridization conditions, determination of the linear dynamic range of gene expression levels, and assessment of differential gene expression patterns of known vitamin biosynthetic genes. In minimal medium, we detected transcripts for approximately 70% of the known open reading frames (ORFs). In addition, we were able to monitor the transcript level of known biosynthetic genes regulated by riboflavin, biotin, or thiamine. Moreover, novel transcripts were also detected within intergenic regions and on the opposite coding strand of known ORFs. Several of these novel transcripts were subsequently correlated to new coding regions.

Amino Acid Sequence↗
PubMed2001

Extraintestinal Crohn's disease: case report and review of the literature.

Crohn's disease is a granulomatous inflammatory bowel disease. Its pathologic findings include noncontiguous chronic inflammation and noncaseating granulomas. Any segment of the gastrointestinal tract can be involved, but it is uncommon to find that Crohn's disease has spread beyond the intestine. We describe the case of a man with extraintestinal Crohn's disease that was marked by quiescent involvement of the lower gastrointestinal tract and florid involvement of the nasal cavity, supraglottic structures, glottis, and skin.

Crohn Disease↗
PubMed2000

Self-assembly of an amphiphilic

The template-directed synthesis of a [2]rotaxane, in which a pi-electron deficient ring component-cyclobis(paraquat-p-phenylene)-is assembled around a pi-electron rich asymmetric monopyrrolotetrathiafulvalene unit on the rod section of an amphiphilic dumbbell component that is terminated by a hydrophilic dendritic stopper at one end and a hydrophobic tetraarylmethane stopper at the other end, is reported.

Journal Article↗
PubMed2000

The effects of mitomycin-C and stenting on airway wound healing after laryngotracheal reconstruction in a pig model.

OBJECTIVE: To assess the effects of mitomycin-C (MTC) and endoscopic stenting on airway wound healing after laryngotracheal reconstruction. DESIGN: A prospective, blinded, randomized controlled animal study. SUBJECTS: Twenty-six domestic pigs (Sus scrofula) divided into four groups. INTERVENTIONS: Each animal underwent single-stage laryngotracheal reconstruction (SSLTR) with auricular cartilage grafts and stenting. Group 1 animals were sacrificed on postoperative day 3, and group 2 animals on postoperative day 7. On postoperative day 7, groups 3 and 4 underwent endoscopy, stent removal, and application of MTC (0.5 mg/ml) or placebo (normal saline). Group 3 animals were sacrificed on postoperative day 14, group 4 animals on day 21. Two additional animals from each experimental group were prepared for election microscopy studies. Segments of reconstructed airway were evaluated grossly and histologically for all animals. Additional tonometric evaluation was performed on two stents to determine their compressive strength. MAIN OUTCOME MEASURES: Healing, reepithelization, graft incorporation, and airway diameter. RESULTS: Two-thirds of the animals demonstrated some degree of stent collapse on endoscopy. Granulation tissue formation was seen in all animals, and resolved with stent removal. No animal experienced airway compromise due to granulation tissue formation. Stenting was seen to induce a submucosal fibroproliferative response and scarring, with loss of normal glandular architecture, in all animals. MTC did not affect the acute inflammatory response, reepithelization of the graft site, or formation of the subepithelial fibroproliferative response. MTC treated animals, however, demonstrated better graft incorporation with fibrocartilage proliferation of the graft. Untreated animals demonstrated liquefactive necrosis of the graft, without evidence of neochondrification of the graft. CONCLUSIONS: The pig airway is an adequate model of wound healing following SSLTR and stenting. Metallic ballon expandable stents can be successfully used following SSLTR, allowing for immediate postoperative extubation. However, the formation of a submucosal fibroproliferative response and mucosal scarring seen in our study raises some concerns with the current stent design. Before stenting is widely clinically applied, the optimum stent design needs to be developed. Finally, MTC seems to prevent the liquefactive necrosis of SSLTR grafts and promote neochondrification, allowing improved graft incorporation. Further studies are needed to asses the long-term effects of MTC on healing and restenosis, and its effects on cartilage growth and formation, following SSLTR.

Animals↗
PubMed2000

Percutaneous penetration studies for risk assessment.

During the last few years the general interest in the percutaneous absorption of chemicals has increased. It is generally accepted that there is very few reliable quantitative and qualitative data on dermal exposure to chemicals in the general population and in occupationally exposed workers. In order to predict the systemic risk of dermally absorbed chemicals and to enable agencies to set safety standards, data is needed on the rates of percutaneous penetration of important chemicals. Standardization of in vitro tests and comparison of their results with the in vivo data could produce internationally accepted penetration rates and/or absorption percentages very useful for regulatory toxicology. The work of the Percutaneous Penetration Subgroup of EC Dermal Exposure Network has been focussed on the standardization and validation of in vitro experiments, necessary to obtain internationally accepted penetration rates for regulatory purposes. The members of the Subgroup analyzed the guidelines on percutaneous penetration in vitro studies presented by various organizations and suggested a standardization of in vitro models for percutaneous penetration taking into account their individual experiences, literature data and guidelines already in existence. During the meetings of Percutaneous Penetration Subgroup they presented a number of short papers of up to date information on the key issues. The objective was to focus the existing knowledge and the gaps in the knowledge in the field of percutaneous penetration. This paper is an outcome of the meetings of the Percutaneous Penetration Subgroup and reports the presentations on the key issues identified throughout the 3-year duration of the Dermal Exposure Network (1997-1999).

Journal Article↗
PubMed2000

Angiogenesis and intrauterine growth restriction.

Human placental development involves co-ordinated angiogenesis and trophoblast outgrowth that are compromised in intrauterine growth restriction. Adaptive angiogenesis in IUGR placental villi is a result of an imbalance in the orderly progression of the expression profile of vascular endothelial growth factor, placenta growth factor and angiopoietin during placental development. VEGF receptors and the angiopoietin receptor Tie-2 are expressed on trophoblast, and their activation leads to trophoblast proliferation, migration and production of nitric oxide. Thus, these vascular factors act as autocrine regulators of trophoblast behaviour in the development of the utero-/feto-placental circulation, an action independent of their well-established roles in vascular endothelium.

Animals↗
PubMed2000

Metabolism of fluroxypyr, fluroxypyr methyl ester, and the herbicide fluroxypyr methylheptyl ester. I: during percutaneous absorption through fresh rat and human skin in vitro.

Percutaneous absorption of pesticides is a major determinant for risk assessment. Furthermore, cutaneous metabolism plays a role in penetration of certain chemicals. Therefore, the aim of these studies was to determine the transdermal metabolism of three related compounds [the herbicide, fluroxypyr methylheptyl ester (FPMH), fluroxypyr methyl ester (FPM), and fluroxypyr (FP)] during penetration through human and rat skin in vitro. The data presented in this article show that both FPM and FPMH were completely metabolized during their passage through human and rat skin in vitro. The only metabolite produced was that of the hydrolysis product, FP, with no parent ester penetrating through the skin. The extent of FP formation within the skin was directly correlated to the degree of stratum corneum reservoir formation. The larger the stratum corneum reservoir, the lower the levels of FP recovered from within the skin. This suggests that as the ester partitioned out of the SC it was immediately hydrolyzed to FP, which could then pass freely through the remainder of the epidermis and dermis. Similar metabolic profiles were observed for the transdermal metabolism of FPM and FPMH in previously frozen rat skin, indicating the robust nature of the esterase enzymes involved. In conclusion, systemic exposure after skin contact with FPM or FPMH is likely to be to the acid metabolite, FP, only and not to the parent ester. In addition, the rate and extent of percutaneous absorption will be a major determinant of cutaneous metabolism.

Animals↗
PubMed2000

Metabolism of fluroxypyr, fluroxypyr methyl ester, and the herbicide fluroxypyr methylheptyl ester. II: in rat skin homogenates.

Fluroxypyr methyl ester (FPM) and the herbicide fluroxypyr methylheptyl ester (FPMH) are completely hydrolyzed during penetration through human and rat skin in vitro to the acid metabolite, fluroxypyr (FP) (). This article presents additional studies to determine the enzyme kinetics (K(m) and V(max)) of this ester hydrolysis, using crude rat whole-skin homogenate. Both FPM and FPMH were extensively metabolized in rat skin homogenates to the acid metabolite, FP. In no instance were any other metabolites detected. FPM was essentially hydrolyzed completely within 1 h. In FPMH incubations, there was still parent ester present after 24 h at all concentrations tested. The kinetics of hydrolysis of the two esters were different: V(max) was approximately 3-fold greater for FPM than FPMH (1400 and 490 micromol FP/min/g of tissue, respectively); however, K(m) values were very similar, 251 and 256 microM, respectively. Preliminary inhibitory studies suggest that FPM and FPMH are hydrolyzed by a carboxylesterase, because this reaction was inhibited by bis-p-nitrophenyl phosphate. Mercuric chloride (an inhibitor of A-esterase and arylesterase) and eserine (a cholinesterase inhibitor) had no inhibitory effect on the hydrolysis of FPM or FPMH. Taken together with the data presented by, it can be concluded that no parent ester will pass through the skin in vivo, only the metabolite, FP. Therefore, first pass metabolism will be complete before these compounds reach the systemic circulation.

Animals↗