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C J Porter

Publications and source records attributed to C J Porter.

At least 37 records · Page 2Linked to original sources
PubMed2001

The impact of P-glycoprotein efflux on enterocyte residence time and enterocyte-based metabolism of verapamil.

P-glycoprotein (P-gp) can limit the intestinal permeability of a number of compounds and may therefore influence their exposure to metabolizing enzymes within the enterocyte (e.g. cytochrome P450 3A, CYP 3A). In this study, the intestinal metabolic profile of verapamil, the influence of P-gp anti-transport on the cellular residence time of verapamil, and the impact of this change in residence time on the extent of enterocyte-based metabolism have been investigated in-vitro, utilizing segments of rat jejunum and side-by-side diffusion chambers. Verapamil exhibited concentration-dependent P-gp efflux and CYP 3A metabolism. The P-gp efflux of verapamil (1 microM) increased the cellular residence time across the intestinal membrane (approximately 3-fold) in the mucosal to serosal (m to s) direction relative to serosal to mucosal (s to m), yielding significantly greater metabolism (approximately 2-fold), presumably as a result of the prolonged exposure to CYP 3A. Intestinal metabolism of verapamil generated not only norverapamil, but resulted also in the formation of an N-dealkylated product (D-617). Norverapamil and D-617 accumulated significantly in mucosal chambers, relative to serosal chambers, over the time course of the experiment. Based on these in-vitro data, it was apparent that P-gp efflux prolonged the cellular residence time of verapamil (m to s) and therefore increased the extent of intestinal metabolism, and also played a role in metabolite secretion from within the enterocyte.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2001

Breath-holding spells associated with significant bradycardia: successful treatment with permanent pacemaker implantation.

OBJECTIVE: To determine whether children with pallid breath-holding spells associated with bradycardia can be treated safely and successfully with permanent pacemaker implantation. METHODS: The records of pediatric patients who had apparent breath-holding spells and associated bradycardia and were treated with permanent pacemaker implantation were reviewed. RESULTS: Ten pediatric patients with apparent breath-holding spells associated with bradycardia were treated with a permanent ventricular demand pacemaker at the Mayo Clinic between 1985 and 1995. Patients had onset of symptoms between ages 6 days and 12 months and presented for evaluation between ages 12 months and 5 years. Duration of spells was 15 seconds to 10 minutes. Medications to prevent spells were unsuccessful. Electrocardiograms documented asystolic pauses of 1.7 to 24 seconds (mean: 11.9 seconds). Permanent ventricular demand pacemakers were implanted at 10 months to 5 years of age (median: 14.5 months): 9 endocardial and 1 epicardial. Three patients required pacemaker revision. At follow-up of 38 to 170 months (median: 65.5), 5 patients had complete resolution of spells, 2 had only mild color change without loss of consciousness or seizure activity, and 3 continued to have minor brief spells. CONCLUSIONS: Permanent pacemaker therapy for children with pallid breath-holding spells associated with severe bradycardia is safe, efficacious, and warranted.

Apnea↗
PubMed2000

The formulation of Halofantrine as either non-solubilizing PEG 6000 or solubilizing lipid based solid dispersions: physical stability and absolute bioavailability assessment.

A non-solubilizing solid dispersion formulation (polyethylene glycol 6000) and two solubilizing solid dispersions (Vitamin E TPGS and a Gelucire 44/14/Vitamin E TPGS blend) containing the antimalarial, Halofantrine (Hf), were formulated for bioavailability assessment in fasted beagles to determine if the oral absorption of Hf can be enhanced by these delivery systems. Solid dispersions comprising varying proportions of drug to carrier were prepared by the fusion method. Whilst the non-solubilizing formulation was assessed according to its dispersion characteristics, the solubilizing solid dispersions were assessed by their ability to form microemulsions upon dispersion. Studies in fasted beagles showed that the solid dispersions afforded a five- to seven-fold improvement in absolute oral bioavailability when compared with the commercially available tablet formulation. The delivery of Hf in either a solubilizing or non-solubilizing solid dispersion did not result in significant differences in oral bioavailability. The physical stability of the solid dispersions was studied using differential scanning calorimetry and X-ray powder diffraction.

Antimalarials↗
PubMed2000

Factors limiting the oral bioavailability of N-acetylglucosaminyl-N-acetylmuramyl dipeptide (GMDP) and enhancement of absorption in rats by delivery in a water-in-oil microemulsion.

The bioavailability (BA) of radio-labelled N-acetylglucosaminyl-N-acetylmuramyl dipeptide (GMDP) was low when administered by oral gavage as an aqueous solution to conscious male Sprague-Dawley rats (8.3+/-4.4% (mean+/-S.D., n=3)). To assess the likely factors contributing to the poor BA of GMDP, the stability of GMDP in the lumen of the gastrointestinal (GI) tract was examined in vitro, using ex vivo GI contents. GMDP was degraded by the contents of the small intestine, caecum and large intestine but was more stable in stomach contents. The permeability coefficient (p(app)) of GMDP in isolated sections of rabbit ileum was 1.67x10(-6) cm/s in the mucosal to serosal direction and was not significantly different in the serosal to mucosal direction, indicating that GMDP is poorly permeable and passively transported across the intestinal wall. First pass metabolism was considered to be unlikely to be the primary limitation to the oral bioavailability of GMDP and therefore, that the oral bioavailability of GMDP was likely limited by instability in the lumen of the gastrointestinal tract and low intestinal permeability. A water-in-oil (w/o) microemulsion formulation subsequently developed to address these problems was trialed in a preliminary bioavailability study in rats and enhanced the bioavailability of GMDP ten-fold when administered intraduodenally, indicating that w/o microemulsions may represent a viable mechanism for enhancing the bioavailability of poorly GI-stable and poorly permeable peptide-based molecules.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed2000

fas-fas-ligand antigen expression and its relationship to increased apoptosis in acute renal transplant rejection.

BACKGROUND: To examine the role of fas-fas-ligand interaction and apoptosis in acute transplant rejection. METHODS: Pre- and posttransplant renal allograft biopsies were stained by in situ 3-end labeling of DNA for detection of apoptotic cells (TUNEL) and immunohistochemistry techniques were used for demonstration of fas and fas-ligand antigen expression. RESULTS: Posttransplantation apoptosis was significantly increased in acute rejection and acute tubular necrosis (P<0.0001) compared to preimplantation biopsies and biopsies taken from grafts showing dysfunction not attributed to rejection. Fas and fas-ligand expression was demonstrated predominantly in the tubular epithelium. In preimplant biopsies fas was expressed in 11% (4/37) of cases; posttransplantation expression increased to: 44% (8/18) acute rejection, 63% (5/8) acute tubular necrosis, and 38% (5/13) dysfunction without evidence of rejection. Fas-ligand was expressed by 30% (11/37) of preimplant biopsies, posttransplantation expression was reduced in all groups: 17% (3/18) acute rejection, 13% (1/8) acute tubular necrosis, delayed xenograft rejection and 15% (2/13) dysfunction without evidence of rejection. A correlation with fas-1 expression preimplantation and a subsequent absence of acute rejection post transplant was noted (P<0.001). CONCLUSIONS: Apoptosis is a feature of acute rejection and acute tubular necrosis. Fas expression is uncommon preimplantation and increases non-specifically post transplant. Fas-1 was expressed by a third of preimplantation biopsies and expression was lost non-specifically post transplant. The expression of fas-ligand preimplantation correlated with an absence of acute rejection episodes posttransplant, suggesting some degree of immune privilege. These data suggest that the fas-fas-1 mediated pathway does not play a specific role in apoptosis during acute rejection. We were unable to find any evidence that the fas-fas-1-mediated pathway has a role in the increased apoptosis seen during acute rejection.

Adult↗
PubMed2000

Central mutation databases--a review.

The Internet has been a key component in the coordination of the diverse group of scientists involved in the Human Genome Project. Nowhere has this contribution been more critical than in the maintenance and exchange of information about genetic variation and mutation. Whereas the majority of DNA sequence is generated and stored by a relatively few sites, a far greater number of researchers investigate the variations in that sequence from sites scattered worldwide. It falls to central databases to utilize the Internet to assemble data from these sites and make them available to the greater human genomic community.

Databases, Factual↗
PubMed2000

Systemic availability and lymphatic transport of human growth hormone administered by subcutaneous injection.

Degradation of human growth hormone (hGH) at the injection site has previously been implicated as the basis for its reduced systemic availability following subcutaneous (SC) administration. The goal of these studies was to develop an animal model which would allow mass balance calculations to (i) quantify the loss at the injection site and (ii) determine the role of the lymphatics in the transport of subcutaneously-administered hGH. The animal model utilized a sheep and enabled simultaneous sampling of blood and collection of either peripheral lymph (via the efferent duct of the popliteal lymph node draining the injection site) or central lymph (via the thoracic lymph duct). In non-lymph cannulated sheep, the systemic availability of hGH following SC dosing was 58.4 +/- 9.1% (mean +/- SEM) relative to an intravenous (IV) control. The availability of hGH decreased to approximately 30-40% when either peripheral or central lymph was collected indicating that a proportion of the dose was transported via the lymph. The fraction of the administered dose collected in peripheral lymph was 61.7 +/- 8.5% (mean +/- SEM), whereas only 8.6 +/- 1.3% was collected in central lymph. These results suggested that loss of hGH within the lymphatics contributed significantly to its reduced systemic availability following SC administration. The total recovery (sum of the systemic availability and the cumulative amount recovered in lymph) of hGH was approximately 93% of the dose in the peripherally-cannulated group indicating that loss at the injection site was minimal.

Animals↗
PubMed2000

Lymphatic transport of proteins after subcutaneous administration.

This mini-review summarizes the relevant literature regarding the lymphatic transport of proteins after subcutaneous administration. A review of the physiology of the lymphatics and inherent anatomical differences between blood and lymph capillaries is presented followed by a brief overview of the general characteristics of protein absorption and bioavailability following S.C. injection. A description of factors known to directly affect the lymphatic uptake of macromolecules follows and is supported by representative data from this laboratory. A brief perspective on the importance of lymphatic uptake and transport in understanding the biopharmaceutical properties of protein drugs and potentially targeting the lymphatics is presented.

Animals↗
PubMed2000

Effect of short-, medium-, and long-chain fatty acid-based vehicles on the absolute oral bioavailability and intestinal lymphatic transport of halofantrine and assessment of mass balance in lymph-cannulated and non-cannulated rats.

The contribution of lymphatic transport and absorption directly into the portal blood to the overall oral bioavailability of a model lipophilic drug, halofantrine (Hf), was determined in lymph-cannulated, conscious, unrestrained rats after administration in lipidic vehicles with different fatty acid chain lengths. Both lymphatic transport (C(18)-based vehicle, 15.8% of dose > C(8-10), 5. 5% > C(4), 2.22% > C(0), 0.34%) and total systemic exposure (C(18), 22.7% of dose > C(8-10), 19.2% > C(4), 15.2% > C(0), 6.4%) of Hf were enhanced by the presence of lipids in the formulation and specifically by an increase in the fatty acid chain length of the coadministered lipid. Increases in lymphatic drug transport appeared to correlate with increases in lymphatic lipid transport. Surprisingly, where lymphatic transport was the primary mechanism of drug transport to the systemic circulation (i.e., after administration in a C(18)-based lipid vehicle), Hf bioavailability assessed in nonlymph-cannulated animals was lower than the extent of total availability measured in lymph-cannulated animals (estimated as percent appearing in the intestinal lymph plus percent transported directly into the blood), suggesting either presystemic drug clearance within the lymphatics or an altered systemic clearance pattern for lymphatically transported drug.

Animals↗
PubMed1999

Differences in the lipoprotein binding profile of halofantrine in fed and fasted human or beagle plasma are dictated by the respective masses of core apolar lipoprotein lipid.

Halofantrine hydrochloride (Hf) is an orally active, highly lipophilic antimalarial indicated for the treatment of multi-drug resistant Plasmodium falciparum. In this study, we have examined the binding profile of Hf to the various classes of human and beagle plasma lipoproteins as such interactions have been implicated in a post-prandial plasma lipoprotein-induced decrease in the total clearance and volume of distribution of Hf. The distribution of Hf within plasma was dominated by interaction with the various classes of plasma lipoproteins, and the characteristics and extent of binding were markedly different between species and between pre- and post-prandial plasma. In an attempt to understand the basis for the differential binding of Hf to the various lipoprotein fractions, the relationship between the proportion of Hf associated with each lipoprotein fraction (as a function of the respective mass of protein, triglyceride, cholesterol, and phospholipid) was investigated. The data indicated that the distribution of Hf between plasma lipoproteins was highly correlated with the apolar lipid load of individual plasma lipoprotein fractions suggesting that the mechanism of association was primarily via solubilization in the lipoprotein apolar lipid core. These data suggest that acute changes in plasma lipoprotein profiles, such as encountered post-prandially or in disease states such as malaria, will likely have an impact on the plasma lipoprotein binding of Hf.

Animals↗
PubMed1999

Differences in the lipoprotein distribution of halofantrine are regulated by lipoprotein apolar lipid and protein concentration and lipid transfer protein I activity: in vitro studies in normolipidemic and dyslipidemic human plasmas.

The purpose of these studies was to determine the distribution of a lipophilic antimalarial agent, halofantrine hydrochloride (Hf), in fasted plasma from hypo-, normo-, and hyperlipidemic patients that displayed differences in lipoprotein concentration and lipid transfer protein I (LTP I) activity. To assess the influence of modified lipoprotein concentrations and LTP I activity on the plasma distribution of Hf, Hf at a concentration of 1000 ng/mL was incubated in either hypo-, normo-, or hyperlipidemic human plasma for 1 h at 37 degreesC. Following incubation, the plasma samples were separated into their lipoprotein and lipoprotein-deficient plasma (LPDP) fractions by density gradient ultracentrifugation and assayed for Hf by high-pressure liquid chromatography. The activity of LTP I in the dyslipidemic plasma samples was determined in terms of its ability to transfer cholesteryl ester from low-density lipoproteins (LDL) to high-density lipoproteins (HDL). Total plasma and lipoprotein cholesterol (esterified and unesterified), triglyceride, and protein levels in the dyslipidemic plasma samples were determined by enzymatic assays. When Hf was incubated in normolipidemic plasma for 1 h at 37 degreesC, the majority of drug was found in the LPDP fraction. When Hf was incubated in human plasma of varying total lipid, lipoprotein lipid, and protein concentrations and LTP I activity, the following relationships were observed. As the triglyceride-rich lipoprotein (TRL) lipid and protein concentration increased from hypolipidemia through to hyperlipidemia, the proportion of Hf associated with TRL increased (r > 0.90). As the HDL lipid and protein concentration increased, the proportion of Hf associated with HDL decreased (r > 0.70). As the total and lipoprotein lipid levels increased, the LTP I activity of the plasma also proportionally increased (r > 0.85). Furthermore, with the increase in LTP I activity, the proportion of Hf associated with the TRL fraction increased (r > 0.70) and the proportion of Hf associated with the HDL fraction decreased (r > 0.80). In addition, a positive correlation between the proportion of apolar lipid and Hf recovered within each lipoprotein fraction was observed within hypo- (r > 0.80), normo- (r = 0.70), and hyperlipidemic (r > 0.90) plasmas. These findings suggest that changes in the HDL and TRL lipid and protein concentrations, LTP I activity, and the proportion of apolar lipid within each lipoprotein fraction may influence the plasma lipoprotein distribution of Hf in dyslipidemia.

Antimalarials↗
PubMed1999

A comprehensive view of human chromosome 1.

Comprehensive representations of human chromosomes combining diverse genomic data sets, localizing expressed sequences, and reflecting physical distance are essential for disease gene identification and sequencing efforts. We have developed a method (CompView) for integrating genomic information derived from available cytogenetic, genetic linkage, radiation hybrid, physical, and transcript-based mapping approaches. CompView generates chromosome representations with substantially higher resolution, coverage, and integration than current maps of the human genome. The CompView process was used to build a representation of human chromosome 1, yielding a map with >13,000 unique elements, an effective resolution of 910 kb, and a marker density of 50 kb. CompView creates comprehensive and fully integrated depictions of a chromosome's clinical, biological, and structural information.

Chromosome Mapping↗
PubMed1999

Swimming, a gene-specific arrhythmogenic trigger for inherited long QT syndrome.

OBJECTIVE: To determine the genetic basis for long QT syndrome (LQTS) in a cohort of patients with a personal history or an extended family history of a swimming-triggered cardiac event. PATIENTS AND METHODS: After review of the Mayo Clinic unit medical record system, blood samples or archived autopsy tissue samples were obtained from a retrospective cohort of 35 cases diagnosed as having autosomal dominant LQTS. Exon-specific amplification by polymerase chain reaction and direct sequence analyses were performed on the entire KVLQT1 gene. RESULTS: Six cases had a personal history or an extended family history of a near drowning or drowning. In all 6 cases, LQTS-causing mutations in KVLQT1 gene were identified: 3 deletion mutations, 2 donor splice site mutations, and 1 missense mutation. One of the mutations, a novel donor splicing defect, was determined by postmortem molecular analysis of a paraffin-embedded tissue block from a 12-year-old girl who died in 1976. Distinct KVLQT1 mutations were demonstrated in 3 of the remaining 29 cases. The overall frequency of KVLQT1 defects in LQTS was 100% (6/6) in those with and 10% (3/29) in those without a personal history or an extended family history of drowning or near drowning (P<.001). CONCLUSION: Swimming appears to be a gene-specific (KVLQT1) arrhythmogenic trigger for LQTS. This study provides proof of principle that an unexplained drowning or near drowning may have a genetic basis.

Adolescent↗
PubMed1998

Predictors of early- and late-onset supraventricular tachyarrhythmias after Fontan operation.

BACKGROUND: The objectives of our study were to determine the frequency of supraventricular tachyarrhythmias (SVTAs) among modifications of the Fontan operation and identify risk factors for developing SVTA. METHODS AND RESULTS: The population consisted of all patients who had any modification of the Fontan operation at the Mayo Clinic between 1985 and 1993. Clinically significant SVTAs were those requiring initiation or change of antiarrhythmic treatment, and they were divided into early SVTAs (<30 days after the operation) and late SVTAs (>/=30 days after the operation). Clinical histories were reviewed, and health status questionnaires were sent. Four hundred ninety-nine patients had various modifications of the Fontan operation. Frequency of early SVTA was 15%. Risk factors identified by multivariate analysis for early SVTA were AV valve regurgitation, abnormal AV valve, and preoperative SVTA. Frequency of late SVTA was 6% by 1 year, 12% by 3 years, and 17% by 5 years. Risk factors for late SVTA were age at operation (<3 or >/=10 years) and systemic AV valve replacement. By univariate and multivariate analysis, the type of Fontan operation was not a significant risk factor for late SVTA when all 6 modifications were considered. However, when we analyzed the frequency of late SVTA for the 2 recently used modifications, we found a lower frequency of late SVTA in patients with atriopulmonary connection with lateral tunnel compared with those with total cavopulmonary connection. CONCLUSIONS: Postoperative SVTA continues to be a significant problem. Risk factors for SVTA are AV valve regurgitation, abnormal AV valve, preoperative SVTA, and age at operation. Frequency of SVTA does not appear to be related to type of Fontan procedure except for slightly lower frequency in patients with atriopulmonary connection with lateral tunnel compared with those with total cavopulmonary connection.

Adolescent↗
PubMed1998

GDB: the Human Genome Database.

The Genome Database (GDB, http://www.gdb.org ) is a public repository of data on human genes, clones, STSs, polymorphisms and maps. GDB entries are highly cross-linked to each other, to literature citations and to entries in other databases, including the sequence databases, OMIM, and the Mouse Genome Database. Mapping data from large genome centers and smaller mapping efforts are added to GDB on an ongoing basis. The database can be searched by a variety of methods, ranging from keyword searches to complex queries. Major functionality extensions in the last year include the ongoing computation of integrated human genome maps, called Comprehensive Maps, and the use of those maps to support positional queries and graphic displays. The capabilities of the GDB map viewer (Mapview) have been extended to include map printing and the graphical display of ad hoc query results. The HUGO Nomenclature Committee continues to curate the proposed and official gene symbols and related data in collaboration with GDB. As genome research shifts its emphasis from mapping to sequencing and functional analysis, the scope of the GDB schema is being extended. We are in the process of adding representations of gene function and expression, and improving our representation of human polymorphism and mutation.

Animals↗
PubMed1998

Right-sided maze procedure for right atrial arrhythmias in congenital heart disease.

BACKGROUND: Atrial fibrillation and flutter, commonly associated with congenital heart anomalies that cause right atrial dilatation, may cause significant morbidity and reduction of quality of life, even after surgical repair of the anomalies. METHODS: In an effort to reduce the incidence of atrial tachyarrhythmias after repair of right-sided congenital heart disease, we performed a concomitant right-sided maze procedure. RESULTS: Eighteen patients with paroxysmal atrial fibrillation or flutter (n = 12) or chronic atrial fibrillation or flutter (n = 6) aged 10.9 to 68.4 years (mean 34.9 years) underwent a right-sided maze in association with repair of Ebstein's anomaly (n = 15), congenital tricuspid insufficiency (n = 2), and isolated atrial septal defect (n = 1). There were no early deaths, reoperations, or complete heart block. Discharge rhythm was sinus (n = 16) or junctional (n = 2). Follow-up was complete in all 18 patients and ranged from 3.1 to 17.2 months (mean 8.1 months); all are in New York Heart Association class I. Early postoperative arrhythmias developed in 3 patients (all were converted to sinus rhythm by antiarrhythmic drugs). There were no late deaths or reoperations. CONCLUSIONS: The inclusion of a right-sided maze procedure with cardiac repair in patients having congenital heart anomalies that cause right atrial dilatation and associated atrial tachyarrhythmias is effective in eliminating or reducing the incidence of those arrhythmias.

Adolescent↗
PubMed1998

Association of halofantrine with postprandially derived plasma lipoproteins decreases its clearance relative to administration in the fasted state.

The oral bioavailability of halofantrine (Hf), a highly lipophilic phenanthrenemethanol antimalarial, is significantly enhanced when ingested with food. Although food enhances the absorption of Hf, it also alters the intrinsic pharmacokinetics of Hf as the observed postprandial absolute bioavailability was greater than 100% (Humberstone et al., J. Pharm. Sci. 1996, 85, 525-529). In this study, the association of Hf with plasma lipoproteins and the effect of postprandial lipoproteins on the pharmacokinetics of Hf after intravenous administration was examined in beagles. In fasted dogs, approximately 50% of plasma Hf was associated with lipoproteins, with HDL accounting for 42-43%, LDL for 4-5%, and triglyceride rich lipoproteins (TRL) for 2-3%. At 0.5 and 2 h postdosing in the postprandial state, the proportion of Hf present in both TRL and LDL increased to 7-10%. Changes in Hf distribution between lipoprotein fractions reflected the respective postprandial changes in plasma triglyceride (TG) concentrations. In terms of pharmacokinetics, when an equivalent dose of Hf was administered intravenously in a crossover study to fed and fasted beagles, plasma Hf AUC values were significantly higher, and CL and Vss were significantly lower, in the fed state compared to the fasted state (p < 0.05). The mean postprandial increase in plasma AUC values was 19% (range 14-34%), with corresponding decreases in CL (15%) and Vss (21%). A broadly linear relationship between increased postprandial Hf concentrations at specific time points (fed vs fasted) and corresponding postprandial increases in TG concentrations suggested that the decreased postprandial clearance of Hf was a function of increased association with TG-rich plasma lipoproteins. This study confirms that the clearance of Hf is influenced by plasma lipoprotein profiles, and the findings have implications for the design and interpretation of fed/fasted bioavailability studies of lipophilic drugs and determination of their intrinsic pharmacokinetic parameters in subjects or patients with dyslipidemic profiles.

Animals↗