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Biomedical subjects

D M Killian

Publications and source records attributed to D M Killian.

7 recordsLinked to original sources
PubMed2001

Predominant functional activity of the large, neutral amino acid transporter (LAT1) isoform at the cerebrovasculature.

In this study, we identify the predominant functional expression of the large, neutral amino acid transporter (LAT1) isoform at the blood-brain barrier (BBB). An in situ rat brain perfusion technique allowed perfusion of the radiotracer [(14)C]-L-Leu (a ligand for both LAT1 and LAT2) alone or competed with excess concentration of either LAT1 or LAT2 specific amino acids. The LAT2 specific amino acid, [(14)C]-L-Asn, was perfused alone or with excess concentration of various amino acids. The brain uptake of [(14)C]-L-Leu was not significantly inhibited by LAT2 specific amino acids, but was inhibited significantly (up to 90%) by the LAT1 specific amino acid, D-Met. L-Asn did not demonstrate saturable brain uptake. These data clearly demonstrate that LAT1 is the functionally predominant isoform expressed at the BBB which is responsible for brain uptake of large, neutral amino acids. In addition, the functional activity of cerebrovascular LAT2 is insignificant, or absent.

Amino Acid Transport Systems↗
PubMed2001

A bioreversible prodrug approach designed to shift mechanism of brain uptake for amino-acid-containing anticancer agents.

By derivatization at the N-terminus of amino acid-based anticancer agents (e.g. melphalan and acivicin) to form a drug delivery system (TDDS), we demonstrate a change in the mechanism of brain uptake from the large neutral amino acid transporter (LAT) pathway to passive. An in situ rat brain perfusion technique was used to determine the brain capillary permeability-surface area (PA) product for [(14)C]L-Leu as control (5.18 +/- 0.32 x 10(-2) mL/s/g), which was inhibited competitively (to 7-18% of control) by an excess concentration of the amino-acid-containing anticancer agents, acivicin and melphalan. However, TDDS did not compete for LAT-mediated brain uptake of the radiotracer [(14)C]L-Leu. Brain uptake of TDDS was determined after in situ brain perfusion followed by RP-HPLC along with LC-MS/MS detection of the analytes in brain samples. The PA product for CH(3)-TDDS containing melphalan (5.09 +/- 2.0 x 10(-2) mL/s/g) shows that these agents rapidly cross the blood-brain barrier. Furthermore, competition studies of CH(3)-TDDS with [(3)H]verapamil suggest that the TDDS interacts significantly with the multidrug resistant efflux system (P-glycoprotein) at the blood-brain barrier. Therefore, TDDS were shown to lack LAT-mediated brain uptake. The drug delivery systems, however, showed uptake predominantly via the passive route along with recognition by the multidrug resistant efflux protein at the cerebrovasculature.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1994

Acute procedural results in the treatment of 30 coronary artery bifurcation lesions with a double-wire atherectomy technique for side-branch protection.

Percutaneous treatment of bifurcation lesions has been consistently shown to be associated with lower acute success rates, higher initial complication rates, and an increased rate of restenosis when compared with findings in nonbifurcation lesions. Recent analysis of data from a CAVEAT subgroup suggests that directional atherectomy of bifurcation lesions can improve initial success rates and lower restenosis rates but at the cost of high complication rates. Reports from several angioplasty series document improved success rates and lower complication rates with the use of a two-wire technique to protect side branches when treating bifurcation lesions. Our experience with a two-wire atherectomy technique that uses a nitinol wire to protect important side branches is presented.

Adult↗
PubMed1993

Examination of common PTCA guide wires used for side branch protection during directional coronary atherectomy of bifurcation lesions performed in vivo and in vitro.

Side branch protection of bifurcation lesions with guide wires treated with directional coronary atherectomy has been performed safely in a small number of patients using a nickel/titanium (Nitinol) alloy guide wire. There is no information about the safety of using other guide wires in this scenario. The purpose of this study was to microscopically examine a variety of guide wires exposed to the directional coronary atherectomy (DCA) device in vitro. Eight common guide wires used in percutaneous coronary angioplasty were positioned in a side branch of a simulated coronary bifurcation and exposed to the operating DCA device. The guide wires were examined grossly and under scanning electron microscopy. The Nitinol guidewire suffered no discernible damage in comparison to varying degrees of damage seen on the other guide wires, and this guidewire appears to be best suited for side branch protection. Examination of the protecting guide wire and cutting cylinder used in the initial patients also showed no damage. Further clinical trials are necessary to assess the efficacy of DCA under such conditions.

Angioplasty, Balloon, Coronary↗
PubMed1989

Constrictive pericarditis after cardiac surgery.

Forty-five patients were identified as having constrictive pericarditis after cardiac surgery. The mean patient age was 61 years (range, 40 to 77 years). Twenty-three of 37 patients with adequate clinical information were reported to have had a diagnosis of postpericardiotomy syndrome after the original surgery. The mean interval from original surgery to presentation with constriction was 23.4 months (range, 1 to 204 months). Computerized tomography was helpful in establishing a diagnosis of constriction in 23 of 29 patients (79%). Bypass graft patency was 93% (85 of 91 grafts). Severe pulmonary hypertension (pulmonary artery systolic pressure greater than or equal to 60 mm Hg) was present in nine patients; 8 had coexistent valvular disease (seven cases of mitral valve disease, and aortic valve disease in one). Thirty-seven of the 45 patients underwent pericardial stripping, 28 of whom experienced marked symptomatic improvement. One patient had persistent right heart failure, which was not documented to be secondary to constriction. Four patients had persistent constrictive physiologic conditions. Three of these patients had more extensive pericardial stripping and showed clinical improvement. Four patients (11%) died within 30 days of stripping. Eight patients received medical therapy alone. The decision to treat patients medically was based either on favorable response to medical therapy (five patients), or poor general clinical status.

Coronary Artery Bypass↗
PubMedDate not supplied

Modulating blood-brain barrier interactions of amino acid-based anticancer agents.

The large neutral amino acid (LNAA) transporter at the blood-brain barrier (BBB) mediates brain uptake of amino acid-based anticancer agents (e.g., melphalan and acivicin). In this study, we blocked the amino acid terminus of the anticancer agents using a bioreductive drug delivery system (TDDS). This molecular modification of the anticancer agents is expected to prevent LNAA carrier-mediated transport across the BBB. In this study, we demonstrate that the parent amino acid containing anticancer agents are substrates for the LNAA transporter at the BBB, whereas the TDDS is not recognized by the LNAA transporter. An in situ rat brain perfusion technique was used to determine competition for LNAA carrier-mediated transport at the BBB using [14C]L-leucine. The BBB capillary permeability-surface area (PA) product for the radiotracer [14C]L-leucine (control) was determined to be 5.18 +/- 0.32 x 10(-2) ml/s/g (100%). The control PA value for [14C]L-leucine was competitively inhibited (down to 7-18% of control) by excess L-phenylalanine as well as by excess concentration of the anticancer amino acids, melphalan and acivicin, showing competition for the LNAA transporter at the BBB. In contrast, brain perfusion of [14C]L-leucine in presence of excess TDDS resulted in no competition for brain uptake of [14C]L-leucine via the LNAA transporter. Thus, bioreversible derivatization of the parent anticancer amino acids resulted in blocking the amino acid functional group, thereby leading to loss of recognition for the cerebrovascular LNAA transporter at the BBB.

Algorithms↗