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1.
Circulation ; 104(4): 473-9, 2001 Jul 24.
Article in English | MEDLINE | ID: mdl-11468212

ABSTRACT

BACKGROUND: Paclitaxel can inhibit vascular smooth muscle proliferation in vitro, and early studies suggest that paclitaxel may be useful in preventing restenosis. Early and late intimal growth and local vascular pathological changes associated with paclitaxel delivered via stents have not been fully explored. METHODS AND RESULTS: Localized drug delivery was accomplished with balloon-expandable stainless steel stents coated with a cross-linked biodegradable polymer, chondroitin sulfate and gelatin (CSG), containing various doses of paclitaxel. CSG-coated stents with paclitaxel (42.0, 20.2, 8.6, or 1.5 microgram of paclitaxel per stent), CSG-coated stents without paclitaxel, and uncoated stents (without paclitaxel or CSG) were deployed in the iliac arteries of New Zealand White rabbits, which were killed 28 days after implant. Mean neointimal thickness at stent strut sites was reduced 49% (P<0.0003) and 36% (P<0.007) with stents containing 42.0 and 20.2 microgram of paclitaxel per stent, respectively, versus CSG-coated stents without paclitaxel. However, histological findings suggested incomplete healing in the higher-dose (42.0 and 20.2 microgram) paclitaxel-containing stents consisting of persistent intimal fibrin deposition, intraintimal hemorrhage, and increased intimal and adventitial inflammation. Stents coated with CSG alone (without paclitaxel) had similar neointimal growth as uncoated stents. In a separate group of rabbits killed at 90 days, neointimal growth was no longer suppressed by CSG-coated stents containing 42.0 or 21.0 microgram of paclitaxel CONCLUSIONS: CSG coating appears to be a promising medium for localized drug delivery. Paclitaxel polymer-coated stents reduce neointima formation but are associated with evidence of incomplete healing at 28 days. However, neointimal suppression was not maintained at 90 days.


Subject(s)
Angiogenesis Inhibitors/pharmacology , Drug Delivery Systems/methods , Paclitaxel/pharmacology , Stents , Angiogenesis Inhibitors/pharmacokinetics , Animals , Cell Division/drug effects , Chondroitin Sulfates , Dose-Response Relationship, Drug , Fibrin/drug effects , Fibrin/metabolism , Gelatin , Hemorrhage/chemically induced , Hemorrhage/pathology , Iliac Artery/drug effects , Iliac Artery/metabolism , Iliac Artery/pathology , Inflammation/chemically induced , Inflammation/pathology , Male , Paclitaxel/blood , Paclitaxel/pharmacokinetics , Polymers , Rabbits , Time Factors , Tunica Intima/drug effects , Tunica Intima/metabolism , Tunica Intima/pathology
2.
Circulation ; 103(18): 2289-95, 2001 May 08.
Article in English | MEDLINE | ID: mdl-11342479

ABSTRACT

BACKGROUND: Despite limiting elastic recoil and late vascular remodeling after angioplasty, coronary stents remain vulnerable to restenosis, caused primarily by neointimal hyperplasia. Paclitaxel, a microtubule-stabilizing drug, has been shown to inhibit vascular smooth muscle cell migration and proliferation contributing to neointimal hyperplasia. We tested whether paclitaxel-coated coronary stents are effective at preventing neointimal proliferation in a porcine model of restenosis. METHODS AND RESULTS: Palmaz-Schatz stents were dip-coated with paclitaxel (0, 0.2, 15, or 187 microgram/stent) by immersion in ethanolic paclitaxel and evaporation of the solvent. Stents were deployed with mild oversizing in the left anterior descending coronary artery (LAD) of 41 minipigs. The treatment effect was assessed 4 weeks after stent implantation. The angiographic late loss index (mean luminal diameter) decreased with increasing paclitaxel dose (P<0.0028 by ANOVA), declining by 84.3% (from 0.352 to 0.055, P<0.05) at the highest level tested (187 microgram/stent versus control). Accompanying this change, the neointimal area decreased (by 39.5%, high-dose versus control; P<0.05) with increasing dose (P<0.040 by ANOVA), whereas the luminal area increased (by 90.4%, high-dose versus control; P<0.05) with escalating dose (P<0.0004 by ANOVA). Inflammatory cells were seen infrequently, and there were no cases of aneurysm or thrombosis. CONCLUSIONS: Paclitaxel-coated coronary stents produced a significant dose-dependent inhibition of neointimal hyperplasia and luminal encroachment in the pig LAD 28 days after implantation; later effects require further study. These results demonstrate the potential therapeutic benefit of paclitaxel-coated coronary stents in the prevention and treatment of human coronary restenosis.


Subject(s)
Coronary Vessels/drug effects , Graft Occlusion, Vascular/prevention & control , Paclitaxel/administration & dosage , Stents , Tunica Intima/drug effects , Animals , Coronary Angiography , Coronary Vessels/chemistry , Coronary Vessels/surgery , Disease Models, Animal , Dose-Response Relationship, Drug , Female , Graft Occlusion, Vascular/pathology , Hyperplasia/pathology , Hyperplasia/prevention & control , Infusion Pumps, Implantable , Male , Paclitaxel/analysis , Surface Properties , Swine, Miniature , Tunica Intima/pathology , Tunica Intima/surgery
4.
Forensic Sci Int ; 52(2): 231-4, 1992 Jan.
Article in English | MEDLINE | ID: mdl-1601354

ABSTRACT

A case is presented where an individual ingested a fatal dose of chloral hydrate. Trichloroethanol (TCE), the metabolite of chloral hydrate, was initially identified by the Fujiwara reaction and quantified by gas chromatography/mass spectrometry in blood )127 mg/l), urine (128 mg/l) and stomach contents (25 mg total).


Subject(s)
Chloral Hydrate/poisoning , Ethylene Chlorohydrin/analogs & derivatives , Gastrointestinal Contents/chemistry , Suicide , Adult , Chloral Hydrate/pharmacokinetics , Drug Overdose/diagnosis , Ethylene Chlorohydrin/analysis , Female , Gas Chromatography-Mass Spectrometry , Half-Life , Humans
5.
Proc Natl Acad Sci U S A ; 83(20): 7741-5, 1986 Oct.
Article in English | MEDLINE | ID: mdl-2429317

ABSTRACT

Electrical properties of native sarcoplasmic reticulum membranes from rabbit skeletal muscle were investigated using the patch-clamp technique. Bilayers were assembled at the tip of patch pipettes from monolayers formed at the air-water interface of sarcoplasmic reticulum membrane suspensions. The membranes were found to contain a spontaneously active cation channel of small conductance (5 pS in 200 mM CaCl2, symmetrical solutions) that was selective for Ca2+ and Ba2+. Between 50 and 200 mM CaCl2 (symmetrical) the increase in conductance as a function of [Ca2+] fit a hyperbola (K0.5, 83 mM, and gamma max, 7.9 pS) that extrapolated to a single-channel conductance of 0.5 pS at physiological Ca2+ levels. The channel opened in bursts followed by long silent periods of up to a minute. During a burst the channel fluctuated very rapidly with time constants in the millisecond range. The mean burst duration was voltage dependent, increasing from 1.8 s at a pipette voltage of +60 mV to 4.1 s at +80 mV. Over this range, burst frequency decreased with increasing voltage such that the fraction of time spent in the open state (fb) remained constant. Application of 1.6 mM caffeine resulted in activation of the channel that appeared as an increase in mean burst duration. In contrast, 50 microM dantrolene significantly decreased burst frequency, whereas 10 microM nitrendipine had no effect. The functional and pharmacological properties of this Ca2+ channel suggest that it may be important in mediating Ca2+ release from the sarcoplasmic reticulum during excitation-contraction coupling.


Subject(s)
Calcium/metabolism , Ion Channels/physiology , Sarcoplasmic Reticulum/physiology , Animals , Dantrolene/pharmacology , In Vitro Techniques , Ion Channels/drug effects , Kinetics , Muscles/physiology , Rabbits
6.
J Biol Chem ; 260(4): 2035-7, 1985 Feb 25.
Article in English | MEDLINE | ID: mdl-2982802

ABSTRACT

ADP-sensitive (E1P) and K+-sensitive (E2P) phosphoenzymes are sequentially formed intermediates in the reaction pathways catalyzed by the Na+,K+- and Ca2+-ATPases. The kinetics of dephosphorylation of these intermediates were examined by means of rapid quenching with acid at 21 degrees C. Under conditions favoring the formation of E2P (25 mM Na+ and O K+), addition of 5 mM ADP + 10 mM EDTA to the Na+,K+-ATPase phosphoenzyme produced a biphasic pattern of dephosphorylation. Both phases of phosphoenzyme decomposition were accompanied by approximately stoichiometric amounts of inorganic phosphate (Pi) release. The rate of decay of the rapid phase was 10 times faster than the rate of phosphoenzyme turnover under phosphorylating conditions indicating acceleration of E2P hydrolysis by ADP. Similar patterns of ADP-stimulated phosphoenzyme decay and Pi release were observed in the Ca2+-ATPase from sarcoplasmic reticulum phosphorylated at low (0.1 mM) Mg2+ in the absence of KCl. These results demonstrate that ADP can enhance the rate of E2P hydrolysis in the cases of the Na+,K+-ATPase and Ca2+-ATPase. As a consequence measurement of "ADP-sensitive EP" may overestimate E1P.


Subject(s)
Adenosine Diphosphate/pharmacology , Calcium-Transporting ATPases/metabolism , Phosphoproteins/metabolism , Sodium-Potassium-Exchanging ATPase/metabolism , Animals , Edetic Acid/pharmacology , Electric Organ/enzymology , Electrophorus , Hydrolysis , Kinetics , Phosphorylation , Potassium/pharmacology , Rabbits , Sarcoplasmic Reticulum/enzymology
7.
Biochemistry ; 24(1): 126-36, 1985 Jan 01.
Article in English | MEDLINE | ID: mdl-3158340

ABSTRACT

The kinetics of formation of the ADP-sensitive (EP) and ADP-insensitive (E*P) phosphoenzyme intermediates of the CaATPase in sarcoplasmic reticulum (SR) were investigated by means of the quenched-flow technique. At 21 degrees C, addition of saturating ADP to SR vesicles phosphorylated for 116 ms with 10 microM ATP gave a triphasic pattern of dephosphorylation in which EP and E*P accounted for 33% and 60% of the total phosphoenzyme, respectively. Inorganic phosphate (Pi) release was less than stoichiometric with respect to E*P decay and was not increased by preincubation with Ca2+ ionophore. The fraction of E*P present after only 6 ms of phosphoenzyme formation was similar to that at 116 ms, indicating that isomerization of EP to E*P occurs very rapidly. Comparison of the time course of E*P formation with intravesicular Ca2+ accumulation measured by quenching with ethylene glycol bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid + ADP revealed that Ca2+ release on the inside of the vesicle was delayed with respect to E*P formation. Since Ca2+ should dissociate rapidly dissociation from the low-affinity transport sites, these results suggest that Ca2+ remains "occluded" after phosphoenzyme isomerization and that a subsequent slow transition controls the rate of Ca2+ release at the intravesicular membrane surface. Analysis of the forward and reverse rate constants for the EP to E*P transition gave an expected steady-state distribution of phosphoenzymes strongly favoring the ADP-insensitive form. In contrast, the observed ratio of EP to E*P was about 1:2. To account for this discrepancy, a mechanism is proposed in which stabilization of the ADP-sensitive phosphoenzyme is brought about by a conformational interaction between adjacent subunits in a dimer.


Subject(s)
Adenosine Diphosphate/pharmacology , Calcium-Transporting ATPases/metabolism , Muscles/enzymology , Sarcoplasmic Reticulum/enzymology , Animals , Calcimycin/pharmacology , Calcium/metabolism , Calcium Chloride/pharmacology , Kinetics , Magnesium/pharmacology , Magnesium Chloride , Protein Binding , Rabbits
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