Homologous transplantation of prepubertal testes in the dog.
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Animals↗
Biomedical subjects
P H Lin
Publications and source records attributed to P H Lin.
Characterization of metabolic activation of pentachlorophenol to quinones and semiquinones in rodent liver.
Pentachlorophenol (PCP), a widely used biocide, induces liver tumors in mice but not in rats. Metabolic activation of PCP to chlorinated quinones and semiquinones in liver cytosol from Sprague-Dawley rats and B6C3F1 mice was investigated in vitro (1) with microsomes in the presence of either beta-nicotinamide adenine dinucleotide phosphate (NADPH) or cumene hydroperoxide (CHP), (2) with CHP in the absence of microsomes, and (3) with horseradish peroxidase (HRP) and H2O2. Mono-S- and multi-S-substituted adducts of tetrachloro-1,4-benzoquinone (Cl4-1,4-BQ) and Cl4-1,2-BQ and their corresponding semiquinones [i.e. tetrachloro-1,4-benzosemiquinone (Cl4-1,4-SQ) and tetrachloro-1,2-benzosemiquinone (Cl4-1,2-SQ)] were measured by gas chromatography-mass spectrometry (GC-MS). Qualitatively, the metabolites of PCP were the same in both rats and mice for all activation systems. Induction of PCP metabolism by either 3MC or PB-treated microsomes was observed in NADPH- but not in CHP-supported systems. In rats, the amount of induction was comparable with either 3MC or PB. 3MC was a stronger inducer than PB in mice and also induced a greater amount of metabolism than in rats. This suggests that induction of specific P450 isozymes may play a role in the toxicity of PCP to mice. Both HRP/H2O2 and CHP led to production of the full spectrum of chlorinated quinones and semiquinones, confirming the direct oxidation of PCP. CHP (with or without microsomes) converted PCP into much greater quantities of quinones and semiquinones than did microsomal P450/NADPH or HRP/H2O2 in both species. This implies that, under conditions of oxidative stress, endogenous lipid hydroperoxides may increase PCP metabolism sufficiently to enhance the toxicity and carcinogenicity of PCP.
Animals↗
Effects on blood pressure of reduced dietary sodium and the Dietary Approaches to Stop Hypertension (DASH) diet. DASH-Sodium Collaborative Research Group.
BACKGROUND: The effect of dietary composition on blood pressure is a subject of public health importance. We studied the effect of different levels of dietary sodium, in conjunction with the Dietary Approaches to Stop Hypertension (DASH) diet, which is rich in vegetables, fruits, and low-fat dairy products, in persons with and in those without hypertension. METHODS: A total of 412 participants were randomly assigned to eat either a control diet typical of intake in the United States or the DASH diet. Within the assigned diet, participants ate foods with high, intermediate, and low levels of sodium for 30 consecutive days each, in random order. RESULTS: Reducing the sodium intake from the high to the intermediate level reduced the systolic blood pressure by 2.1 mm Hg (P<0.001) during the control diet and by 1.3 mm Hg (P=0.03) during the DASH diet. Reducing the sodium intake from the intermediate to the low level caused additional reductions of 4.6 mm Hg during the control diet (P<0.001) and 1.7 mm Hg during the DASH diet (P<0.01). The effects of sodium were observed in participants with and in those without hypertension, blacks and those of other races, and women and men. The DASH diet was associated with a significantly lower systolic blood pressure at each sodium level; and the difference was greater with high sodium levels than with low ones. As compared with the control diet with a high sodium level, the DASH diet with a low sodium level led to a mean systolic blood pressure that was 7.1 mm Hg lower in participants without hypertension, and 11.5 mm Hg lower in participants with hypertension. CONCLUSIONS: The reduction of sodium intake to levels below the current recommendation of 100 mmol per day and the DASH diet both lower blood pressure substantially, with greater effects in combination than singly. Long-term health benefits will depend on the ability of people to make long-lasting dietary changes and the increased availability of lower-sodium foods.
Blood Pressure↗
Image of the month. Carotid body tumor: intercarotid paraganglioma.
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Aged↗
Endovascular revascularization of renal artery stenosis in the solitary functioning kidney.
The treatment of renal artery stenosis by angioplasty and stenting is an effective and accepted alternative to surgery for the treatment of renovascular hypertension and preservation of renal function. We report the technical and clinical outcomes of renal artery stenting in patients with a solitary functioning kidney and renal artery stenosis. From October 1993 to November 1999, 30 stents were placed in the renal arteries of 27 patients (mean age 72+/-8 years) with a solitary functioning kidney and azotemia. The mean diameter renal artery stenosis was 86+/-14%. The mean preprocedure serum creatinine (Cr) level was 3.0+/-1.5 mg/dL (range 1.5-7.5 mg/dL), arterial blood pressure was 171+/-29/85+/-13 mmHg, and the number of antihypertensive drugs was 2.9+/-1.1. Indications for stenting were suboptimal balloon dilation (n = 16), intimal dissection (n = 6), and restenosis following angioplasty (n = 5). Atherosclerotic ostial lesions were present in 25 (93%) of 27 renal arteries. This represents the largest series of renal artery stenting in patients with a solitary functioning kidney, and demonstrates this treatment modality to be a relatively safe alternative to conventional surgery in this high-risk patient group. Most (74%) of the patients in this series had improved or stabilized renal function. Further efforts to define preprocedural indicators of success are necessary to identify the patients who may benefit from revascularization of their solitary kidney.
Aged↗
Respiration and initiation of atrial fibrillation.
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Aged↗
Evaluation of thrombolysis in a porcine model of chronic deep venous thrombosis: an endovascular model.
PURPOSE: The advancement of catheter-based interventions for vascular recanalization has underscored the need for an experimental animal model of vascular thrombosis that can be used for the evaluation of interventional therapies. In this model, a porcine model of deep venous thrombosis with a novel endovascular technique was described, and the efficacy of thrombolytic therapy with urokinase was evaluated. METHODS: An endovascular device that consisted of a tapered polytetrafluoroethylene graft attached within a self-expanding nitinol stent was delivered to bilateral common iliac veins in 20 pigs. Venous thrombosis occurred as a result of flow stasis created by the intrastent stenosis. Catheter-directed pulse-spray thrombolysis with urokinase (250,000 units) and heparin (5000 IU) was performed on one limb while the contralateral limb received control saline solution. Thrombolysis was performed in 1 hour (n = 4), 8 hours (n = 4), 3 days (n = 4), 7 days (n = 4), and 14 days (n = 4) after the stent-graft deployment. Venography and intravascular ultrasound were used to evaluate the efficacy of thrombolysis. Light microscopy was used for histologic analysis of the thrombus. RESULTS: Complete thrombolysis was achieved in groups with deep vein thrombosis that were younger than 1 day. Angioplasty of the tapered stent-grafts in the completely thrombolysed iliac vein was successful in restoring venous flow. The efficacy of thrombolysis in 3-day, 7-day, and 14-day groups was 86% +/- 7%, 73% +/- 13%, and 42% +/- 23%, respectively. The thrombolytic efficacy was enhanced to 92% +/- 16% and 86% +/- 18% (P <.05) in 3-day and 7-day groups, respectively, when doses of the pulse-spray thrombolysis were doubled. Increased dosages of the thrombolytic agent, however, did not significantly enhance the thrombus dissolution in the 14-day group. CONCLUSION: The thrombolytic efficacy of urokinase correlated with the chronicity of deep venous thrombosis in our model. An increased dose of urokinase may be used to enhance the efficacy of thrombolysis in a 1-week-old thrombus.
Animals↗
Endovascular revascularization of renal artery stenosis: technical and clinical results.
PURPOSE: The natural history of renal artery stenosis is progression with subsequent deterioration of kidney function and development of renovascular hypertension. Percutaneous transluminal renal angioplasty is effective in the treatment of nonostial lesions but less effective for ostial stenoses. Because of the poor technical success experienced with percutaneous transluminal renal angioplasty, stenting of ostial stenoses is becoming the standard of endovascular care. In this retrospective study we analyzed the technical and clinical outcomes after renal artery stenting in 73 consecutive patients. PATIENTS AND METHODS: From July 1992 to January 1999, 88 Palmaz stents were deployed in 85 renal artery stenoses in 73 patients, with a mean age of 67.9 +/- 9.4 years. Twelve patients (16%) underwent bilateral stent placement. Atheromatous lesions were the most prevalent (99%: 82% ostial, 16% nonostial). Most stents were implanted for suboptimal balloon dilation (52%) or dissection (24%). Mean percent stenosis was 86% +/- 12%. Renal insufficiency (creatinine level > or = 1.5 mg/dL) was present in 50 (68%) patients, and uncontrolled hypertension (systolic > or = 160 mm Hg or diastolic > or = 90 mm Hg with more than two medications) was present in 57 (78%). RESULTS: Primary technical success was achieved in 89%. At the initial procedure, three additional stents were placed for residual stenoses, and urokinase was used to treat one intraprocedural stent thrombosis, resulting in an assisted primary technical success rate of 94%. Major complications occurred in 9.1% of stents placed: access artery thrombosis (n = 4), renal artery extravasation (n = 1), renal artery thrombosis (n = 1), and hematoma requiring operation (n = 2). Long-term clinical data were available on 69 (95%) patients at 20 +/- 17 months. Overall, a significant decrease in systolic and diastolic pressures (P <.001) and reduction of medication (P <.01) were noted without a change in renal function (P = NS). Angiography was performed on 22 patients at 11.3 +/- 10.3 months for persistent or worsening renal function or hypertension or for other reasons; 10 patients had significant restenoses in 14 renal arteries. CONCLUSION: Our retrospective analysis demonstrates that endovascular stenting of renal artery stenosis in patients with poorly controlled hypertension or deteriorating renal function is a safe and effective alternative treatment to surgical management.
Adult↗
Early experience with the bifurcated Excluder endoprosthesis for treatment of the abdominal aortic aneurysm.
PURPOSE: This report describes our initial experience with the modular, bifurcated Excluder endoprosthesis and its safety and efficacy in the primary endovascular repair of infrarenal abdominal aortic aneurysms (AAAs). METHODS: AAAs (mean diameter, 58.2 +/- 14.3 mm) were repaired in 19 patients with this device between March 1999 and January 2000. The mean age of patients was 71.8 +/- 8.4 years (range, 57-86 years). This modular device was inserted through an 18F introducer sheath placed in one femoral artery, and the contralateral artery was cannulated with a 12F introducer sheath. All procedures were performed in a standard operating room with angiographic capabilities. RESULTS: Endograft deployment was successful in all patients. The average surgical time was 135 +/- 37 minutes, with a mean blood loss of 229 +/- 138 mL. In eight patients, the use of either aortic or iliac extenders was required for enhanced sealing or additional length. An external iliac artery dissection occurring at the time of endograft insertion was successfully treated with a Wallstent. Type II leaks initially found to be present by means of intraoperative completion angiography had spontaneously thrombosed by the 1-month follow-up computed tomography scan. There was one perioperative death (5.3%). Complications included superficial wound infections (n = 3) and a nonfatal myocardial infarction (n = 1). The mean length of hospital stay was 2.9 +/- 1.2 days, and only six patients required intensive care. Endoleaks were seen in four patients (21%) by means of the 30-day computed tomography scan; three of these endoleaks had spontaneously sealed at the time of the 6-month follow-up examination (5.5% 6-month endoleak rate). Aneurysm size did not increase in the patients with leaks. CONCLUSION: The Excluder endoprosthesis was an effective means of excluding an infrarenal AAA from the systemic circulation in this selected group of patients. The smaller sheath sizes may increase the pool of potential candidates. Further study of this device is warranted, and continued assessment of the long-term durability of the device will be necessary.
Aged↗
Intra-arterial thrombin injection of an ascending aortic pseudoaneurysm complicated by transient ischemic attack and rescued with systemic abciximab.
Thrombin injection as a means of inducing thrombus formation has recently received wide attention as an alternative treatment for pseudoaneurysm. We present a case of a 67-year-old man in whom a large mycotic pseudoaneurysm developed in the ascending aorta because of sternal osteomyelitis and mediastinitis after coronary artery bypass grafting. Transcatheter intra-arterial thrombin injection was performed, and it successfully induced pseudoaneurysm thrombosis. However, the procedure was complicated by a sudden transient ischemic attack caused by thrombus propagation into the cerebral circulation. Complete thrombus dissolution in the cerebral circulation with the resolution of neurologic symptoms was achieved by means of intravenous abciximab.
Abciximab↗
Sloughing of the scrotal skin and impotence subsequent to bilateral hypogastric artery embolization for endovascular aortoiliac aneurysm repair.
Sloughing of the scrotal skin is an extremely rare event due to pelvic ischemia. We report herein one case of scrotal skin sloughing and impotence after bilateral hypogastric artery embolization for endoluminal aortoiliac aneurysm repair. Postoperative penile plethysmography demonstrated a 75% reduction in the penile brachial index, suggesting that pelvic ischemia is the main culprit for this complication. The devastating morbidity in our patient underscores the importance of maintaining pelvic collateral circulation when planning for endovascular aortoiliac aneurysm repair.
Aged↗
Detection of isolated hook fractures 36 months after implantation of the Ancure endograft: a cautionary note.
Two cases of delayed (36-month) Ancure hook fracture are reported in patients who experienced a decrease in aneurysm size and no evidence of endoleak. Both devices used redesigned hooks and are otherwise identical to those devices currently used in clinical practice. Notably, hook fractures were not visualized on all abdominal radiographic views, nor were they noted on the final "institutional" report by the reviewing radiologist. Careful clinical follow-up with multiple-view abdominal radiographs remains essential for all patients treated with an endovascular graft, with particular attention directed to the integrity of the metal components. The broader clinical significance of this observation with respect to the Ancure endograft remains to be defined.
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Effects on blood lipids of a blood pressure-lowering diet: the Dietary Approaches to Stop Hypertension (DASH) Trial.
BACKGROUND: Effects of diet on blood lipids are best known in white men, and effects of type of carbohydrate on triacylglycerol concentrations are not well defined. OBJECTIVE: Our goal was to determine the effects of diet on plasma lipids, focusing on subgroups by sex, race, and baseline lipid concentrations. DESIGN: This was a randomized controlled outpatient feeding trial conducted in 4 field centers. The subjects were 436 participants of the Dietary Approaches to Stop Hypertension (DASH) Trial [mean age: 44.6 y; 60% African American; baseline total cholesterol: < or = 6.7 mmol/L (< or = 260 mg/dL)]. The intervention consisted of 8 wk of a control diet, a diet increased in fruit and vegetables, or a diet increased in fruit, vegetables, and low-fat dairy products and reduced in saturated fat, total fat, and cholesterol (DASH diet), during which time subjects remained weight stable. The main outcome measures were fasting total cholesterol, LDL cholesterol, HDL cholesterol, and triacylglycerol. RESULTS: Relative to the control diet, the DASH diet resulted in lower total (-0.35 mmol/L, or -13.7 mg/dL), LDL- (-0.28 mmol/L, or -10.7 mg/dL), and HDL- (-0.09 mmol/L, or -3.7 mg/dL) cholesterol concentrations (all P < 0.0001), without significant effects on triacylglycerol. The net reductions in total and LDL cholesterol in men were greater than those in women by 0.27 mmol/L, or 10.3 mg/dL (P = 0.052), and by 0.29 mmol/L, or 11.2 mg/dL (P < 0.02), respectively. Changes in lipids did not differ significantly by race or baseline lipid concentrations, except for HDL, which decreased more in participants with higher baseline HDL-cholesterol concentrations than in those with lower baseline HDL-cholesterol concentrations. The fruit and vegetable diet produced few significant lipid changes. CONCLUSIONS: The DASH diet is likely to reduce coronary heart disease risk. The possible opposing effect on coronary heart disease risk of HDL reduction needs further study.
Adult↗
Oxidative damage and direct adducts in calf thymus DNA induced by the pentachlorophenol metabolites, tetrachlorohydroquinone and tetrachloro-1,4-benzoquinone.
DNA damage induced by quinoid metabolites of pentachlorophenol (PCP), i.e. tetrachloro-1,4-benzoquinone (Cl(4)BQ) and tetrachlorohydroquinone (Cl(4)HQ), was investigated in calf thymus DNA. The (32)P-post-labeling assay revealed four major and several minor adducts (3.5 adducts per 10(5) total nucleotides) that were produced in calf thymus DNA treated with Cl(4)BQ (5 mM). These DNA adducts were chemically stable even after conditions that induce thermal depurination and are unlikely to undergo depurination/depyrimidination to form apurinic/apyrimidinic (AP) sites. In addition, increases in 8-hydroxy-deoxyguanosine (8-HO-dG) (5 8-HO-dG per 10(5) nucleotides) and AP sites (0.5 AP sites per 10(5) nucleotides) were observed in Cl(4)BQ-modified calf thymus DNA. Further investigation indicated that in the presence of Cu(II) and NADPH, low concentrations of Cl(4)BQ (1 microM) induced a doubling of 8-HO-dG (10 8-HO-dG per 10(5) nucleotides) and dramatic increases in AP sites (20 AP sites per 10(5) nucleotides) and DNA single-strand breaks. The types of DNA damage induced by Cl(4)HQ plus Cu(II) were similar to those by Cl(4)BQ plus Cu(II) and NADPH, whereas catalase inhibited the formation of DNA damage. These data suggest that oxidative damage is causally involved in the formation of AP sites. Concentration-dependent increases in 8-HO-dG induced by Cl(4)HQ plus Cu(II) and Cl(4)BQ plus Cu(II) and NADPH were correlated with the formation of AP sites (r(2) = 0.977) with a ratio of 8-HO-dG to AP sites at 1:1.6. The AP site-cleavage assay confirmed that approximately 85% of the AP sites induced by Cl(4)HQ and Cu(II) were detected as 5'-cleaved AP sites. Since hydrogen peroxide alone causes similar DNA damage, these results suggest the involvement of Cu(II) and hydrogen peroxide in the induction of oxidative DNA damage by Cl(4)HQ/Cl(4)BQ. The data demonstrate that PCP quinone and hydroquinone induce direct and oxidative base modifications as well as the formation of 5'-cleaved AP sites in genomic DNA. These lesions may have important implications for PCP clastogenicity and carcinogenicity.
8-Hydroxy-2'-Deoxyguanosine↗
Induction of direct adducts, apurinic/apyrimidinic sites and oxidized bases in nuclear DNA of human HeLa S3 tumor cells by tetrachlorohydroquinone.
DNA damage induced by tetrachlorohydroquinone (Cl(4)HQ), the quinonoid metabolite of pentachlorophenol (PCP), was investigated in human HeLa S3 tumor cells. Formation of one major and two minor DNA adducts in cells treated with Cl(4)HQ (50-300 microM) was detected by (32)P-post-labeling assay and the adducts accumulated over the course of the experiment (0.5-2 h), with total adduct levels estimated to be 3-6 per 10(8) nucleotides. These adducts did not correspond to those derived from calf thymus DNA treated with tetrachloro-1,4-benzoquinone. Results from the apurinic/apyrimidinic (AP) sites assay indicated that the number of AP sites was 2-fold greater in cells exposed to Cl(4)HQ (300 microM) than the corresponding control. Further characterization of the AP sites confirmed that Cl(4)HQ induced predominantly (75%) putrescine-excisable AP sites in HeLa S3 cells. In parallel, the concentration of 8-hydroxy-2'-deoxyguanosine (8-HO-dG) in cells treated with Cl(4)HQ for 0.5 and 2 h was increased 2- and 5-fold, respectively, compared with the control. The extent of oxidative DNA damage induced by Cl(4)HQ was approximately two orders of magnitude greater than those of direct DNA adducts. Overall, it appears that reactive oxygen species mediate the parallel formation of AP sites and 8-HO-dG in HeLa S3 cells following treatment with Cl(4)HQ and that the contribution of depurination/depyrimidination of direct DNA adducts is relatively insignificant compared with the formation of oxidized AP sites. We conclude that putrescine-excisable AP sites represent a major type of ROS-mediated oxidative DNA damage in cellular DNA induced by Cl(4)HQ and may play a role in PCP-induced clastogenicity in mammalian cells.
8-Hydroxy-2'-Deoxyguanosine↗
Endoluminal stent placement and coil embolization for the management of carotid artery pseudoaneurysms.
PURPOSE: To present a series of carotid artery pseudoaneurysms treated successfully using an endovascular approach. METHODS: From April 1995 to November 1999, 5 patients with neurological symptoms not explained by computed tomography of the head were identified by carotid angiography as having internal carotid artery (ICA) pseudoaneurysms. Three patients had sustained blunt trauma, and 2 had previous elective carotid endarterectomies for atherosclerotic disease. The time between injury and treatment ranged from 3 days to 10 years. The patients were treated with endovascular stent placement for exclusion of the pseudoaneurysm, followed by filling of the cavity with multiple detachable coils. Patients were maintained on oral antiplatelet agents or anticoagulant therapy after the procedure. RESULTS: Primary technical success was 100%. No patient suffered permanent neurological sequelae. Postprocedure angiography demonstrated a patent ICA in all cases, with complete obliteration of the pseudoaneurysm. At a mean 8.4-month follow-up (range 2-21), all patients remained symptom free; angiograms in 3 patients at a mean 11.7 months demonstrated continued ICA patency. One patient had a 60% focal narrowing of the distal common carotid artery, which was treated successfully with balloon dilation and stenting. CONCLUSIONS: Endovascular treatment of carotid artery pseudoaneurysms is a useful alternative to standard surgical repair. This modality avoids the necessity for surgical exposure at the skull base with its inherent morbidity.
Adult↗
Effect of dietary patterns on serum homocysteine: results of a randomized, controlled feeding study.
BACKGROUND: Elevated blood levels of homocysteine are associated with an increased risk of atherosclerotic cardiovascular disease. Although numerous studies have assessed the impact of vitamin supplements on homocysteine, the effect of dietary patterns on homocysteine has not been well studied. METHODS AND RESULTS: During a 3-week run-in, 118 participants were fed a control diet, low in fruits, vegetables, and dairy products, with a fat content typical of US consumption. During an 8-week intervention phase, participants were then fed 1 of 3 randomly assigned diets: the control diet, a diet rich in fruits and vegetables but otherwise similar to control, or a combination diet rich in fruits, vegetables, and low-fat dairy products and reduced in saturated and total fat. Between the end of run-in and intervention periods, mean change in homocysteine was +0.46 micromol/L in the control diet, +0.21 micromol/L in the fruits and vegetables diet (P=0.47 compared with control), and -0.34 micromol/L in the combination diet (P=0.03 compared with control, P=0.12 compared with the fruits and vegetables diet). In multivariable regression models, change in homocysteine was significantly and inversely associated with change in serum folate (P=0.03) but not with change in serum vitamin B(12) (P=0.64) or pyridoxal 5' phosphate, the coenzyme form of vitamin B(6) (P=0.83). CONCLUSIONS: Modification of dietary patterns can have substantial effects on fasting levels of total serum homocysteine. These results provide additional insights into the mechanisms by which diet might influence the occurrence of atherosclerotic cardiovascular disease.
Adult↗
Antithrombotic and hemostatic capacity of factor Xa versus thrombin inhibitors in models of venous and arteriovenous thrombosis.
Thrombin plays a central role in venous and arterial thrombosis. We utilized two different rabbit models of in vivo thrombosis to investigate the effect of inhibitors of thrombin generation and thrombin activity. The agents tested were specific inhibitors of factor Xa (fXa) [N2-[(phenylmethyl)sulfonyl]-D-arginyl-N-[(1S)-4-[(aminoiminomethyl++ +)a mino]-1-(2-thiazolylcarbonyl)butyl]-glycinamide (C921-78)] and thrombin [D-phenylalanyl-N-[4-[(aminoiminomethyl)amino]-1-(chloroacetyl)but yl]-L-prolinamide (PPACK)], as well as drugs that affect both thrombin and fXa, unfractionated and low molecular weight (enoxaparin) heparin. The agents administered as constant intravenous infusion were evaluated for antithrombotic efficacy in anesthetized rabbits. All four agents were capable of dose dependent inhibition of thrombosis in venous and arteriovenous thrombosis models. However, due to the more aggressive nature of thrombotic stimulation in the arteriovenous shunt model, complete cessation of thrombus growth was not achieved for any of the agents at the doses tested. Comparison between the agents focused on the differences in extension of coagulation parameters (activated partial thromboplastin time, prothrombin time, thrombin clotting time), changes in hematological parameters, and extension of rabbit cuticle bleeding time at doses required to produce maximum inhibition in the thrombosis models. In the venous thrombosis model at the maximally effective dose, C921-78 had minimal extension of ex vivo clotting parameters, while enoxaparin and unfractionated heparin demonstrated a two to sevenfold increase in activated partial thromboplastin times, and PPACK had a threefold extension of thrombin clotting times. In addition, unlike the other three agents, which exhibited no significant changes in hematological parameters, PPACK demonstrated dose dependent thrombocytopenia. A standardized cuticle bleeding time was used as a measure of perturbation of hemostasis. The agents were evaluated for significant increases in bleeding time at doses up to eight times that needed to completely inhibit venous thrombus formation. Unfractionated heparin displayed a significant bleeding time effect at the dose required to inhibit venous thrombosis (100 u/kg+2 u/kg/min). Enoxaparin and PPACK caused significant bleeding time extensions at four times the fully efficacious venous dose (800 u/kg+8 u/kg/min and 30 microg/kg/min). By contrast, C921-78 did not significantly increase bleeding time even at eight times the maximally effective dose (240 microg/kg+7.2 microg/kg/min). Our results demonstrate that specific inhibition of fXa can be utilized to derive potent antithrombotic activity without disrupting extravascular hemostasis.
Amino Acid Chloromethyl Ketones↗