Effect of aminocaproic acid on clot strength and clot lysis of canine blood determined by use of an in vitro model of hyperfibrinolysis.

OBJECTIVE To determine pharmacodynamic and pharmacokinetic profiles of aminocaproic acid (ACA) by use of a thromboelastography (TEG)-based in vitro model of hyperfibrinolysis and high-performance liquid chromatography-mass spectrometry. ANIMALS 5 healthy adult dogs. PROCEDURES A single dose of injectable ACA (20, 50, or 100 mg/kg) or an ACA tablet (approximately 100 mg/kg) was administered orally. Blood samples were collected at 0, 15, 30, 45, 60, 90, 120, and 240 minutes after ACA administration for pharmacokinetic analysis. Samples were obtained at 0, 60, and 240 minutes for pharmacodynamic analysis by use of a TEG model of hyperfibrinolysis. RESULTS No adverse effects were detected. In the hyperfibrinolysis model, after all doses, a significantly higher TEG maximum amplitude (clot strength), compared with baseline, was detected at 60 and 240 minutes. Additionally, the percentage of fibrinolysis was reduced from the baseline value at 60 and 240 minutes, with the greatest reduction at 60 minutes. At 240 minutes, there was significantly less fibrinolysis for the 100 mg/kg dose than the 20 mg/kg dose. Maximum plasma ACA concentration was dose dependent. There was no significant difference in pharmacokinetic parameters between 100 mg/kg formulations. CONCLUSIONS AND CLINICAL RELEVANCE In an in vitro model of hyperfibrinolysis, ACA inhibited fibrinolysis at all doses tested. At 240 minutes after administration, the 100 mg/kg dose inhibited fibrinolysis more effectively than did the 20 mg/kg dose. Thus, ACA may be useful for in vivo prevention of fibrinolysis in dogs. IMPACT FOR HUMAN MEDICINE These data may improve research models of hyperfibrinolytic diseases.

PHARMACOKINETIC STUDY OF ORAL ε-AMINOCAPROIC ACID IN THE NORTHERN ELEPHANT SEAL (MIROUNGA ANGUSTIROSTRIS).

ε-Aminocaproic acid (EACA) is a lysine analogue antifibrinolytic drug used to treat bleeding disorders in humans and domestic animals. Its use in zoological medicine is rare, and dosage is anecdotal. One possible application of EACA is to treat bleeding associated with prepatent Otostrongylus arteritis in Northern elephant seals ( Mirounga angustirostris ) presenting to wildlife rehabilitation centers. This study used an in vitro model of hyperfibrinolysis and a thromboelastograph-based assay to estimate the therapeutic plasma concentration of EACA in elephant seals (85 µg/ml, 95% confidence interval = 73.8-96.8 µg/ml). A concurrent pharmacokinetic study of orally administered, single-dose EACA found that doses of 75 and 100 mg/kg achieved therapeutic plasma concentrations (>85 µg/ml), but the drug was rapidly eliminated and remained in the therapeutic range for only 0.4 and 1.5 hr, respectively. Models of repeated oral dosing at 100 mg/kg every 6 hr predict that therapeutic plasma concentration will be maintained for 31.7% (7.6 hr) of a 24-hr period. More frequent dosing would be required to maintain continuous therapeutic concentrations but would be impractical in a wildlife rehabilitation setting. Further pharmacodynamic studies to evaluate the duration of action of EACA in elephant seals and a prospective, placebo-controlled study are needed to determine if EACA is effective in decreasing bleeding associated with prepatent Otostrongylus arteritis and other bleeding disorders in this species.

Pharmacokinetics of ε-Aminocaproic Acid in Neonates Undergoing Cardiac Surgery with Cardiopulmonary Bypass.

BACKGROUND: Antifibrinolytic medications such as ε-aminocaproic acid (EACA) are used in pediatric heart surgery to decrease surgical bleeding and transfusion. Dosing schemes for neonates are often based on adult regimens, or are simply empiric, in part due to the lack of neonatal pharmacokinetic information. The authors sought to determine the pharmacokinetics of EACA in neonates undergoing cardiac surgery and to devise a dosing regimen for this population. METHODS: Ten neonates undergoing cardiac surgery with cardiopulmonary bypass were given EACA according to standard practice, and blood was drawn at 10 time points to determine drug concentrations. Time-concentration profiles were analyzed using nonlinear mixed effects models. Parameter estimates (standardized to a 70-kg person) were used to develop a dosing regimen intended to maintain a target concentration shown to inhibit fibrinolysis in neonatal plasma (50 mg/l). RESULTS: Pharmacokinetics were described using a two-compartment model plus an additional compartment for the cardiopulmonary bypass pump. First-order elimination was described with a clearance of 5.07 l/h × (WT/70). Simulation showed a dosing regimen with a loading dose of 40 mg/kg and an infusion of 30 mg · kg · h, with a pump prime concentration of 100 mg/l maintained plasma concentrations above 50 mg/l in 90% of neonates during cardiopulmonary bypass surgery. CONCLUSIONS: EACA clearance, expressed using allometry, is reduced in neonates compared with older children and adults. Loading dose and infusion dose are approximately half those required in children and adults.

Population pharmacokinetics of ϵ-aminocaproic acid in adolescents undergoing posterior spinal fusion surgery.

BACKGROUND: Despite demonstrated efficacy of ϵ-aminocaproic acid (EACA) in reducing blood loss in adolescents undergoing spinal fusion, there are no population-specific pharmacokinetic data to guide dosing. The aim of this study was to determine the pharmacokinetics of EACA in adolescents undergoing spinal fusion surgery and make dosing recommendations. METHODS: Twenty children ages 12-17 years were enrolled, with 10 children in each of two groups based on diagnosis (idiopathic scoliosis or non-idiopathic scoliosis). Previously reported data from infants undergoing craniofacial surgery were included in the model to enable dosing recommendations over a wide range of weights, ages, and diagnoses. A population non-linear mixed effects modelling approach was used to characterize EACA pharmacokinetics. RESULTS: Population pharmacokinetic parameters were estimated using a two-compartment disposition model with allometrically scaled weight and an age effect on clearance. Pharmacokinetic parameters for the typical patient were a plasma clearance of 153 ml min(-1) 70 kg(-1) (6.32 ml min(-1) kg(-0.75)), intercompartmental clearance of 200 ml min(-1) 70 kg(-1) (8.26 ml min(-1) kg(-0.75)), central volume of distribution of 8.78 litre 70 kg(-1) (0.13 litre kg(-1)), and peripheral volume of distribution of 15.8 litre 70 kg(-1) (0.23 litre kg(-1)). Scoliosis aetiology did not have a clinically significant effect on drug pharmacokinetics. CONCLUSIONS: The following dosing schemes are recommended according to patient weight: weight <25 kg, 100 mg kg(-1) loading dose and 40 mg kg(-1) h(-1) infusion; weight ≤25 kg-<50 kg, 100 mg kg(-1) loading dose and 35 mg kg(-1) h(-1) infusion; and weight ≥50 kg, 100 mg kg(-1) loading dose and 30 mg kg(-1) h(-1) infusion. An efficacy trial employing this dosing strategy is warranted. CLINICAL TRIAL REGISTRATION: NCT01408823.

Therapeutic plasma concentrations of epsilon aminocaproic acid and tranexamic acid in horses.

BACKGROUND: Antifibrinolytic drugs such as epsilon aminocaproic acid (EACA) and tranexamic acid (TEA) are used to treat various bleeding disorders in horses. Although horses are hypofibrinolytic compared to humans, dosing schemes have been derived from pharmacokinetic studies targeting plasma concentrations in humans. HYPOTHESIS/OBJECTIVES: We hypothesized therapeutic plasma concentrations of antifibrinolytic drugs in horses would be significantly lower than in humans. Our objective was to use thromboleastography (TEG) and an in vitro model of hyperfibrinolysis to predict therapeutic concentrations of EACA and TEA in horses and humans. ANIMALS: Citrated plasma collected from 24 random source clinically healthy research horses. Commercial pooled human citrated plasma with normal coagulation parameters was purchased. METHODS: Minimum tissue plasminogen activator (tPA) concentration to induce complete fibrinolysis within 10 minutes was determined using serial dilutions of tPA in equine plasma. Results used to create an in vitro hyperfibrinolysis model with equine and human citrated plasma, and the minimum concentrations of EACA and TEA required to completely inhibit fibrinolysis for 30 minutes (estimated therapeutic concentrations) determined using serial dilutions of the drugs. RESULTS: Estimated therapeutic concentrations of EACA and TEA were significantly lower in horses (5.82; 95% CI 3.77-7.86 µg/mL and 0.512; 95% CI 0.277-0.748 µg/mL) than in humans (113.2; 95% CI 95.8-130.6 µg/mL and 11.4; 95% CI 8.62-14.1 µg/mL). CONCLUSIONS AND CLINICAL IMPORTANCE: Current dosing schemes for EACA and TEA in horses may be as much as 20× higher than necessary, potentially increasing cost of treatment and risk of adverse effects.

Reduced clearance of ε-acetamidocaproic acid in rats with acute renal failure induced by uranyl nitrate.

OBJECTIVES: Anti-ulcer drugs are frequently used in patients with acute renal failure (ARF). Zinc acexamate is ionized to zinc and ε-acetamidocaproic acid and free EACA exerts a potent therapeutic effect in treating gastric or duodenal ulcers with few side effects. Thus, pharmacokinetic changes in rats with acute renal failure induced by uranyl nitrate (U-ARF rats) were investigated in this study. METHODS: The in-vivo pharmacokinetics and in-vitro hepatic/intestinal metabolism of EACA were assessed using control and U-ARF rats. The mechanism of urinary excretion of EACA was further investigated in rats. KEY FINDINGS: After intravenous and oral administration of zinc acexamate to U-ARF rats, there were significant increases in the values of the area under the curve (AUC) and decreases in the values for time-averaged renal and nonrenal clearances (Cl(r) and Cl(nr) , respectively) compared with control rats. Slower Cl(nr) was partly due to a decrease in the metabolism in liver and/or intestine. Slower Cl(r) could have been due to urine flow rate-dependent timed-interval renal clearance, decrease in organic anion transporter-mediated renal excretion (drug interaction with probenecid and decrease in the relative contribution of net secretion compared with glomerular filtration in U-ARF rats) and/or impaired kidney function. CONCLUSIONS: The pharmacokinetics were significantly altered in U-ARF rats due to the changes in both the hepatic/intestinal metabolism and urinary excretion.

64Cu-NO2A-RGD-Glu-6-Ahx-BBN(7-14)NH2: a heterodimeric targeting vector for positron emission tomography imaging of prostate cancer.

INTRODUCTION: The present study describes the design and development of a new heterodimeric RGD-bombesin (BBN) agonist peptide ligand for dual receptor targeting of the form (64)Cu-NO2A-RGD-Glu-6-Ahx-BBN(7-14)NH(2) in which Cu-64=a positron emitting radiometal; NO2A=1,4,7-triazacyclononane-1,4-diacetic acid; Glu=glutamic acid; 6-Ahx=6-aminohexanoic acid; RGD=the amino acid sequence [Arg-Gly-Asp], a nonregulatory peptide that has been used extensively to target α(v)ß(3) receptors up-regulated on tumor cells and neovasculature; and BBN(7-14)NH(2)=Gln-Trp-Ala-Val-Gly-His-Leu-Met-NH(2), an agonist analogue of bombesin peptide for specific targeting of the gastrin-releasing peptide receptor (GRPr). METHODS: RGD-Glu-6-Ahx-BBN(7-14)NH(2) was manually coupled with NOTA (1,4,7-triazacyclononane-1,4,7-triacetic acid), and the resulting conjugate was labeled with (64)Cu to yield (64)Cu-NO2A-RGD-Glu-6-Ahx-BBN(7-14)NH(2). Purification was achieved via reversed-phase high-performance liquid chromatography and characterization confirmed by electrospray ionization-mass spectrometry. RESULTS: Competitive displacement binding assays displayed single-digit nanomolar IC(50) values showing very high binding affinities toward the GRPr for the new heterodimeric peptide analogues. In vivo biodistribution studies showed high uptake and retention of tumor-associated radioactivity in PC-3 tumor-bearing rodent models with little accumulation and retention in nontarget tissues. The radiolabeled conjugate also exhibited rapid urinary excretion and high tumor-to-background ratios. Micro-positron emission tomography (microPET) molecular imaging investigations produced high-quality, high-contrast images in PC-3 tumor-bearing mice 15 h postinjection. CONCLUSIONS: Based on microPET imaging experiments that show high-quality, high-contrast images with virtually no residual gastrointestinal radioactivity, this new heterodimeric RGD-BBN conjugate can be considered as a promising PET tracer candidate for the diagnosis of GRPr-positive tumors in human patients.

Determination of caprolactam and 6-aminocaproic acid in human urine using hydrophilic interaction liquid chromatography-tandem mass spectrometry.

A simple and rapid assay based on hydrophilic interaction liquid chromatography with tandem mass spectrometry has been first developed and validated for simultaneous determination of caprolactam (CA) and 6-aminocaproic acid (6-ANCA) in human urine using 8-aminocaprylic acid as internal standard. A 20µL aliquot of urine was injected directly into the liquid chromatography tandem mass spectrometry (LC-MS-MS) system. The analytes were separated on a Phenomenex Luna HILIC column with gradient elution. Detection was performed on Triple Quadrupole LC-MS in positive ions multiple reaction monitoring mode using electrospray ionization. The calibration curves were linear (r(2)≥0.995) over the concentration range from 62.5 to 1250ng/mL for CA and 31.25 to 1000ng/mL for 6-ANCA. The detection limits of CA and 6-ANCA were 62.5 and 15.6ng/mL, respectively. The intra-day and inter-day precisions were within 8.7% and 9.9%, respectively. The intra-day and inter-day accuracy were between 5.3% and 3.5%, and between 6.1% and 6.6%, respectively. The method proved to be simple and time efficient, and was successfully applied to evaluate the kinetics of caprolactam in one unusual case of caprolactam poisoning.

ε-Acetamidocaproic acid pharmacokinetics in rats with gastric ulcer or small bowel inflammation.

The pharmacokinetics of ϵ-acetamidocaproic acid (AACA) were evaluated after the intravenous and oral administration of an antiulcer agent, zinc acexamate (ZAC) at a dose of 20 mg kg⁻¹ (ion pairing between zinc and AACA) in rats with indomethacin-induced acute gastric ulcer (IAGU) or indomethacin-induced small bowel inflammation (ISBI). In IAGU rats, the area under the curves (AUCs) of AACA were significantly smaller after both the intravenous (551 versus 1270 µg min ml⁻¹) and oral (397 versus 562 µg min ml⁻¹) administration of ZAC than controls, possible due to the significantly faster CL(R) of AACA. In ISBI rats, however, the AUCs of AACA were comparable with controls after both the intravenous and oral administration of ZAC. In IAGU rats, the significantly smaller AUCs of AACA were due to the significantly faster CL(R) (due to the decreased urinary pH by indomethacin treatment) than controls. AACA has a basic secondary amine group. On the other hand, the comparable AUCs of AACA in ISBI rats were due to the comparable CL(R)s between ISBI and control rats. AACA was excreted in the urine via active renal tubular secretion in all rats studied.

Pharmacokinetic interaction between ϵ-acetamidocaproic acid (AACA) and cimetidine in indomethacin-induced acute gastric ulcer and control rats: inhibition of active renal secretion of AACA by cimetidine.

After both the intravenous and oral administration of zinc acexamate [ZAC; ion-pairing between zinc and ϵ-acetamidocaproic acid (AACA)] and cimetidine together, the areas under the curve (AUCs) of AACA were significantly greater [by 28.2 and 98.9% after the intravenous and oral administration, respectively, for control rats and 13.5 and 16.9% for indomethacin-induced acute gastric ulcer (IAGU) rats, respectively] than those of ZAC alone due to the significantly slower renal clearance (CL(R)). The significantly greater AUCs of AACA after both the intravenous and oral administration of ZAC and cimetidine together in control and IAGU rats could have been due to the inhibition of active renal tubular secretion of AACA by cimetidine. After the intravenous and oral administration of both drugs together, the AUCs of cimetidine in control and IAGU rats were not different compared with those with cimetidine alone.

Pharmacokinetics and first-pass effects of epsilon-acetamidocaproic acid after administration of zinc acexamate in rats.

1. Zinc acexamate (ZAC) is ionized to zinc and epsilon-acetamidocaproic acid (AACA). Thus, the pharmacokinetics and tissue distribution of zinc and AACA after intravenous (50 mg kg(-1)) and oral (100 mg kg(-1)) administration of ZAC were evaluated in rats. Also the pharmacokinetics of AACA after intravenous (10, 20, 30, and 50 mg kg(-1)) and oral (20, 50, and 100 mg kg(-1)) administration of ZAC and the first-pass extractions of AACA at a ZAC dose of 20 mg kg(-1) were evaluated in rats. 2. After oral administration of ZAC (20 mg kg(-1)), approximately 0.408% of the oral dose was not absorbed, the F value was approximately 47.1%, and the hepatic and gastrointestinal (GI) first-pass extractions of AACA were approximately 8.50% and 46.4% of the oral dose, respectively. The incomplete F value of AACA was mainly due to the considerable GI first-pass extraction in rats. 3. Affinity of rat tissues to zinc and AACA was low-the tissue-to-plasma (T/P) ratios were less than unity. The equilibrium plasma-to-blood cells partition ratios of AACA were independent of initial blood ZAC concentrations of 1, 5, and 10 microg ml(-1)-the mean values were 0.481, 0.490, and 0.499, respectively. The bound fractions of zinc and AACA to rat plasma were 96.6% and 39.0%, respectively.

Pharmacokinetics and pharmacodynamics of epsilon-aminocaproic acid in horses.

OBJECTIVE: To determine the pharmacokinetics and pharmacodynamics of epsilon-aminocaproic acid (EACA), including the effects of EACA on coagulation and fibrinolysis in healthy horses. ANIMALS: 6 adult horses. PROCEDURES: Each horse received 3.5 mg of EACA/kg/min for 20 minutes, i.v. Plasma EACA concentration was measured before (time 0), during, and after infusion. Coagulation variables and plasma alpha(2)-antiplasmin activity were evaluated at time 0 and 4 hours after infusion; viscoelastic properties of clot formation were assessed at time 0 and 0.5, 1, and 4 hours after infusion. Plasma concentration versus time data were evaluated by use of a pharmacokinetic analysis computer program. RESULTS: Drug disposition was best described by a 2-compartment model with a rapid distribution phase, an elimination half-life of 2.3 hours, and mean residence time of 2.5 +/- 0.5 hours. Peak plasma EACA concentration was 462.9 +/- 70.1 microg/mL; after the end of the infusion, EACA concentration remained greater than the proposed therapeutic concentration (130 microg/mL) for 1 hour. Compared with findings at 0 minutes, EACA administration resulted in no significant change in plasma alpha(2)-antiplasmin activity at 1 or 4 hours after infusion. Thirty minutes after infusion, platelet function was significantly different from that at time 0 and 1 and 4 hours after infusion. The continuous rate infusion that would maintain proposed therapeutic plasma concentrations of EACA was predicted (ie, 3.5 mg/kg/min for 15 minutes, then 0.25 mg/kg/min). CONCLUSIONS AND CLINICAL RELEVANCE: Results suggest that EACA has potential clinical use in horses for which improved clot maintenance is desired.

Quantitative assessment of fibrinogen cross-linking by epsilon aminocaproic acid in patients with end-stage liver disease.

Analysis of the effectiveness of antifibrinolytic therapy for liver transplant recipients is hampered by lack of quantitative assays for assessing drug effects. We adapted chemical engineering tools used in polymerization studies to quantify fibrinogen cross-linking by plasma from liver transplant patients obtained before and after epsilon aminocaproic acid (EACA) therapy. A target fluorescein isothiocyanate-fibrinogen (FITC-fibrinogen) molecule was constructed; it fluoresces in a quantifiable pattern when in solution, and undergoes cross-linking in the presence of plasmin inhibitors. Cross-linking quenches the fluorescent signal, and the quenching is a quantifiable endpoint. Thus fluorescence from this reporter molecule can be used to assess functional improvement in fibrinogen cross-linking as a result of antifibrinolytic therapies, and it is sensitive to picomolar amounts of plasmin inhibitors and activators. Cross-linking of FITC-fibrinogen by patient plasma, before and after EACA therapy, was assessed using fluorescence spectrometry. Fluorescence patterns from FITC-fibrinogen indicated no significant cross-linking of the target fibrinogen as a consequence of EACA in posttreatment plasma. When the fibrinogen-FITC target was assayed without plasma in the presence of EACA at concentrations that bracket therapeutic levels (100 and 400 microg/ml), significant fluorescence quenching (target FITC-fibrinogen cross-linking) was achieved. These results suggest that fibrinogen-FITC fluorescence is sensitive enough to detect EACA activity in clinically relevant ranges, but that EACA given in usual doses is insufficient to promote fibrinogen cross-linking in patients with end-stage liver disease.

The pharmacokinetics of epsilon-aminocaproic acid in children undergoing surgical repair of congenital heart defects.

UNLABELLED: epsilon-Aminocaproic acid (epsilonACA) is often administered to children undergoing cardiac surgery by using empiric dosing techniques. We hypothesized that children would have different pharmacokinetic variables and require a dosing scheme different from adults to maintain stable and effective serum epsilonACA concentrations. Eight patients were enrolled in our study. epsilonACA 50 mg/kg was administered three times IV: before, during, and after cardiopulmonary bypass (CPB). Nine serum samples were obtained. epsilonACA plasma concentrations were measured by using high-performance liquid chromatography, and pharmacokinetic modeling was done by using NONMEM. The best fit was seen with a two-compartment model with volume of distribution (V(1)) adjusted for weight and CPB. Compared with published results in adults, modeling suggests that weight-adjusted V(1) is larger in children than in adults before, during, and after CPB. Clearance from the central compartment (k(10)) was also greater in children than adults, and declined during CPB. Redistribution rates from the central compartment, k(12) and k(21), were greater in children and not affected by CPB. We modeled several different dosing regimens for epsilonACA based on the larger V(1), and higher redistribution and clearance variables. We conclude that, because of the developmental differences in pharmacokinetic variables of epsilonACA, when compared with adult patients, a larger initial dose and faster infusion rate as well as an addi-tional dose on CPB are needed to maintain similar concentrations. IMPLICATIONS: Pharmacokinetic modeling of epsilon-aminocaproic acid in children undergoing cardiac surgery suggests that there are developmental differences in pharmacokinetic variables. Based on these data, a dosing modification in children is suggested which may better maintain serum concentrations in children when compared with adults.

Gender does not influence epsilon-aminocaproic acid concentrations in adults undergoing cardiopulmonary bypass.

Epsilon-aminocaproic acid (epsilon-ACA) is administered to cardiac surgery patients to reduce blood transfusions. Highly water-soluble drugs, such as epsilon-ACA, often have larger distribution volumes in males than in females. We hypothesized that epsilon-ACA concentrations using this dosing scheme would differ by gender because of differences in body composition and weight-adjusted volumes of distribution. Ten men and 10 women undergoing elective coronary artery surgery with cardiopulmonary bypass (CPB) received a 50 mg/kg epsilon-ACA initial dose over 20 min and a 25 mg. kg(-1) x h(-1) epsilon-ACA maintenance infusion for 4 h. The area under the epsilon-ACA arterial concentration versus time curves was compared by using analysis of variance. Measured epsilon-ACA concentrations were smaller than predicted by the published model, but the area under the concentration versus time curves was not significantly different between men and women. Combining the present concentration data with that previously published, our updated two-compartment model included the following estimated population pharmacokinetic values: V(1) (11.8 L pre-CPB, 14.9 L during and after CPB), V(2) (12.0 L pre-CPB, 15.0 L during and after CPB), Cl(1) (0.125 L/min pre-CPB, 0.037 L/min during CPB, 0.156 L/min after CPB), Cl(2) (0.155 L/min pre-CPB, 0.013 L/min during CPB, 0.193 L/min after CPB).

Co-administration of aprotinin and epsilon-aminocaproic acid during cardiopulmonary bypass in a swine model.

Despite the beneficial effects of pharmacological interventions to prevent bleeding and to reduce the need for autogeneic blood, there are concerns that these agents induce a prothrombotic state. The purpose of this study was to examine the coagulation phenomena influenced by the coadministration of epsilon-aminocaproic acid (EACA) and aprotinin during cardiopulmonary bypass (CPB). A swine model of CPB was utilized in this study. During 120 min of CPB, treatment animals (N = 5) received 6 x 10(6) Kiu of aprotinin and 30 grams of EACA; whereas, control animals (N = 3) received an equal volume of 0.9% saline. Indices of thrombogenicity included hematological variables, gross pathology, and circuit examination for the presence of thrombus. The application of both antifibrinolytics resulted in an increase use of heparin. Total heparin requirements were significantly different between treatment group (58,800 +/- 3493 iu) versus control group (51,000 +/- 3464 iu). D-dimer concentration was also significantly higher in the control group (500-1000 ng mL-1) than in the treatment group (250-500 ng mL-1) at 5 and 30 min postprotamine. Other coagulation markers tested were not observed to be statistically significant between groups. Thromboelastographic (TEG) index decreased in the treatment group during the surgical procedure and bypass from 2.74 +/- 2.9 to -1.36 +/- 4.1 as compared to an increase from 2.62 +/- 2.9 to 4.05 +/- 0.4 in the control group. Pathologic analysis revealed occurrences of thrombus formation in small vessels in the lung and kidney glomeruli of treatment animals. The concurrent use of both aprotinin and EACA may induce a prothrombotic or coagulant state as determined by histological assessment.

Pharmacokinetic profile and adverse gastric effect of zinc-piroxicam in rats.

Complexation of piroxicam with zinc extends its absorption time in rats. The time of peak concentration value for complexed piroxicam was 5.27 hr compared to only 2.56 hr for the uncomplexed agent. Piroxicam and zinc-piroxicam show similar inhibitory effects on carrageenin-induced paw edema. Zinc-piroxicam is less irritating than piroxicam on the gastric mucosa.

Pharmacokinetics of epsilon-aminocaproic acid in patients undergoing aortocoronary bypass surgery.

BACKGROUND: Epsilon-aminocaproic acid (EACA) is commonly infused during cardiac surgery using empiric dosing schemes. The authors developed a pharmacokinetic model for EACA elimination in surgical patients, tested whether adjustments for cardiopulmonary bypass (CPB) would improve the model, and then used the model to develop an EACA dosing schedule that would yield nearly constant EACA blood concentrations. METHODS: Consenting patients undergoing elective coronary artery surgery received one of two loading doses of EACA, 30 mg/kg (group I, n = 7) or 100 mg/kg (group II, n = 6) after CPB, or (group III) a 100 mg/kg loading dose before CPB and a 10 mg x kg(-1) x h(-1) maintenance infusion continued for 4 h during and after CPB (n = 7). Two patients with renal failure received EACA in the manner of group III. Blood concentrations of EACA, measured by high-performance liquid chromatography, were subjected to mixed-effects pharmacokinetic modeling. RESULTS: The EACA concentration data were best fit by a model with two compartments and corrections for CPB. The elimination rate constant k10 fell from 0.011 before CPB to 0.0006 during CPB, returning to 0.011 after CPB. V1 increased 3.8 l with CPB and remained at that value thereafter. Cl1 varied from 0.08 l/min before CPB to 0.007 l/min during CPB and 0.13 l/min after CPB. Cl2 increased from 0.09 l/min before CPB to 0.14 l/min during and after CPB. Two patients with renal failure demonstrated markedly reduced clearance. Using their model, the authors predict that an EACA loading infusion of 50 mg/kg given over 20 min and a maintenance infusion of 25 mg x kg(-1) x h(-1) would maintain a nearly constant target concentration of 260 microg/ml. CONCLUSIONS: EACA clearance declines and volume of distribution increases during CPB. The authors' model predicts that more stable perioperative EACA concentrations would be obtained with a smaller loading dose (50 mg/kg given over 20 min) and a more rapid maintenance infusion (25 mg x kg(-1) x h(-1)) than are typically employed.

Zinc uptake in five sectors of the rat gastrointestinal tract: kinetic study in the whole colon.

PURPOSE: The uptake of zinc as acexamic acid salt in the rat gastrointestinal tract, using an in situ static technique, was studied. Our aim was to investigate an absorption window for zinc and the uptake kinetics in the colon. METHODS: To detect selectivity phenomena in zinc absorption, buffered saline solutions of zinc (50 micrograms/ ml) were perfused in stomach, whole colon and three 33-cm fractions of the small intestine (proximal, middle and distal segments). To characterize zinc uptake kinetics in whole colon, five different zinc concentrations (5, 25, 50, 150 y 250 micrograms/ml) were assayed. Zinc secreted into the gastrointestinal tract during the experiments was deducted from the uptake. RESULTS: Zinc secretion was characterized as an apparent zero-order process for all the studied segments (mean secretion rate = 0.10 +/- 0.03 microgram/(ml x min)). The stomach exhibited little ability to absorb zinc (apparent first order rate constant = 0.17 +/- 0.07 h-1), whereas the highest transport rates were found in the last two thirds of the small intestine and colon (first order constants: 0.66 +/- 0.13 h-1, 1.00 +/- 0.06 h-1, 0.97 +/- 0.14 h-1, 0.96 +/- 0.19 h-1 for proximal, middle, distal and colon segments, respectively). Zinc uptake in the colon was characterized by means of a Michaelis-Menten and first-order combined kinetics, with the following parameters: Vm = 0.36 +/- 0.02 microgram/(ml x min), Km = 18.01 +/- 0.40 microgram /ml and Ka = 0.40 +/- 0.01 h-1. CONCLUSIONS: Zinc is preferably absorbed in the middle and distal parts of the rat gastrointestinal tract. In the colon a saturable mechanism may be involved in apparent absorption.