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QUANTITATIVE CLINICAL PHARMACOLOGY |
From the Department of Pharmacy and Pharmaceutical Technology; School of Pharmacy; University of Navarra, Pamplona, Spain (Dr Trocóniz) and Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany (Ms Tillmann, Mr Liesenfeld, Dr Schäfer, Dr Stangier).
Address for reprints: Address for correspondence: Christiane Tillmann, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Str. 68, 88397 Biberach, Germany; e-mail: Christiane.Tillmann{at}bc.boehringer-ingelheim.com.
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONAPPENDIXACKNOWLEDGEMENTSREFERENCES |
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Key Words: dabigatran etexilate in total hip replacement • population pharmacokinetics • NONMEM
BIBR 953 ZW (dabigatran) is a novel, synthetic, nonpeptidic, potent, specific, competitive, and reversible inhibitor of thrombin. Because BIBR 953 ZW is not orally bioavailable, BIBR 1048, dabigatran etexilate, a double prodrug of BIBR 953 ZW conveying oral bioavailability, has been synthesized.2 After oral absorption, dabigatran etexilate is converted into the active moiety, BIBR 953 ZW. Dabigatran etexilate is under development as an orally active anticoagulant for the prevention of venous thromboembolism after orthopedic surgery and for the long-term prevention of stroke in patients with atrial fibrillation.3,4
The pharmacokinetics (PK) of BIBR 953 ZW, obtained from phase I studies, show linear behavior, biexponential kinetics in plasma, and a terminal half-life of 12 to 14 hours. The drug is mainly eliminated by renal excretion because, after intravenous administration of BIBR 953 ZW, urinary recovery amounts to 80% of the dose. BIBR 953 ZW is metabolically stable, and cytochrome P450 isoenzymes are apparently not involved in its metabolism. With regard to the absorption characteristics, its bioavailability (F) is susceptible to elevated gastric pH if administered as a preliminary tablet formulation, as used in the BISTRO I study.5
To date, the population PK of BIBR 953 ZW in patients have not been reported, and therefore the aim of the current study is to develop a population PK model of BIBR 953 ZW after administration of the prodrug dabigatran etexilate in patients undergoing elective total hip replacement, assessing the interindividual and residual variability in the PK model parameters and identifying covariates potentially affecting BIBR 953 ZW plasma concentrations in a clinically significant degree. Information on drug exposure obtained in this first study in patients supported the planning of a phase IIb dose range finding study.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONAPPENDIXACKNOWLEDGEMENTSREFERENCES |
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In total, 289 patients received dabigatran etexilate orally at dose levels of 12.5 (n = 27), 25 (n = 28), 50 (n = 30), 100 (n = 40), 150 (n = 29), 200 (n = 28), and 300 (n = 20) mg bid or 150 (n = 41) and 300 (n = 46) mg qd. Of the 289 patients who received study medication, 262 completed the study, and 27 discontinued prior to study completion, but all data available from these patients were included in the analysis. Two patients were excluded because no PK information was provided by these patients. Table I lists the demographic characteristics of the studied population.
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Inclusion and Exclusion Criteria
The inclusion criteria were as follows: men or women 18 years or older scheduled to undergo a primary elective total hip replacement, weighing at least 40 kg, and giving a written informed consent for study participation. Patients fulfilling 1 of the following criteria were excluded from the trial: bleeding diathesis; gastrointestinal or pulmonary bleeding within the past year; constitutional or acquired coagulation disorders; cardiovascular disease, including uncontrolled hypertension at time of enrollment or history of myocardial infarction within the past 6 months; known liver, renal, or active malignant disease; history of deep venous thrombosis or thrombocytopenia; major surgery or trauma within the past 3 months (hip fractures associated with plate revisions at any time) or leg amputee; any history of hemorrhagic stroke; intracranial or intraocular bleeding or cerebral ischemic attacks; use of long-term anticoagulants, antiplatelet drugs, or fibrinolytics within 7 days prior to hip replacement operation; current H2-blocker, proton pump inhibitor, or cytostatic treatment; treatment with an investigational drug in the past month; known allergy to radio opaque contrast media; alcohol or drug abuse; and women of childbearing potential.
Drug Administration
The study treatment was to be continued for 6 to 10 days after surgery. The first dose was given 4 to 8 hours after completion of the surgery (ie, in the afternoon of day 0). The next dose was given on the following day (day 1) at approximately 8:00 AM, resulting in a dosing interval of about 12 to 16 hours. If the patient vomited or had bleeding events after the operation, the first dose of dabigatran etexilate could be postponed until the morning after surgery. Study drug could be administered either at fasted or fed conditions. For twice-daily dosing regimens, study drug was administered in the morning and in the evening. For once-daily dosing regimens, study drug was administered in the morning.
Study medication consisted of tablets of dabigatran etexilate, which were manufactured in strengths of 12.5-, 25-, 50-, 100-, and 200-mg free base of dabigatran etexilate by Boehringer Ingelheim (Biberach, Germany). The experimental tablet formulation did not contain excipients maintaining drug solubility at elevated gastric pH.
Sample Collection
Plasma concentrations of BIBR 953 ZW were determined on the basis of the following blood sampling scheme:
Day 0, surgery: sample collected after surgery, before drug administration (predose), and sample taken 4 hours after drug administration
Days 1 to 3: sample taken immediately before the morning dose and 1 additional sample at 2 hours postdose
Day 4: samples taken at trough and from 0 to 2, 2 to 4, 4 to 8, and 8 to 12 hours postdose
Day 5 until the last treatment day: sample taken immediately before the morning dose and 1 additional sample at 2 hours postdose except for the last treatment day
In a subpopulation, a more extensive pharmacokinetic sampling scheme with 7 blood samples collected on day 4 was performed in only 1 center at the following specific times: predose and 0.5, 1, 2, 4, 8, 12, and 14 hours postdose (2 hours after evening dose on twice-daily regimen). The blood sampling scheme in all the study patients and on day 4 of treatment in the subpopulation mentioned above is represented in Figure 1.
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289.5 (dabigatran), 478.2 295.6 (internal standard), and 648.2 288.9 (dabigatran glucuronide). The lower limit of quantification (LOQ) was 1 ng/mL. The linearity of the method (ie, the mean correlation coefficient of the standard curves) was 0.99953. At the lower limit of quantification, the precision of the analytical method was 6.67% coefficient of variation (CV), and accuracy (bias) was -2.66%.
Data Analysis
Total BIBR 953 ZW (free plus conjugated BIBR 953 after cleavage of the glucuronide conjugate) in plasma has been used for population PK analysis. BIBR 953 ZW is subject to conjugation with glucuronic acid to yield pharmacologically active acylglucuronides. Because the thrombin inhibitory potency of those conjugates is comparable to free, nonconjugated BIBR 953 ZW, the use of total BIBR 953 ZW, which is free plus BIBR 953 ZW released from conjugates after alkaline cleavage, was considered necessary.
The population PK analyses and simulations were carried out in concordance with the Food and Drug Administration (FDA) guidance on population pharmacokinetics,6 using the software NONMEM (Version V) and the first-order conditional estimation method with the INTERACTION option implemented in NONMEM.7,8
Model selection was done based on a number of criteria such as the goodness-of-fit plots, precision of model parameter estimates, and the difference in the minimum value of the objective function (-2 log[likelihood]; -2LL) provided by NONMEM. A difference of 3.84, 6.63, and 10.8 points in -2LL between 2 nested models differing by 1 parameter is significant at the 5%, 1%, and 0.1% levels, respectively. The model-building process was performed in 3 steps:
1. Development of the basic population model. A model without incorporating any of the covariates was first developed. Disposition of drug in plasma was described by compartmental models parameterized in terms of elimination and distribution clearances, as well as apparent volumes of distribution. Drug absorption was described using a first-order rate of absorption model. Interindividual variability (IIV) was modeled exponentially, and a combined error model was initially used to account for the residual variability. No interoccasion variability was tested because there was only 1 visit with more than 1 plasma sample per occasion.9 During this step, the significance of the off-diagonal elements of the variance-covariance matrix 
was also evaluated.
BIBR 953 ZW is mainly eliminated by renal excretion, which led to the expectation that renal function status would have a major effect on CL/F, the apparent plasma clearance. Therefore, creatinine clearance (CRCL) was tested a priori during the basic model development. In addition, and taking into account that the absorption process might be slower directly after surgery than on the following days because the motility of the gastrointestinal tract is decreased because of surgical trauma and comedications,10 day of surgery was also tested as a categorical covariate on the absorption parameters.
2. Covariate model selection. Table I shows the covariates tested for significance. Categorical covariates were investigated only if at least 2 categories were available, and each represents more than 10% of the population. Therefore, only 8 out of 18 comedication classes were tested as covariates. Also vomiting, considered as a potentially significant covariate, was not tested because of the above criteria. Each covariate was added individually to the base model. Covariates were then incorporated, starting with the covariate that led to the largest drop in -2LL, one at a time until the full covariate model was obtained (forward inclusion). Afterward and starting from the full model, if a covariate was found to be not significant, it was dropped in favor of the simpler model, and this continued until no more terms could be dropped (backward elimination). During the forward inclusion and backward elimination, the significance levels used were 5% and 0.1%, respectively.
3. Model evaluation. The final population PK model was evaluated using internal evaluation methods. One hundred new data sets with the same number of patients, the same covariates, and the same dosing history and sampling schedule as the original data set were simulated, based on the model parameters estimated from the original data set. Then model parameters were estimated for each of the simulated data sets. Bias and precision of the population PK model parameter estimates were evaluated by computing, across the simulated data sets, the median performance error (MPE) and the median of the absolute performance error (MAPE).11 For each of the simulated data sets, the performance error (PE) for a specific PK parameter was estimated as follows: PE = [(Psim - Por)/Por] x 100, where Psim and Por were the population estimate for a parameter using the simulated data set and the final model parameter obtained from the original data set, respectively. The absolute performance error (APE) was defined as the absolute value of PE.
The impact of the selected covariates on the plasma concentration versus time profiles was investigated by computer simulations. For the case of a continuous covariate, 1000 individuals were simulated for each of the values corresponding to the 5th, 50th, and 95th percentiles of the covariate in the studied population, assuming a 5-day treatment with BIBR 1048 administered bid at the dose of 150 mg.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONAPPENDIXACKNOWLEDGEMENTSREFERENCES |
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Development of the Basic Model
A 2-compartment model with first-order elimination, parameterized in terms of CL/F, V2/F (apparent volume of distribution of the central compartment), V3/F (apparent volume of distribution of the peripheral compartment), and Q/F (apparent distribution clearance), described the disposition of the drug in plasma significantly better than the 1-compartment model (P < .001). A 3-compartment model was not statistically better than the 2-compartment model (P > .05). Drug absorption was best described with a first-order model including a lag time, although other models, such as the zero-order model and the combination of zero- and first-order models, were also tested.
CRCL was found to have a linear and significant effect on CL/F from days 2 to 10 (CL/F(>24 h), P < .001), and absorption could be best described computing different estimates of the apparent first-order rate constant of absorption (ka) for days 0 to 1 (ka(<24 h)) and for days 2 to 10 (ka(>24 h)). CL/F was also found to be different on days 0 to 1 (CL/F(<24 h)) and days 2 to 10 (P < .001).
Visual inspection of the goodness-of-fit plots showed that data from the once- and twice-daily dosing schemes were described similarly, providing an indication that the pharmacokinetics of dabigatran were not affected by those schedule differences.
Interindividual variability was included exponentially on CL/F (different between days 0 to 1 and days 2 to 10) and ka, although IIV on ka could only be estimated for ka(>24 h). Off-diagonal elements of the variance-covariance matrix were found to be nonsignificant (P > .05). Residual variability was accounted for using a combined and proportional error model for days 0 to 1 and days 2 to 10, respectively. Table II shows the expressions corresponding to the pharmacostatistical structure of the selected basic population model, and Table III lists the model parameter estimates and RSE for the basic population model.
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Covariate Model Selection
CL/F(<24 h) and CL/F(>24 h) were influenced by fasted serum gastrin concentrations (GAST) significantly (P < .001). Serum creatinine concentrations (SCR) and age (AGE) were covariates significantly affecting ka(>24 h) (P < .001). An increase in both SCR and AGE would result in a slower absorption rate.
Based on a decrease in -2LL, comedication classes COM3 (gastrointestinal passage accelerating drugs) and COM12 (other drugs) were found to significantly affect CL/F (P < .001). In addition, it was found that patients of the 12.5-mg and 25-mg dose groups and patients receiving once-daily treatment would show a slightly faster absorption. However, in all cases, the 95% confidence intervals of the parameter estimates were overlapping, and the respective covariates explained only a negligible portion of IIV. Therefore, those results did not represent a biological/physiological significance, and consequently, they were not retained in the model. None of the other covariates was found to significantly decrease -2LL (P > .05).
Table IV shows the expressions corresponding to the pharmacostatistical structure of the selected final population model where all parameters appear estimated with adequate precision, and Table III lists also the model parameter estimates and RSE for the final population model. Figure 3 represents the goodness-of-fit plots split by dose group and treatment schedule. For the population predictions, the tendency to underpredict high concentrations was always present, although different models for disposition or absorption were tested. Figure 4 represents the relationship between the individual model estimates of CL/F(>24 h) and the individual values of CRCL together with the typical population model prediction.
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Model Evaluation
The values of MPE for all the model parameters were lower than ±6.2%, with the exception of the parameter CL/F(<24 h), which showed a value of +20.5%. With respect to the MAPE calculations, all parameters in the model showed values lower than 32%.
Figure 5 displays the impact of the covariates SCR and AGE on ka(>24 h) with regard to the plasma concentration versus time profiles of BIBR 953 ZW. The values for ka(>24 h) in Figure 5 correspond to the lowest, median, and highest values computed using the covariate model selected and the lowest, median, and highest values of SCR and AGE in the studied population. Figure 6 shows the median plasma concentration versus time profiles together with the 5th and 95th percentiles simulated for the following groups representing different renal impairment status: normal (CRCL > 90 mL/min), mild (60 < CRCL 
90 mL/min), moderate (40 < CRCL 60 mL/min), and moderate to severe (CRCL 40 mL/min). In Figure 7, the model-predicted differences between the pharmacokinetic characteristics of the first day of administration with respect to the rest of the treatment period are presented.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONAPPENDIXACKNOWLEDGEMENTSREFERENCES |
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The pharmacokinetics of BIBR 953 ZW were best described by a 2-compartment model with first-order absorption and first-order elimination. Inclusion of a lag time was also required. The main characteristic of the population model selected was the fact that the rate constant of drug absorption and the apparent plasma clearance during days 0 and 1 of treatment were significantly lower (P < .01) compared to days 2 to 10. This finding can be explained by the fact that absorption might be slower directly after surgery due to changes in gastrointestinal motility caused by surgical effects or comedication (eg, opioids).10 In this context, a comparison with the direct competitor melagatran is not possible because it was given subcutaneously first, subsequently followed by oral administration for continuous treatment.12,13 Other model parameterizations were tested to account for the difference in systemic exposure between days 0 to 1 and days 2 to 10, by means of estimating relative bioavailability in conjunction with different IIVs for these parameters, resulting in similar fits. However, because no intravenous data were available to estimate absolute bioavailability of the oral dosage form to confirm the change in clearance and/or in bioavailability, model development was continued from the basic model represented in Table II.
The estimate of ka(<24 h) of 0.022 h-1 corresponds to an absorption half-life of 31.5 hours, implying that a flip-flop situation with the ka(<24 h) is related to elimination rather than absorption. The flip-flop situations are supported by the fact that in the final model, SCR and AGE were identified as statistical significant covariates in ka(>24 h) because those 2 covariates are likely to affect the elimination rate rather than the rate of absorption.
Weight, gender, most laboratory measurements, smoking, or alcohol consumption could not be shown to influence significantly dabigatran pharmacokinetics. As expected, on the basis of urinary unaltered drug recovery data obtained in previous studies, CRCL affected significantly drug exposure. Figure 4 shows the individual model-predicted CL/F(>24 h) estimates versus CRCL relationship. In general, the CL versus CRCL relationship is modeled with a step function predicting a linear increase in CL up to a certain value of CRCL, usually between 120 and 150 mL/min. In the current study, most of the individual CRCL values were below 120 mL/min, which justifies the use of the linear function. The covariate model predicts an increase in drug exposure from day 2 onward of 11% for each 10-mL/min decrease in CRCL. Such prediction is very similar to the one reported recently for ximelagatran in patients with acute deep vein thrombosis.13 Despite the statistically significant effect of CRCL on CL/F(>24 h), results from simulations represented in Figure 6 show an apparent degree of overlapping in the drug concentration versus time profiles for patients with normal renal function and patients with mild, moderate, and severe impairment, suggesting the use of a fixed dose for next clinical trials. These results should be interpreted with caution and necessitate further confirmation in the future because only a very small number of patients with severe renal impairment (n = 9) were enrolled in the current study.
On the day of operation, a blood sample was drawn after the patient had fasted for 12 hours so that the serum level of gastrin could be analyzed. Gastrin is a hormone releasing gastric acid from the parietal cells.14 Significantly elevated levels of fasted serum gastrin are thought to indicate low gastric acid secretion, resulting in increased gastric pH.14 The fact that a higher GAST value resulted in a lower exposure to BIBR 953 ZW suggests a reduction in bioavailability. The effect of GAST on CL/F(<24 h) was estimated to be 100% higher than the effect on CL/F(>24 h), a finding that might be explained by a change in GAST production and release during and just after surgery.15 However, such a potential source of interindividual variability is likely to be overcome in the future and also due to changes in drug formulation, based on results showing that an alternative capsule formulation with tartaric acid as the relevant excipient was less susceptible to elevated gastric pH. Tartaric acid provides an acid environment and improves solubility and drug absorption. Administration of 150-mg BIBR 1048 capsules with pantoprazole pretreatment resulted in a 30% reduction of AUC compared to the AUC without pantoprazole, in contrast to the 80% reduction in bioavailability found after a concomitant administration of an experimental tablet formulation of BIBR 1048 with pantoprazole.5 In the current analysis, the food effect was not evaluated, but in previous studies, it was found that administration of 150-mg dabigatran etexilate capsules with a high-fat, high-caloric breakfast did not affect the extent of absorption.5
To summarize the results from the current study, the pharmacokinetics of dabigatran were best described by a 2-compartment model. The data supported the estimation of different first-order absorption rate constants and apparent plasma clearances for days 0 to 1 and days 2 to 10 after surgery. Age and serum creatinine influenced ka, whereas gastrin and CRCL, only for days 2 to 10, affected CL/F (P < .001). The typical values for ka for a 67-year-old patient with a serum creatinine of 0.964 mg/dL were 0.022 and 0.093 h-1 on days 0 to 1 and days 2 to 10, respectively. The typical value for CL/F for a patient with a gastrin of 34.58 pmol/L and a CRCL of 76.16 mL/min were 70.87 and 106.2 L/h on days 0 to 1 and days 2 to 10, respectively. The differences found in the pharmacokinetics of dabigatran during the first 24 hours after surgery compared to the following days are most likely due to alterations in gastric motility and gastric pH following surgery. As a consequence, the rate of absorption is reduced and interindividual variability in drug exposure increased. On the following days, the pharmacokinetic behavior of BIBR 953 ZW is less variable.
The present study provides population pharmacokinetic parameter estimates that will facilitate clinical trial simulation studies aimed at a thorough characterization of the pharmacokinetic profile in patients with different stages of renal impairment.
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APPENDIX |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONAPPENDIXACKNOWLEDGEMENTSREFERENCES |
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The members of the BISTRO I (Boehringer Ingelheim Study in ThROmbosis) study group were as follows: Steering Committee: B. I. Eriksson (Study Chair), O. E. Dahl, L. Ahnfelt, J. Stangier, G. Nehmiz, K. Hermansson, V. Kohlbrenner; Central Adjudication Committee: Venograms: P. Kälebo and B. E. Zachrisson, Bleeding: P. U. Angerås; Statistician: G. Nehmiz; Sponsor: Boehringer Ingelheim AB, Sweden.
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ACKNOWLEDGEMENTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONAPPENDIXACKNOWLEDGEMENTSREFERENCES |
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Conflict of interest: Trocóniz is a consultant for Boehringer Ingelheim and has declared no conflict of interest with regard to this publication.
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REFERENCES |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONAPPENDIXACKNOWLEDGEMENTSREFERENCES |
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4. Eriksson BI, Dahl OE, Buller HR, et al, for the BISTRO II Study Group. A new oral direct thrombin inhibitor, dabigatran etexilate, compared with enoxaparin for prevention of thromboembolic events following total hip or knee replacement: the BISTRO II randomized trial. J Thromb Haemost. 2005;3: 103-111.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
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13. Cullberg M, Eriksson UG, Wahlander K, Eriksson H, Schulman S, Karlsson MO. Pharmacokinetics of ximelagatran and relationship to clinical response in acute deep vein thrombosis. Clin Pharmacol Ther. 2005;77: 279-290.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
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