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Tele-impedance augments classic teleoperation by enabling the human operator to actively command remote robot stiffness in real-time, which is an essential ability to successfully interact with the unstructured and unpredictable environment. However, the literature is missing a study on benefits and drawbacks of different types of stiffness command interfaces used in bilateral tele-impedance. In this article, we introduce a term called coupling effect, which pertains to the coupling between human-commanded stiffness going to the remote robot and force feedback coming from the remote robot. We hypothesize that, whenever the operator's commanded stiffness and force feedback are subject to coupling effect (e.g., muscle activity based stiffness command interfaces), force feedback can invoke involuntary changes in the commanded stiffness due to human reflexes. Although the coupling effect takes away some degree of the operator's control over the commanded stiffness, these involuntary changes can be either beneficial (e.g., during position tracking) or detrimental (e.g., during force tracking) to the task performance on the remote robot side. We examined the coupling effect in an experimental study with $\mathbf {16}$ participants, who performed position and force tracking tasks by using both coupled type (muscle activity based) and decoupled type (external device based) of interface. The results demonstrate a benefit of the coupling effect when the remote robot is operating in presence of unexpected force perturbations, where lower absolute error in position tracking task was observed. On the other hand, the decoupled type of interface is beneficial for force tracking tasks on the remote robot side, such as establishing or maintaining a stable contact with objects. However, the coupling effect negatively influences the commanding of reference stiffness to the remote robot in both position and force tracking tasks for the coupled type of interface, compared to the decoupled type of interface, which is not affected.

We propose a novel human-in-the-loop approach for teaching robots how to solve assembly tasks in unpredictable and unstructured environments. In the proposed method the human sensorimotor system is integrated into the robot control loop though a teleoperation setup. The approach combines a 3-DoF end-effector force feedback with an interface for modulation of the robot end-effector stiffness. When operating in unpredictable and unstructured environments, modulation of limb impedance is essential in terms of successful task execution, stability and safety. We developed a novel hand-held stiffness control interface that is controlled by the motion of the human finger. A teaching approach was then used to achieve autonomous robot operation. In the experiments, we analysed and solved two part-assembly tasks: sliding a bolt fitting inside a groove and driving a self-tapping screw into a material of unknown properties. We experimentally compared the proposed method to complementary robot learning methods and analysed the potential benefits of direct stiffness modulation in the force-feedback teleoperation.

In this letter, we propose a novel method that enables the robot to autonomously devise an appropriate control strategy from human demonstrations without a prior knowledge of the demonstrated task. The method is primarily based on observing the patterns and consistency in the observed dataset. This is obtained through a demonstration setting that uses a motion capture system, a force sensor, and muscle activity measurements. The variables (position and force) in the collected dataset are then segmented and analysed for each axis of the observed task frame separately. While checking several conditions based on the consistency, value range, and magnitude of repeated observations, the appropriate controller (i.e., position or force) is delegated to each axis of the task frame. In the final stage, the method also checks for a correlation between variables and muscle activity patterns to determine the desired stiffness behaviour. The robot then uses the derived control strategies in autonomous operation through a hybrid force/impedance controller. To validate the proposed method, we performed experiments on real-life tasks involving physical interaction with the environment, where we considered surface wiping, material sawing, and drilling.

In this paper, we introduce and explore a concept called coupling effect, which pertains to the influence of force feedback on the commanded stiffness that is voluntarily controlled by the operator through the stiffness interface during bilateral tele-impedance. The degree of coupling effect depends on the type of interface used to control the impedance of the remote robot. In case of muscle activity based stiffness command interfaces, the force feedback can invoke involuntary changes in the commanded stiffness due to human reflexes. These involuntary changes can be either beneficial (e.g., during position tracking) or detrimental (e.g., during force tracking) to the task performance on the remote robot side. To investigate the coupling effect in different types of stiffness command interfaces (i.e., coupled and decoupled), we conduct an experimental study in which participants are asked to perform position and force tracking tasks. The results show that in both position and force tracking tasks a lower tracking error of the reference stiffness is obtained with a decoupled interface (p

Stairways, public transport and inclined walkways are often considered as sites with higher likelihood of falls due to a sudden loss of balance. Such sites are usually marked with warning signs, equipped with non-slip surfaces and handles or handrails to avert or decrease this likelihood. Especially, handles are supposed to provide additional support in cases of a sudden loss of balance. However, the mechanisms of using handles for balance at different heights are not yet fully disclosed. We simulated full body perturbations by applying an anterior force to the waist and investigated effectiveness and mechanisms of balance recovery in five different postures: step stance and normal stance with or without holding handles at different heights. Results indicate that both step stance and holding handles at different vertical positions sufficiently assist balance recovery, compared to normal stance. While there was no significant effect of handle in CoM displacement, the shoulder height handle required the lowest handle force, indicating a difference in using the handle.

In this study we have investigated the effects of different cell culture conditions on the Calu-3 epithelial cell model. Calu-3 cells were cultured in media A-MEM at the air–liquid (A–L) or liquid–liquid (L–L) interface for one or three wks (weeks). Different cryomethods were tested and the cell line was characterized using histochemistry, immunofluorescence, transmission and scanning electron microscopy, transepithelial resistance (TEER) measurements, permeability studies, and gene profiling of 84 drug transporters. Cell culture was successful in A-MEM with only 2.5% FBS. Cell proliferation and viability depended on the cryopreservation method. All Calu-3 models expressed CK7, occludin, and E-cadherin. The A–L interface resulted in a more biomimetic native bronchial epithelium displaying pseudostratified columnar epithelium with more microvilli and secretory vesicles than at the L–L interface, where the epithelium was cuboidal, but exhibited higher TEER values and lower dextran permeabilities. Longer time in culture significantly decreased dextran permeability and increased the expression of specific drug transporters. Drug transporter expression was also notably influenced by the culture interface, where the A–L interface yielded a higher expression of drug transporter genes than the L–L interface. Since cell culture interface and time in culture affect Calu-3 cell differentiation, barrier integrity, permeability properties, and drug transporter expression, culture conditions need to be considered and standardized when using the Calu-3 cell line as an in vitro model for aerosol drug delivery and screening of bronchial drug candidates.

The further characterization of the cell line RPMI 2650 and the evaluation of different culture conditions for an in vitro model for nasal mucosa. Cells were cultured in media MEM or A-MEM at air-liquid (A-L) or liquid-liquid (L-L) interfaces for 1 or 3 weeks. Different cryopreservation methods and cell culture techniques were evaluated with immunolabelling of junctional proteins, ultrastructural analysis using electron microscopy, transepithelial electrical resistance (TEER) measurements, permeation studies with dextran and jacalin, and gene expression profiling of 84 drug transporters. Cell proliferation and differentiation depended on the used medium. The established epithelia expressed occludin, claudin-1, and E-cadherin under all conditions. Cells grown at the A-L interface formed more layers and exhibited a higher TEER and lower dextran and jacalin permeability than at the L-L interface, where cells morphologically exhibited a more differentiated phenotype. The expression of ABC and SLC transporters depended on culture duration and interface. The RPMI 2650 cells form a polarized epithelium resembling nasal mucosa. However, different culture conditions have a significant effect on cell ultrastructure, barrier integrity, and gene expression, and should be considered when using this cell line as an in vitro model for drug permeability studies and screening of nasal drug candidates.

The aim of this study was to develop a sirolimus (BCS class II drug substance) solid oral dosage form containing a precipitation inhibitor, which would result in an improved sirolimus absorption in humans compared to the formulation containing nanosized sirolimus without a precipitation inhibitor, i.e., Rapamune. The selection of the precipitation inhibitor was based on the results of a screening campaign that identified two "hit" excipients: HPMC 603 (i.e., Pharmacoat 603) and Poloxamer 407. However, in a confirmatory precipitation inhibitor study using biorelevant media (Fa/FeSSIF) HPMC 603 more effectively inhibited sirolimus precipitation than Poloxamer 407. In the PAMPA assay, HPMC 603, but not Poloxamer 407, significantly increased the flux of the sirolimus across the membrane lipid layer. Additionally, a differential scanning calorimetry (DSC) and an infrared (IR) spectroscopy study revealed that interactions between the sirolimus and HPMC 603 were developed that could lead to the observed precipitation inhibition effect. Based on the above data, two formulations with HPMC 603-coated sirolimus particles were developed, namely, formulation A (d (0.5) = 0.21 μm) and formulation B (d (0.5) = 1.7 μm). A human pharmacokinetic study outlined that significantly higher AUC and Cmax were obtained for formulations A and B in comparison to Rapamune. This result could be attributed to the HPMC 603 (Pharmacoat 603) mediated sirolimus precipitation inhibition resulting in improved sirolimus absorption from the gastrointestinal tract in humans.

When balance is exposed to perturbations, hand contacts are often used to assist postural control. We investigated the immediate and the transitionary effects of supportive hand contacts during continuous anteroposterior perturbations of stance by automated waist-pulls. Ten young adults were perturbed for five minutes and required to maintain balance by holding to a stationary, shoulder-high handle and following its removal. Centre of pressure (COP) displacement, hip, knee, and ankle angles, leg and trunk muscle activity and handle contact forces were acquired. The analysis of results show that COP excursions are significantly smaller when the subjects utilize supportive hand contact and that the displacement of COP is strongly correlated to the perturbation force and significantly larger in the anterior than posterior direction. Regression analysis of hand forces revealed that subjects utilized the hand support significantly more during the posterior than anterior perturbations. Moreover, kinematical analysis showed that utilization of supportive hand contacts alters posture of the whole body and that postural readjustments after the release of the handle occur at different time scales in the hip, knee, and ankle joints. Overall, our findings show that supportive hand contacts are efficiently used for balance control during continuous postural perturbations and that utilization of a handle has significant immediate and transitionary effects on whole body posture.

The toxicity of amiodarone Lek formulation (test formulation) was investigated after a single intravenous (i.v.) administration to mice and rats. When compared to the reference item, Cordarone (Cordarone(®); Wyeth Pharmaceuticals Inc., Collegeville, Pennsylvania, USA), median lethal dose (LD(50)) after i.v. administration in female mice was 294.0 mg/kg body weight (b.w.) for the test formulation and 227.5 mg/kg b.w. for Cordarone. In female rats after i.v. administration, the LD(50) value was 269.9 mg/kg b.w. for the test formulation and 192.4 mg/kg b.w. for Cordarone. By altering the particle size of amiodarone in the Lek formulation, we were able to improve the solubility of amiodarone, thereby decreasing the number and quantity of excipients needed for preparation of the i.v. formulation and, consequently, reduced the acute toxic effects observed in the present study.

The drawbacks and limitations of existing anticoagulant therapy which may result in serious adverse effects and a high mortality rate, have given rise to many anticoagulant development programmes in the last decade, focusing mainly at development of thrombin and FXa low-molecular weight inhibitors. A detailed understanding of blood coagulation pathways, functioning of the serine proteases thrombin, FXa, FVIIa and FIXa and elucidation of their crystal structures resulted in many potent compounds, among which some have entered the clinical phase or have been approved for use in clinical practice. Recently, the focus of anticoagulant research turned to inhibition of the TF:FVIIa complex, with some promising clinical candidates on the horizon. This article provides an overview of the current development status of serine protease inhibitors as anticoagulants, including new trends such as dual coagulation factor inhibitors.

The common structural feature of LK direct thrombin inhibitors is a strong basic group attached to the azaphenylalanine scaffold, which is important for the appropriate interaction at the thrombin active site. Our previous results have shown that this basic group could be responsible for a reduction of tracheal air flow and a fall of mean arterial pressure in anaesthetized rats, an undesired effect of direct thrombin inhibitors which correlated with their ability to release histamine from mast cells. In the present study, we investigated the mechanism of LK direct thrombin inhibitors-induced histamine release from rat peritoneal mast cells. We demonstrated that thrombin inhibitors with basic character (LK-732, LK-639 and LK-6063) provoked release of histamine from mast cells, while less basic analogs (LK-658, LK-633 and LK-6062) had no effect. Histamine released by LK-732 and LK-639 was suppressed by removal of sialic acid residues by neuraminidase and by pertussis toxin, an inhibitor of G i protein activity. Additional demonstration that G proteins are the targets of LK-732 and LK-639 was provided by the increase of GTPγS binding rate to G proteins in rat brain cortical membranes. Our results indicate that basic direct thrombin inhibitors LK-732 and LK-639 provoke release of histamine from mast cells by direct activation of G i proteins through the similar biochemical pathway as basic secretagogues.

SummaryThe main structural feature of direct thrombin inhibitor LK-732 responsible for the appropriate interaction at the thrombin active site is a strong basic group. A possibility that a strong basic group of LK-732 might contribute to the mast cell degranulation effect and consequent reduction of tracheal air flow (TAF) and fall of mean arterial blood pressure (MAP) in rats was investigated in the present study. At doses up to5 mg/kg (i. v.), LK-732 did not cause significant changes of TAF and MAP. At 7 mg/kg (i. v.),a sudden reduction of TAF and a fall of MAP was observed within 5 min after LK-732 administration (75% mortality, p=0. 007). A less basic direct thrombin inhibitor LK-658 (21 mg/ kg, i. v.) did not significantly disturb TAF and MAP. A reduction of TAF and a fall of MAP caused by LK-732 (7 mg/kg, i. v.) was almost completely abolished in rats with degranulated mast cells (0% mortality, p=0. 008). LK-732 concentration-dependently degranulated rat peritoneal mast cells in vitro (pEC50=1. 92±0. 05 µM). A structure-activity relationship (SAR) study revealed that the terminal basic groups attached to the aromatic ring are responsible for the mast cell degranulation effect. A good correlation was observed between mast cell degranulation and pKb of analogues of LK-732 (R2=0. 49), but not between mast cell degranulation and thrombin Ki (R2=0. 23). LK-732-induced reduction of TAF, the fall of MAP and high mortality originate from LK732-induced mast cell degranulation. As judged by the SAR study, this effect could be overcome by reducing the basicity of LK-732.

SummaryThe antithrombotic potential of new direct thrombin inhibitors built on the azaphenylalanine scaffold (LK-732, LK-639 and LK-731) and their amidoxime prodrugs (LK-658, LK-633 and LK-730) was studied in comparison to argatroban and nadroparin in two rat models of venous thrombosis, induced either by complete stasis combined with hypercoagulability (model 1) or by partial stasis combined with vessel injury (model 2). In initial experiments LK-732 was established as the most promising antithrombotic of the LK inhibitors and as such was further tested. In model 1, intravenous bolus administration of LK-732 produced a dose-dependent inhibition of thrombus formation with an ID50 value of 1.3 mg/kg. This ID50 value was approximately four times higher than the ID50 value of argatroban (0.3 mg/kg; p=0.011). However, in model 2, LK-732 and argatroban decreased thrombus weight by 50% at similar ID50 values (3.8 mg/kg vs 3.0 mg/kg, respectively; p=0.726). The ex vivo anticoagulant effect of LK-732 was substantially weaker compared to argatroban at doses that produced comparable antithrombotic effects. After subcutaneous administration, in vivo thrombus weight reduction of LK inhibitors (10 mg/kg) ranged between 22 to 48%. However, their oral antithrombotic effect at a dose of 30 mg/kg was rather low. LK amidoxime prodrugs failed to produce a substantial antithrombotic effect after subcutaneous (10 mg/ kg) as well as after oral administration (30 mg/kg). In conclusion, thrombin inhibitors built on the azaphenylalanine scaffold represent a new group of intravenously effective antithrombotics. However, optimisation of the oral antithrombotic effect of amid-oxime prodrug LK-658 of the lead inhibitor LK-732 is required for justifying further development of these inhibitors.

Due to copyright restrictions, the access to the full text of this article is only available via subscription. Exoskeletons are successful at supporting human motion only when the necessary amount of power is provided at the right time. Exoskeleton control based on EMG signals can be utilized to command the required amount of support in real-time. To this end, one needs to map human muscle activity to the desired task-specific exoskeleton torques. In order to achieve such mapping, this paper analyzes two distinct methods to estimate the human-elbow-joint torque based on the related muscle activity. The first model is adopted from pneumatic artificial muscles (PAMs). The second model is based on a machine learning method known as Gaussian Process Regression (GPR). The performance of both approaches were assessed based on their ability to estimate the elbow-joint torque of two able-bodied subjects using EMG signals that were collected from biceps and triceps muscles. The experiments suggest that the GPR-based approach provides relatively more favorable predictions. ImPACT Program of Council for Science Technology and Innovation ; NEDO ; SRPBS of the MEXT ; MEXT KAKENHI ; JST-SICP ; MIC-SCOPE ; JSPS-MIZS ; Slovene Human Resources Development and Scholarship Fund.

Literature and experimental data relevant for the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate release (IR) solid oral dosage forms containing levetiracetam are reviewed. Data on solubility and permeability suggest that levetiracetam belongs to class I of the biopharmaceutical classification system (BCS). Levetiracetam's therapeutic use, its wide therapeutic index, and its favorable pharmacokinetic properties make levetiracetam a valid candidate for the BCS-based biowaiver approach. Further, no BE studies with levetiracetam IR formulations in which the test formulation failed to show BE with the comparator have been reported in the open literature. On the basis of the overall evidence, it appears unlikely that a BCS-based biowaiver approach for levetiracetam IR solid oral dosage forms formulated with established excipients would expose patients to undue risks. Thus, the BCS-based biowaiver approach procedure is recommended for IR solid oral dosage form containing levetiracetam, provided the excipients in the formulation are also present in products that have been approved in countries belonging to or associated with the International Committee on Harmonization and are used in their usual quantities, and provided the dissolution profiles of the test and reference product comply with the current requirements for BCS-based biowaivers.

The excipient-mediated precipitation inhibition is classically determined by the quantification of the dissolved compound in the solution. In this study, two alternative approaches were evaluated, one is the light scattering (nephelometer) and other is the turbidity (plate reader) microtiter plate-based methods which are based on the quantification of the compound precipitate. Following the optimization of the nephelometer settings (beam focus, laser gain) and the experimental conditions, the screening of 23 excipients on the precipitation inhibition of poorly soluble fenofibrate and dipyridamole was performed. The light scattering method resulted in excellent correlation (r>0.91) between the calculated precipitation inhibitor parameters (PIPs) and the precipitation inhibition index (PI(classical)) obtained by the classical approach for fenofibrate and dipyridamole. Among the evaluated PIPs AUC100 (nephelometer) resulted in only four false positives and lack of false negatives. In the case of the turbidity-based method a good correlation of the PI(classical) was obtained for the PIP maximal optical density (OD(max), r=0.91), however, only for fenofibrate. In the case of the OD(max) (plate reader) five false positives and two false negatives were identified. In conclusion, the light scattering-based method outperformed the turbidity-based one and could be reliably used for identification of novel precipitation inhibitors.

The objective of this study was to evaluate the suitability and acceptance criteria of isolated rat jejunum model for Biopharmaceutics Classification System (BCS)—permeability classification. The evaluation followed recommended procedures including investigation of tissue integrity by applying damage triggers (nitrogen gassing, elevated temperature, azide addition), characterization of transporter functionality, and expression and development of correlation between rats' apparent permeability coefficient ( P app ) versus humans' and versus oral fraction absorbed ( f a ) in humans. Firstly, damage triggers caused a decrease in transepithelial resistance and potential difference and increase in lucifer yellow (LY) and fluorescein isothiocyanate (FITC)–dextran P app . However, only FITC–dextran P app 's increase was considered significant in all treatment groups, making FITC–dextran a better indicator of jejunum integrity than LY. Secondly, the expression level of selected intestinal transporters highly correlated between rat and human and functionality of P-glycoprotein was confirmed. P app of investigated drugs correlated with human f a ( R 2 = 0.85, n = 20) and with human permeability coefficients ( R 2 = 0.86, n = 13). Utility of described model for BCS classification was shown on levetiracetam, where significantly higher permeability of levetiracetam as compared with internal standard metoprolol was determined ( t -test, p = 0.005). In conclusion, isolated rat jejunum model is a useful tool not only for mechanistic investigation, but also for permeability classification according to BCS and consequently for BCS-based biowaiver procedures.

The feasibility of incorporating a solid dispersion containing poorly soluble antidiabetic drug glimepiride and poly(ester amide) hyperbranched polymer into a tablet using a direct-compression tabletting technique was investigated. Tablet cores were additionally coated with hydroxypropyl methylcellulose phthalate in order to protect the extremely hygroscopic solid dispersion from atmospheric moisture. Preliminary stability studies show that glimepiride, which is in amorphous form within solid dispersion, is chemically stable, even if tablets are exposed to elevated temperature and/or moisture. In-vitro dissolution studies show some impact of storage conditions on the tablet cores disintegration time and, consequently, drug release rate. Glimepiride solubility also deteriorates somewhat, most probably due to its partial recrystallization. Storage conditions much less affect the physical stability of coated tablets, which was ascribed to reduced tablet hygroscopicity due to the presence of protecting coating. The hyperbranched polymers are rather new and complex macromolecules. Therefore, we addressed also the biocompatibility of hyperbranched polymer, i.e., its impact on haemolysis of the red blood cells. The concentration required for the haemolytic effect on the red blood cells is around 100-times higher than its expected gastrointestinal luminal concentration, which makes the occurrence of hyperbranched polymer mediated cytotoxicity very unlikely.

Despite intensive research in the field of oral anticoagulants over the last decade, simple and effective long-term prevention of thromboembolism is still an unmet need. In addition to drug discovery approaches, the development of novel oral drug delivery systems (DDSs) of clinically well-established anticoagulants presents an intriguing mean of improvement of anticoagulant therapy. The latter topic is therefore the focus of the present review. All relevant clinical trials with anticoagulants formulated in the oral DDS are reviewed, and selected preclinical examples of promising novel anticoagulant DDSs are also described. For greater understanding, a background on DDS and drug absorption from the gastrointestinal tract is also provided. Three leading approaches for the oral anticoagulant DDS are currently being investigated in clinical settings, all relying on coadministration of anticoagulants with specific carriers. In contrast to the clinical setting, a diverse range of possibilities for oral delivery of anticoagulant are being investigated in preclinical trials (e.g., nanotechnology), and it would be therefore interesting to examine their performance in clinical trials.

Introduction Permanent implantation of vascular catheters allows multiple blood sampling from the experimental animal. The aim of the study was firstly to establish four cannulation procedures in rats, which will result in high rate of catheter patency after the post surgical recovery period and secondly to determine a suitability of food and water consumption (FC and WC) and body weight gain (BW) as markers for the estimation of the length of recovery period. Methods Cannulation of the jugular vein ( n = 12), femoral vein ( n = 15), ileocolic vein ( n = 13) and the dual cannulation of the jugular vein/duodenum ( n = 7) were performed in the rat. Catheter patency was monitored throughout the recovery period. Rats were considered fully recovered after return of BW, FC and WC to the preoperative values. Results A decrease of catheter patency in the recovery period followed a linear regression model in all cannulation groups ( P R 2 > 0.87). BW significantly decreased in the rats subjected to ileocolic and jugular/duodenum cannulation procedures only. A significant transient decrease of FC and increase of WC was observed in all cannulation groups. FC returned to the preoperative values more slowly than BW and WC. Therefore FC was considered as the most sensitive parameter for the estimation of the length of recovery period, resulting in the recovery period of 10 days and catheter patency of 75–85% in the case of jugular vein, femoral vein and dual jugular vein/duodenum cannulation procedures. After the cannulation of the ileocolic vein FC did not return to the preoperative values. Discussion The catheter patency at the end of recovery period, which was estimated by the FC, was assured in the majority of rats in all cannulation groups, with the exception of the ileocolic vein cannulation group. In this particular cannulation group FC did not return to preoperative values, thus indicating that further optimization of the ileocolic vein cannulation procedure is required.

Many basic compounds, including numerous drugs, can release histamine and other infl ammatory mediators from mast cells [1]. Drug-induced degranulation of mast cells is an undesired effect and therefore should be avoided. One of the consequences of drug-induced mast cell degranulation is a drop of the mean arterial blood pressure (MAP) [2]. Prevention of the drop of MAP with specifi c agents, targeting either the action of released mediators from mast cells or the extent of mast cell degranulation, is a reasonable approach to clarify the mechanism of this undesired effect. In this study we evaluated three in vivo models using this approach. In all three models compound 48/80 was used as a tool to mimic the undesired mast cell degranulation effect of potential new drugs and the drop of MAP was measured following its application. In the fi rst two models inhibition of the drop of MAP with the selective H1 antagonist clemastine and with the mast cell stabilizer cromolyn was determined respectively. In the third model the drop of MAP was studied in mast cell depleted rats.

0049-3848/$ see front matter D 2004 Elsevier Ltd. All rights reserv doi:10.1016/j.thromres.2004.10.007 Abbreviations: N, number of observations; S.E.M., standard error of mean; aPTT, activated partial thromboplastin time; TT, thrombin time; PT, prothrombin time; model 1, complete stasis combined with a hypercoagulability induced venous thrombosis model; model 2, partial stasis combined with a vessel injury induced venous thrombosis model. * Corresponding author. Lek Pharmaceuticals d.d., Drug Discovery, Verovskova 57, 1526 Ljubljana, Slovenia; Tel.: +38 615802639; fax: +38 615682340. E-mail address: luka.peternel@lek.si (L. Peternel). including experimental models of venous thrombosis [1—5]. A common feature shared by experimental animal models of venous thrombosis is a trigger of the thrombogenic state, which is usually composed of two components of Virchow’s triad [6]. Either hypercoagulability or vessel injury combined with a reduced blood flow may be used to achieve a thrombogenic state. From the perspective of interlaboratory comparisons, the most problematic component of achieving a thrombogenic state seems to be hypercoagulability, which is usually triggered by an intravenous injection of recombinant or animal thromboplastin [1—4]. The activity of thromboplastin of different origin may vary considerably, which is clearly reflected by the high variation in thromboplastin dose required to achieve the hypercoagulable state in the animal experimental models of venous thrombosis [1—4]. Thus, the need for an in-house determination of the thromboplastin dose needed to achieve the hypercoagulable state is essential. In the present study, two experimental venous thrombosis models in the rat were evaluated. The Thrombosis Research (2005) 115, 527—534