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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.

Due to copyright restrictions, the access to the full text of this article is only available via subscription. We propose an approach to efficiently teach robots how to perform dynamic anipulation tasks in cooperation with a human partner. The approach utilises human sensorimotor learning ability where the human tutor controls the robot through a multi-modal interface to make it perform the desired task. During the tutoring, the robot simultaneously learns the action policy of the tutor and through time gains full autonomy. We demonstrate our approach by an experiment where we taught a robot how to perform a wood sawing task with a human partner using a two-person crosscut saw. The challenge of this experiment is that it requires precise coordination of the robot’s motion and complianceaccording to the partner’s actions. To transfer the sawing skill from the tutor to the robot we used Locally Weighted Regression for trajectory generalisation, and adaptive oscillators for adaptation of the robot to the partner’s motion. Slovenian Research Agency ; Slovenian Ministry of Higher Education, Science and Technology.

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.

Multiple blood sampling in rat pharmacokinetic (PK) and toxicokinetic studies can result in a pathophysiological response and misleading data interpretation. This study investigated whether these drawbacks can be minimized by replacing withdrawn blood with saline, gelofusine, or donor blood.Rats with cannulated jugular veins were subjected to 12 withdrawals of 250 and 500 microl of blood followed by replacement with the same amount of saline, gelofusine, or donor blood. Red blood cell, hematocrit, hemoglobin, total protein, albumin, glucose, Na, and Cl levels were determined in the drawn blood.Multiple blood sampling caused a time-dependent decrease in red blood cell counts and hematocrit, hemoglobin, total protein, and albumin levels in all the treatment groups, but these effects were significantly alleviated in the blood-treated group. Withdrawal of 500 microl of blood caused more pronounced changes than 250 microl blood withdrawal in the saline- and gelofusine-treatment groups, but not in the blood-treatment group. Plasma glucose and Na remained unchanged in all the treatment groups, while slight changes in Cl levels were observed in the saline- and gelofusine-treatment groups.Blood sample volume had a crucial impact on the measured parameters, which were least affected in the donor blood-treated group. Regardless of the treatment, up to five 250 microl blood samples can be drawn without causing significant changes in a rat's normal condition. However, for a proper determination of PK profile, more than five blood samples are required and therefore drawn blood should be replaced, preferably with donor blood.

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