Background: UR-63325 is a new H 4 receptor (H 4 R) antagonist for treatment of asthma and allergi... more Background: UR-63325 is a new H 4 receptor (H 4 R) antagonist for treatment of asthma and allergic rhinitis. A first into man (FiM) study concluded good tolerability of single doses in healthy volunteers (HV), providing detailed pharmacokinetic (PK) and pharmacodynamic (PD) data. A multiple ascending dose (MAD) study is ongoing. Because of lack of clinical data on other H 4 R antagonists, the best approach to a proof of concept (PoC) study on the activity of UR-63325 in allergic conditions has been sought, considering the new mechanism of action (MoA) and available PK/PD data. Objectives: To design the best approach to assess the antiallergic effect of UR-63325 in a clinical setting, and to calculate the best dose to test using data from previous studies in HV. Methods: A detailed analysis of the MoA identified the key processes where UR-63325 could better show antiallergic effect and key activity markers to measure in the PoC study. A PK/PD model with FiM data was used to choose UR-63325 dosing schedule to ensure relevant H 4 R antagonism during the treatment period. Results: Through PK/PD modelling, daily dosing of 40 mg of UR-63325 for 7 days was expected to reach sustained H 4 R blockade above 75% for 24 hours and was proposed for the PoC study based on expected clinically relevant activity. Preliminary results from MAD study will be used to validate the model. A nasal challenge in volunteers with seasonal allergic rhinitis has been adapted to improve sensitivity of the main measurement. Conclusions: The design of the PoC study of UR-63325 has been guided by MoA and PK/PD to increase chances of obtaining clinically relevant data on potential antiallergic activity.
• Very good tolerability results allowed full sequential dose escalation as per protocol, up to 1... more • Very good tolerability results allowed full sequential dose escalation as per protocol, up to 100 mg
We discus several alternatives to the rational Bézier model, based on using curves generated by m... more We discus several alternatives to the rational Bézier model, based on using curves generated by mixing polynomial and trigonometric functions, and expressing them in bases with optimal shape preserving properties (normalized B-bases). For this purpose we develop new tools for finding Bbases in general spaces. We also revisit the C-Bézier curves presented by , which coincide with the helix spline segments developed by , and are nothing else than curves expressed in the normalized B-basis of the space P 1 = span{1, t, cos t, sin t}. Such curves provide a valuable alternative to the rational Bézier model, because they can deal with both free form curves and remarkable analytical shapes, including the circle, cycloid and helix. Finally, we explore extensions of the space P 1 , by mixing algebraic and trigonometric polynomials. In particular, we show that the spaces P 2 = span{1, t, cos t, sin t, cos 2t, sin 2t}, Q = span{1, t, t 2 , cos t, sin t} and I = span{1, t, cos t, sin t, t cos t, t sin t} are also suitable for shape preserving design, and we find their normalized B-basis.
An n × n real matrix is called sign regular if, for each k (1 k n), all its minors of order k hav... more An n × n real matrix is called sign regular if, for each k (1 k n), all its minors of order k have the same nonstrict sign. The zero entries which can appear in a nonsingular sign regular matrix depend on its signature because the signature can imply that certain entries are necessarily nonzero. The patterns for the required nonzero entries of nonsingular sign regular matrices are analyzed.
A pivoting strategy of O(n) operations for the Neville elimination of n × n nonsingular sign regu... more A pivoting strategy of O(n) operations for the Neville elimination of n × n nonsingular sign regular matrices is introduced. Among other nice properties, it is proved that it preserves sign regularity. It is also shown its relationship with scaled partial pivoting strategies for Neville elimination.
The subject of linear algebra is rich with many different and important notions of 'Positivity', ... more The subject of linear algebra is rich with many different and important notions of 'Positivity', many of which have enjoyed a long and illustrious history.
We show that the tensor product B-spline basis and the triangular Bernstein basis are in some sen... more We show that the tensor product B-spline basis and the triangular Bernstein basis are in some sense best conditioned among all nonnegative bases for the spaces of tensor product splines and multivariate polynomials, respectively. We also introduce some new condition numbers which are analogs of component-wise condition numbers for linear systems introduced by Skeel.
It is well known that Bernstein polynomials on triangles preserve monotonicity. In this paper we ... more It is well known that Bernstein polynomials on triangles preserve monotonicity. In this paper we define and study three kinds of monotonicity preservation of systems of bivariate functions on a triangle. We characterize and compare several of these systems and derive some geometric applications.
Proceedings Sixth International Conference on Information Visualisation, 2002
In this paper we study the monotonicity preservation of Wang-Ball system and of another system of... more In this paper we study the monotonicity preservation of Wang-Ball system and of another system of polynomials useful in computer-aided geometric design. We also prove that rational Wang-Ball representations are not always monotonicity preserving.
Background: UR-63325 is a new H 4 receptor (H 4 R) antagonist for treatment of asthma and allergi... more Background: UR-63325 is a new H 4 receptor (H 4 R) antagonist for treatment of asthma and allergic rhinitis. A first into man (FiM) study concluded good tolerability of single doses in healthy volunteers (HV), providing detailed pharmacokinetic (PK) and pharmacodynamic (PD) data. A multiple ascending dose (MAD) study is ongoing. Because of lack of clinical data on other H 4 R antagonists, the best approach to a proof of concept (PoC) study on the activity of UR-63325 in allergic conditions has been sought, considering the new mechanism of action (MoA) and available PK/PD data. Objectives: To design the best approach to assess the antiallergic effect of UR-63325 in a clinical setting, and to calculate the best dose to test using data from previous studies in HV. Methods: A detailed analysis of the MoA identified the key processes where UR-63325 could better show antiallergic effect and key activity markers to measure in the PoC study. A PK/PD model with FiM data was used to choose UR-63325 dosing schedule to ensure relevant H 4 R antagonism during the treatment period. Results: Through PK/PD modelling, daily dosing of 40 mg of UR-63325 for 7 days was expected to reach sustained H 4 R blockade above 75% for 24 hours and was proposed for the PoC study based on expected clinically relevant activity. Preliminary results from MAD study will be used to validate the model. A nasal challenge in volunteers with seasonal allergic rhinitis has been adapted to improve sensitivity of the main measurement. Conclusions: The design of the PoC study of UR-63325 has been guided by MoA and PK/PD to increase chances of obtaining clinically relevant data on potential antiallergic activity.
• Very good tolerability results allowed full sequential dose escalation as per protocol, up to 1... more • Very good tolerability results allowed full sequential dose escalation as per protocol, up to 100 mg
We discus several alternatives to the rational Bézier model, based on using curves generated by m... more We discus several alternatives to the rational Bézier model, based on using curves generated by mixing polynomial and trigonometric functions, and expressing them in bases with optimal shape preserving properties (normalized B-bases). For this purpose we develop new tools for finding Bbases in general spaces. We also revisit the C-Bézier curves presented by , which coincide with the helix spline segments developed by , and are nothing else than curves expressed in the normalized B-basis of the space P 1 = span{1, t, cos t, sin t}. Such curves provide a valuable alternative to the rational Bézier model, because they can deal with both free form curves and remarkable analytical shapes, including the circle, cycloid and helix. Finally, we explore extensions of the space P 1 , by mixing algebraic and trigonometric polynomials. In particular, we show that the spaces P 2 = span{1, t, cos t, sin t, cos 2t, sin 2t}, Q = span{1, t, t 2 , cos t, sin t} and I = span{1, t, cos t, sin t, t cos t, t sin t} are also suitable for shape preserving design, and we find their normalized B-basis.
An n × n real matrix is called sign regular if, for each k (1 k n), all its minors of order k hav... more An n × n real matrix is called sign regular if, for each k (1 k n), all its minors of order k have the same nonstrict sign. The zero entries which can appear in a nonsingular sign regular matrix depend on its signature because the signature can imply that certain entries are necessarily nonzero. The patterns for the required nonzero entries of nonsingular sign regular matrices are analyzed.
A pivoting strategy of O(n) operations for the Neville elimination of n × n nonsingular sign regu... more A pivoting strategy of O(n) operations for the Neville elimination of n × n nonsingular sign regular matrices is introduced. Among other nice properties, it is proved that it preserves sign regularity. It is also shown its relationship with scaled partial pivoting strategies for Neville elimination.
The subject of linear algebra is rich with many different and important notions of 'Positivity', ... more The subject of linear algebra is rich with many different and important notions of 'Positivity', many of which have enjoyed a long and illustrious history.
We show that the tensor product B-spline basis and the triangular Bernstein basis are in some sen... more We show that the tensor product B-spline basis and the triangular Bernstein basis are in some sense best conditioned among all nonnegative bases for the spaces of tensor product splines and multivariate polynomials, respectively. We also introduce some new condition numbers which are analogs of component-wise condition numbers for linear systems introduced by Skeel.
It is well known that Bernstein polynomials on triangles preserve monotonicity. In this paper we ... more It is well known that Bernstein polynomials on triangles preserve monotonicity. In this paper we define and study three kinds of monotonicity preservation of systems of bivariate functions on a triangle. We characterize and compare several of these systems and derive some geometric applications.
Proceedings Sixth International Conference on Information Visualisation, 2002
In this paper we study the monotonicity preservation of Wang-Ball system and of another system of... more In this paper we study the monotonicity preservation of Wang-Ball system and of another system of polynomials useful in computer-aided geometric design. We also prove that rational Wang-Ball representations are not always monotonicity preserving.
Uploads
Papers by Juan Peña