J. De Maeyer

5-HT4 receptor agonists: similar but not the same

Abstract  5‐Hydroxytryptamine4 (5‐HT4) receptors are an interesting target for the management of patients in need of gastrointestinal (GI) promotility treatment. They have proven therapeutic potential to treat patients with GI motility disorders. Lack of selectivity for the 5‐HT4 receptor has limited the clinical success of the agonists used until now. For instance, next to their affinity for 5‐HT4 receptors, both cisapride and tegaserod have appreciable affinity for other receptors, channels or transporters [e.g. cisapride: human ether‐a‐go‐go‐related gene (hERG) is K+ channel and tegaserod: 5‐HT1 and 5‐HT2 receptors]. Adverse cardiovascular events observed with these compounds are not 5‐HT4 receptor‐related. Recent efforts have led to the discovery of a series of selective 5‐HT4 receptor ligands, with prucalopride being the most advanced in clinical development. The selectivity of these new compounds clearly differentiates them from the older generation compounds by minimizing the potential of target‐unrelated side effects. The availability of selective agonists enables the focus to shift to the exploration of 5‐HT4 receptor‐related differences between agonists. Based on drug‐ and tissue‐related properties (e.g. differences in receptor binding, receptor density, effectors, coupling efficiency), 5‐HT4 receptor agonists are able to express tissue selectivity, i.e. behave as a partial agonist in some and as a full agonist in other tissues. Furthermore, the concept of ligand‐directed signalling offers great opportunities for future drug development by enlarging the scientific basis for the generation of agonist‐specific effects in different cell types, tissues or organs. Selective 5‐HT4 receptor agonists might thus prove to be innovative drugs with an attractive safety profile for better treatment of patients suffering from hypomotility disorders.

A double-sampling extended-counting ADC

Extended-counting analog-to-digital conversion combines the accuracy of /spl Sigma//spl Delta/ modulation with the speed of algorithmic conversion. In this paper, a double-sampling technique is introduced for this type of converter. It is based on a variant of the fully floating bilinear integrator. This way, the clock frequency of the converter is almost halved. An experimental converter was designed in a 0.6-/spl mu/m CMOS technology for a bandwidth of 500 kHz at a 3.3-V supply. In the switched-capacitor implementation, the hardware is extensively reused. This way, the converter can be realized with only one operational amplifier. On the other hand, compared to alternative implementations, the amount of switches is increased. These are designed carefully in order not to degrade the performance. The converter converts a sample in 24 clock cycles and achieves a dynamic range of 87 dB. The peak signal-to-noise ratio (SNR) and signal-to-noise-plus-distortion ratio (SNDR) were measured to be 82 and 81 dB, respectively. The power consumption was 28-mW analog and 20-mW digital. The converter core occupies 0.7 mm/sup 2/ including digital logic.

Selective desensitization of the 5-HT4 receptor-mediated response in pig atrium but not in stomach.

Background and purpose:  The time dependency of the effect of 5‐HT4 receptor agonists depends on many specific regulatory mechanisms, which vary between tissues. This has important implications with regard to the effects of endogenous 5‐HT, as well as to the clinical use of 5‐HT4 receptor agonists, and might contribute to tissue selectivity of agonists.

A 250-kHz 94-dB double-sampling /spl Sigma//spl Delta/ modulation A/D converter with a modified noise transfer function

This paper presents a high-order double-sampling single-loop /spl Sigma//spl Delta/ modulation analog-to-digital (A/D) converter. The important problem of noise folding in double-sampling circuits is solved here at the architectural level by placing one of the zeros in the modulators noise transfer function at half the sampling frequency instead of in the baseband. The resulting modulator is of fifth order but has the baseband performance of a fourth-order modulator. Through the use of an efficient switched-capacitor implementation, the overall circuit uses only four operational amplifiers and hence, its complexity is similar to that of a fourth-order modulator. An experimental 1-bit modulator was designed for an oversampling ratio of 96 and a bandwidth of 250 kHz at a 3.3-V supply in a conservative 0.8-/spl mu/m standard CMOS process. Due to the double-sampling, the sampling frequency is 48 MHz, although the circuits operate at a clock frequency of only 24 MHz. The circuit achieves a dynamic range of 94 dB. The peak signal-to-noise ratio and signal-to-noise-plus-distortion ratio were measured to be 90 and 86 dB, respectively. The power consumption of the complete circuit including clock drivers and output pad drivers was 43 mW. The analog blocks (opamps, comparators, etc.) consume 30 mW of this total.

Cholinergic interactions between donepezil and prucalopride in human colon: potential to treat severe intestinal dysmotility.

Cholinesterase inhibitors such as neostigmine are used for acute colonic pseudo‐obstruction, but cardio‐bronchial side‐effects limit use. To minimize side‐effects, lower doses could be combined with a 5‐HT4 receptor agonist, which also facilitates intestinal cholinergic activity. However, safety concerns, especially in the elderly, require drugs with good selectivity of action. These include the AChE inhibitor donepezil (used for Alzheimers disease, with reduced cardio‐bronchial liability) and prucalopride, the first selective, clinically available 5‐HT4 receptor agonist. This study examined their individual and potential synergistic activities in human colon.

Exploratory Study on Domain-Specific Determinants of Opiate-Dependent Individuals’ Quality of Life

Background/Aims: Studies on determinants of quality of life (QoL) among opiate-dependent individuals are scarce. Moreover, findings concerning the role of severity of drug use are inconsistent. This exploratory study investigates the association between domain-specific QoL and demographic, social, person, health and drug-related variables, and potential indirect effects of current heroin use on opiate-dependent individuals’ QoL. Methods: A cohort of opiate-dependent individuals who started outpatient methadone treatment at least 5 years previously (n = 159) were interviewed about their current QoL, psychological distress, satisfaction with methadone treatment and the severity of drug-related problems using the Lancashire Quality of Life Profile, the Brief Symptom Inventory, the Verona Service Satisfaction Scale for Methadone Treatment and the EuropASI. Results: None of the QoL domains were defined by the same compilation of determinants. No direct effect of current heroin use on QoL was retained, but path analyses demonstrated its indirect effects on the domains of ‘living situation’, ‘finances’ and ‘leisure and social participation’. Conclusion: These findings illustrate the particularity of each QoL domain and the need for a multidimensional approach to the concept. The relationship between current heroin use and various domains of opiate-dependent individuals’ QoL is complex, indirect and mediated by psychosocial and treatment-related variables.

Quadrature mismatch shaping with a complex, tree structured DAC

Quadrature SigmaDelta ADCs require a feedback path for both the I and the Q part of the complex feedback signal. If two separated multibit feedback DACs are used, mismatch among the unit DAC elements leads to additional mismatch noise in the output spectrum as well as an unbalance between the I and Q DAC. This paper proposes a new quadrature bandpass mismatch shaping technique. In our approach the I and Q DACs are merged into one complex DAC, which leads to near-perfect I/Q balance. To select the unit DAC elements of the complex, multibit DAC, the well-known tree structured element selection logic is generalized toward a complex structure and necessary conditions for its correct operation are derived. Finally, a very efficient first-order quadrature shaper implementation is proposed and simulations show the effectiveness of the quadrature bandpass mismatch shaping technique

Nyquist criterion based design of continuous time /spl Sigma//spl Delta/ modulators

In this paper we propose a way to design continuous time SigmaDelta modulators. The method is based on the Nyquist stability criterion. Based on this criterion we propose to use the vector gain margin as a robust stability margin. Using this margin as a design criterion we design a robustly stable modulator. Finally, we also show how this margin can be used to evaluate the relative stability of a designed modulator

A Describing Function Study of Saturated Quantization and Its Application to the Stability Analysis of Multi-Bit Sigma Delta Modulators

Just as their single-bit counterparts, multi-bit sigma delta modulators exhibit nonlinear behavior due to the presence of the quantizer in the loop. In the multi-bit case this is caused by the fact that any quantizer has a limited output range and hence gives an implicit saturation effect. Due to this, any multi-bit modulator is prone to modulator overloading. Unfortunately, until now, designers had to rely on extensive time-domain simulations to predict the overloading level, because there is no adequate analytical theory to model this effect.

Addressing static and dynamic errors in bandpass unit element multibit DAC's

This paper describes a general model for static as well as dynamic errors in multibit unit element DACs. Apart from the static mismatch there are two error terms arising from switching imperfections. Based on the model, some bandpass mismatch shaping techniques are presented. These address both the static mismatch as well as the switching imperfections. The technique can significantly improve the in band noise.