Will the Evolution of Overactive Bladder Delivery Systems Increase Patient Compliance?

The negative impact of overactive bladder (OAB) on daily quality of life drives the large market of pharmacotherapy targeted at symptoms of urinary frequency and urgency, with or without urinary urge incontinence. Currently, the primary pharmacologic treatment modality is aimed at modulation of the efferent muscarinic receptors (M2 and M3) predominant in detrusor smooth muscle and responsible for involuntary or unwanted bladder contractions. However, due to drug effects in the muscarinic receptors of the salivary glands and intestinal smooth muscle, as well as extensive first-pass metabolism in the liver and intestinal tract yielding parent drug metabolites, adverse side effects are common and can be quite bothersome. These issues, encountered with many of the oral antimuscarinic formulations, limit their tolerability and affect long-term patient compliance and satisfaction. Thus, the benefit of pharmacotherapy for OAB must be a balance between efficacy and tolerability, also known as therapeutic index. This article reviews the current pharmacologic delivery systems available for the treatment of OAB, patient compliance, and reasons for discontinuation of medication.Key words: Overactive bladder, Pharmacotherapy, Compliance, Antimuscarinic agent, Transdermal delivery systemOveractive bladder syndrome (OAB) is a condition affecting millions of adults in the aging US population, with prevalence rates estimated at 17% in both men and women.¹ Quality of life and symptom bother have become important parameters in the treatment of many disease states, with efficacy of treatment measured by perceived improvements in these variables. OAB is largely characterized by its negative impact on daily quality of life. Specifically, the subjective impact of urinary frequency and urgency (with or without urge incontinence) on psychosocial and physical factors has become an important aspect of caring for this group of patients. The severity and degree of bother associated with OAB symptoms can directly influence a person’s mobility, degree of social isolation, and impairment in work-related productivity, and may also cause clinical depression, disruptions in sleep, and impairment in domestic and sexual life.² In addition, the patient may develop extreme coping strategies including severe, self-imposed fluid restrictions, avoidance of social events and travel, and dependence on costly protective undergarments. Although all of these factors drive patients to seek evaluation and treatment, persistence and compliance with medical OAB therapy remain astoundingly low both in the clinical setting and in large-scale clinical trials. High rates of discontinuation are multifactorial: adverse side effects, lack of perceived efficacy, polypharmacy, medication cost, poor counseling regarding compliance and successful treatment, and dosing frequency. Because adverse side effects are experienced by a significant portion of patients treated with oral antimuscarinic therapy, thereby limiting their long-term utilization, the development of new drug delivery systems for OAB pharmacotherapy has been critical. The focus has been on less frequent dosing intervals with longer acting formulations, reduction in side-effect profile by altering pharmacokinetics of both parent compound and active metabolites, and alternative methods of drug delivery that avoid first-pass liver metabolism.     

What is the function of MSP-I on the malaria merozoite?

In the absence o f any clear enzymatic activity, attempts to define the role of merozoite surface protein-I have focused mainly on analysis of its structure, on its interaction with the immune system and on binding assays. But how does our knowledge of the structure o f this protein contribute to functional studies? Are there data to suggest a role in the evasion of effective host immune responses? Binding studies have used the intact protein or various fragments and peptides, but do such approaches provide a reliable indicator of function? In this article, Tony Holder and Mike Blackman review these areas.     

What is the role of thermodynamics on protein stability?

The most challenging and emerging field of biotechnology is the tailoring of proteins to attain the desired characteristic properties. In order to increase the stability of proteins and to study the function of proteins, the mechanism by which proteins fold and unfold should be known. It has been debated for a long time how exactly the linear form of a protein is converted into a stable 3-dimensional structure. The literature showed that many theories support the fact that protein folding is a thermodynamically controlled process. It is also possible to predict the mechanism of protein deactivation and stability to an extent from thermodynamic studies. This article reviewed various theories that have been proposed to explain the process of protein folding after its biosynthesis in ribosomes. The theories of the determination of the thermodynamic properties and the interpretation of thermodynamic data of protein stability are also discussed in this article.     

What is the function of the claustrum?

The claustrum is a thin, irregular, sheet-like neuronal structure hidden beneath the inner surface of the neocortex in the general region of the insula. Its function is enigmatic. Its anatomy is quite remarkable in that it receives input from almost all regions of cortex and projects back to almost all regions of cortex. We here briefly summarize what is known about the claustrum, speculate on its possible relationship to the processes that give rise to integrated conscious percepts, propose mechanisms that enable information to travel widely within the claustrum and discuss experiments to address these questions.     

What is the effect of soil use on ant communities?

Studies on ant communities in agroecosystems have contributed to the knowledge of the effect of agricultural activities on biological communities. The aim of this study is to explain the effect of soil use on ant communities. We tested the hypothesis that there was a decrease in ant species richness and a change in the species composition at habitats with more intense soil use. We collected ants using sardine baits, subterranean traps and direct sampling at four habitats with different soil use (secundary forest, Acacia forestry, initial stage of succession and mixed crops). The ant species richness did not decrease with intensity of soil use. In successional habitat the species numbers collected using sardine baits and subterranean traps were significantly different. Species composition of communities had a pronounced variation, with the epigaeic and hypogaeic ant faunas of the habitat with high intense soil use (mixed crops) had low similarity with ant communities of the three other habitats. The predator species were restricted to habitats with low intensity of soil use. Then, species composition could better reflect the functional changes on ant communities than species richness. Our data can help to choose the component of ant community that better reflect the response of biodiversity to agricultural impacts.     

What is the function of centrioles?

The function of centrioles has been controversial and remains incompletely resolved. This is because centrioles, in and of themselves, do not directly perform any physiological activity. Instead, their role is only to act as a jig or breadboard onto which other functional structures can be built. Centrioles are primarily involved in forming two structures-centrosomes and cilia. Centrioles bias the position of spindle pole formation, but because spindle poles can self-organize, the function of the centriole in mitosis is not obligatory. Consequently, lack of centrioles does not generally prevent mitosis, although recent experiments suggest acentriolar spindles have reduced fidelity of chromosome segregation. In contrast, centrioles are absolutely required for the assembly of cilia, including primary cilia that act as cellular antennae. Consistent with this requirement, it is now becoming clear that many ciliary diseases, including nephronophthisis, Bardet-Biedl syndrome, Meckel Syndrome, and Oral-Facial-Digital syndrome, are caused by defects in centriole-associated proteins.     

Restoration of Seminatural Grasslands: What is the Impact on Ants?

The number of species‐rich seminatural grasslands in Northern Europe has decreased significantly due to the abandonment of traditional land use practices. To preserve these habitats, an increasing number of abandoned and overgrown grasslands have been restored by cutting down trees and shrubs and reintroducing grazing. These practices are considered a useful tool to recover the species richness of vascular plants, but their impact on other taxa is hardly known. Here we studied ants as one important group of grassland insects. We investigated (1) the effects of restoration of nongrazed and afforested seminatural grasslands, compared to continuously managed reference sites; and (2) the modulating impacts of habitat characteristics and time elapsed since restoration. We found a total of 27 ant species, 11 of these were characteristic of open habitats and seven characteristic of forests. Neither species richness per site nor the number of open‐habitat species, nor the number of forest species differed between restored and reference sites. Yet, within the restored sites, the total species richness and the number of open‐habitat species was positively related to the time since restoration and the percentage of bare rock. High frequencies of most open‐habitat species were associated with low vegetation, older restored sites, and reference sites. Most forest species showed their highest frequencies in tree‐ and shrub‐dominated habitat. We conclude that restoration efforts have been successful in terms of retrieving species richness. A regular and moderate grazing regime subsequent to the restoration is suggested in order to support a high abundance of open‐habitat species.     

What is the impact of transposable elements on host genome variability?

The spread of a transposable element family through a wild population may be of astonishing rapidity. At least three families of transposable genetic elements have recently invaded Drosophila melanogaster worldwide, including the P element. The mechanism has been a process of effectively replicative transposition, and, for the P element, has occurred notwithstanding the sterility induced by unrestricted movement. This element's invasion into D. melanogaster has been accompanied by the development of heterogeneity between P sequences, most of which now have internal deletions. Increasing evidence suggests that some deleted elements can repress P transposition, thereby protecting the host from the harmful effects of complete elements. Such repressing elements may rise to high frequencies in populations as a result of selection at the level of the host. We here investigate selective sweeps invoked by the spread of P sequences in D. melanogaster populations. Numerous high-frequency sites have been identified on the X chromosome, which differ in frequency between populations, and which are associated with repression of P-element transposition. Unexpectedly, sequences adjacent to high-frequency P-element sites do not show reduced levels of genetic diversity, and DNA variability is in linkage equilibrium with the presence or absence of a P element at the adjacent selected site. This might be explained by multiple insertions or through a selection for recombination analogous to that seen in 'hitchhiking'.     

What is the extent of prokaryotic diversity?

The extent of microbial diversity is an intrinsically fascinating subject of profound practical importance. The term 'diversity' may allude to the number of taxa or species richness as well as their relative abundance. There is uncertainty about both, primarily because sample sizes are too small. Non-parametric diversity estimators make gross underestimates if used with small sample sizes on unevenly distributed communities. One can make richness estimates over many scales using small samples by assuming a species/taxa-abundance distribution. However, no one knows what the underlying taxa-abundance distributions are for bacterial communities. Latterly, diversity has been estimated by fitting data from gene clone libraries and extrapolating from this to taxa-abundance curves to estimate richness. However, since sample sizes are small, we cannot be sure that such samples are representative of the community from which they were drawn. It is however possible to formulate, and calibrate, models that predict the diversity of local communities and of samples drawn from that local community. The calibration of such models suggests that migration rates are small and decrease as the community gets larger. The preliminary predictions of the model are qualitatively consistent with the patterns seen in clone libraries in 'real life'. The validation of this model is also confounded by small sample sizes. However, if such models were properly validated, they could form invaluable tools for the prediction of microbial diversity and a basis for the systematic exploration of microbial diversity on the planet.     

What is the role of endothelin system?

Endothelins are a family of three peptides of 21 amino acids with strong vasoconstrictor effects. The three peptides are encoded by three different genes and derived from precursors (" big endothelins") which are cleaved by metalloproteases, named endothelin-converting enzyme. Two receptors have been cloned, ET-A and ET-B which bind the three endothelins with various affinities. The diverse expression pattern of the endothelin system (ET) components is associated with a complex pharmacology and its counteracting physiological actions. New modulators of the ET system have been described : retinoic acid, leptin, prostaglandins, hypoxia. Endothelins can be considered as regulators working in paracrine and autocrine fashion in a variety of organs in different cellular types. The ET system has beneficial and detrimental roles in mammals. The different components have been shown to be essential for a normal embryonic and neonatal development, for renal homeostasis and maintenance of basal vascular tone. They are involved in physiological and tumoral angiogenesis. They affect the physiology and pathophysiology of the liver, muscle, skin, adipose tissue and reproductive tract. The endothelin system participates in the development of atherosclerosis as well as pulmonary hypertension, and mediates cardiac remodeling in heart failure. Elaboration of new animal models (knock-out, pathophysiological models em leader ) will allow the clear genetic dissection of physiological and pathophysiological roles of the endothelin system.     

What is the value of oncology medicines?

Coverage with evidence development (CED), rather than quality-adjusted-life-year (QALY) thresholds, offers the best way forward in balancing evidence-based policy for new oncology products with the needs of developers, payers, physicians and patients.