Sexual Dysfunction Related to Drugs: a Critical Review. Part V: α-Blocker and 5-ARI Drugs.

UNLABELLED: Sexual dysfunction is a potential side effect of BPH (benign prostatic hyperplasia) and LUTS (lower urinary tract symptoms) drugs: this article is a critical review of the current literature. Many studies have been published on this topic. Methodological flaws limit the conclusions of these studies, mainly because of the lack of diagnostic criteria for ejaculatory and sexual desire dysfunction. Few of these studies are RCTs. The α-blocker (also called α1-adrenergic antagonist, alpha-adrenoceptor antagonist, alpha-blocker or AB) and 5-ARI (also called 5α-reductase inhibitor or testosterone-5-alpha reductase inhibitor) drugs can in particular cause erectile dysfunction, ejaculatory disorders and reduction of sexual desire. The sexual side effect profile of these drugs is different. Among the α-blockers, silodosin appears have the highest incidence of ejaculatory disorders. Persistent sexual side effects after discontinuation of finasteride has recently been reported, however further studies are needed to clarify the true incidence and the significance of this finding. It is desirable that future studies include validated tools to assess and diagnose sexual dysfunction induced by these medications, especially for ejaculation and sexual desire disorders. Only a small amount of research has intentionally set out to investigate sexual dysfunction caused by α-blocker and 5-ARI drugs: studies to specifically assess sexual dysfunction induced by these drugs are needed. Further studies are also needed to assess in the long term the role of combined therapy of phosphodiesterase type 5 inhibitors and α-blockers or 5-ARIs in treating LUTS/BPH. METHODS: This study was conducted in 2014 using the paper and electronic resources of the library of the "Azienda Provinciale per i Servizi Sanitari (APSS)" in Trento, Italy (http://atoz.ebsco.com/Titles/2793). The library has access to a wide range of databases including DYNAMED, MEDLINE Full Text, CINAHL Plus Full Text, The Cochrane Library, Micromedex healthcare series, BMJ Clinical Evidence. The full list of available journals can be viewed at http://atoz.ebsco.com/Titles/2793, or at the APSS web site (http://www.apss.tn.it). In completing this review, a literature search was conducted using the key words "benign prostatic hyperplasia drugs", "lower urinary tract symptoms drugs", "α-blockers", "5-ARIs", "sexual dysfunction", "sexual side effects", "treatment-emergent sexual dysfunction", "phosphodiesterase type 5 (PDE5) inhibitors". All resulting listed articles were reviewed. Studies published between 2002 and December 2014 were included in the review. We included all studies that explicitly reported data on sexual dysfunction during treatment with α-blockers and 5-ARIs. We also reviewed studies that have evaluated the use of phosphodiesterase type 5 (PDE5) inhibitors in combination with these drugs. The purpose was to identify possible intervention strategies for sexual dysfunction related to these drugs.

Sexual dysfunction related to drugs: a critical review. Part IV: cardiovascular drugs.

INTRODUCTION: Sexual dysfunction is a potential side effect of cardiovascular drugs: this article is a critical review of the current literature. Many studies have been published on this topic. Most of these studies are not methodologically robust, few are RCTs and most did not use a validated rating scale to evaluate sexual functioning. In addition, other methodological flaws limit greatly the conclusions of these studies. Most studies relate to male populations and only a few have been conducted on women. Also, the majority of studies on sexual dysfunction induced by cardiovascular drugs relate to antihypertensive drugs. While there is evidence to suggest that older antihypertensive drugs (diuretics, beta-blockers, centrally acting agents) have a negative impact on erectile function, newer agents seem to have either neutral (ACE inhibitors, calcium antagonists) or beneficial effects (i. e., angiotensin receptor blockers, nebivolol). Other cardiovascular drugs analyzed in this review also appear to have an inhibitory action on sexual function. For men, there is some weak evidence supporting the use of specific treatment strategies for sexual dysfunction associated with these drugs. METHODS: This study was conducted in 2014 using the paper and electronic resources of the library of the "Azienda Provinciale per i Servizi Sanitari (APSS)" in Trento, Italy (http://atoz.ebsco.com/Titles/2793). The library has access to a wide range of databases including DYNAMED, MEDLINE Full Text, CINAHL Plus Full Text, The Cochrane Library, Micromedex healthcare series, BMJ Clinical Evidence. The full list of available journals can be viewed at http://atoz.ebsco.com/Titles/2793 or at the APSS web site (http://www.apss.tn.it). In completing this review, a literature search was conducted using the key words "cardiovascular", "adrenergic beta antagonist", "α1-adrenoceptor antagonist", "angiotensin converting enzyme inhibitor", "angiotensin receptor antagonist", "angiotensin receptor blocker", "beta blocker", "beta receptor antagonist", "calcium channel blocker", "diuretic", "antihypertensive", "sexual dysfunction", "sexual side effects", "treatment-emergent sexual dysfunction". All resulting listed articles were reviewed. CONCLUSION: The review includes studies that investigated the relationship between these drug treatments and sexual dysfunction. The purpose was to identify possible intervention strategies for sexual dysfunction related to these drugs.

Sexual dysfunction related to psychotropic drugs: a critical review. Part III: mood stabilizers and anxiolytic drugs.

INTRODUCTION: Sexual dysfunction is a potential side effect of mood stabilizers and anxiolytic drugs: this article presents a critical review of the current literature. Although many studies have been published on sexual side effects of psychopharmacological treatment, only a minority relate to mood stabilizers and anxiolytic drugs. Most of these studies are not methodologically robust, few are RCTs and most did not use a validated rating scale to evaluate sexual functioning. In addition, many of the studies on sexual dysfunction associated with mood stabilizers and anxiolytic drugs are limited by other methodological flaws. While there is evidence to suggest that mood stabilizers, with some exceptions, negatively affect sexual functioning, there is still insufficient evidence to draw any clear conclusions about the effects of anxiolytic drugs on sexual function. There is some weak evidence to indicate that switching from enzyme-inducing to non-enzyme-inducing anticonvulsant drugs, could be clinically useful. Some researchers recommend that sexual dysfunction in patients taking antiepileptic drugs should in general be treated according to standard guidelines for the management of sexual dysfunction, since reliable data on special populations is not available. However, specific approaches may be useful, but cannot yet be recommended until further validating research has been conducted. We did not find evidence supporting the use of any specific treatment strategy for sexual dysfunction associated with anxiolytic treatment. METHODS: This study was conducted in 2013 using the paper and electronic resources of the library of the Azienda Provinciale per i Servizi Sanitari (APSS) in Trento, Italy (http://atoz.ebsco.com/Titles/2793). The library has access to a wide range of databases including DYNAMED, MEDLINE Full Text, CINAHL Plus Full Text, The Cochrane Library, Micromedex healthcare series, BMJ Clinical Evidence. The full list of available journals can be viewed at http://atoz.ebsco.com/Titles/2793, or at the APSS web site (http://www.apss.tn.it). In completing this review, a literature search was conducted using the key words "anxiolytic drugs", "mood stabilizers", "benzodiazepines", "psychotrophic drugs", "sexual dysfunction", "sexual side effects", "treatment-emergent sexual dysfunction". All resulting listed articles were reviewed. DISCUSSION: This review includes studies that investigated the relationship between mood stabilizer and anxiolytic drug treatment and sexual dysfunction. The purpose was to identify possible intervention strategies for sexual dysfunction related to these drugs.

Sexual dysfunction related to psychotropic drugs: a critical review part II: antipsychotics.

Sexual dysfunction is a potential side effect of antipsychotic drugs: this article presents a critical review of the current literature. Although many studies have been published on the subject, only some used a validated sexual function rating scale and most lacked either a baseline or placebo control or both. In addition, many of the studies on sexual dysfunction associated with antipsychotic medication are limited by other methodological flaws. However, there is consistent evidence to suggest that a large number of antipsychotic drugs adversely affect one or more of the 3 phases of sexual response (desire, arousal and orgasm). Among the antipsychotics, the so called "prolactin-raising" are probably most associated with sexual dysfunction, even if further studies to confirm this are needed: the reviewed literature shows no consistent evidence that any one antipsychotic drug has a significantly superior side effect profile over another and current information on this topic is often based on methodologically weak research. Clinicians must be aware of drug-induced sexual dysfunction, since its presence can have important consequences for clinical management and compliance.

Sexual dysfunction related to psychotropic drugs: a critical review--part I: antidepressants.

Sexual dysfunction is a potential side effect of antidepressant drugs: this article presents a critical review of the current literature. Although many studies have been published on this subject, only some have used a validated sexual function rating scale and most lacked either a baseline or placebo control or both. In addition, many of the studies on sexual dysfunction associated with antidepressants are limited by other methodological flaws. However, there is consistent evidence to suggest that antidepressant medication adversely affects one or more of the 3 phases of sexual response (desire, arousal and orgasm). Antidepressants with strong serotonergic properties have the highest rate of sexual side effects. Clinicians must be aware of drug-induced sexual dysfunction, since its presence can have important consequences on clinical management and compliance.

Therapeutic drug monitoring in Italian psychiatry.

INTRODUCTION: Therapeutic drug monitoring (TDM) aims to optimize pharmacotherapy treatment. Knowledge, availability and use of TDM for psychiatric patients, however, differ between countries. In this survey we analysed the practice in Italy of TDM for psychoactive drugs. METHODS: A semi-structured questionnaire was sent out to 211 mental health centres (centro di salute mentale) and 10 university hospitals from each region in Italy. RESULTS: Feedback was obtained from 44 centres. Information collected by the questionnaires indicated that in Italian psychiatry TDM is used for lithium, valproic acid and carbamazepine. With regard to clozapine, TDM was regarded as the blood cell counting which is obligatory when prescribing this drug. TDM was not employed for antidepressant or antipsychotic drug prescribing. Moreover, it appeared that only a few laboratories in Italy offer TDM services for psychiatric patients. Nevertheless, interest was expressed about receiving further information about TDM in psychiatry and participating in training programmes. DISCUSSION: This nationwide survey revealed that in Italy, TDM of psychoactive drugs is restricted to only a few drugs. In response to interest expressed, mental health workers should be educated about TDM and more laboratories should be encouraged to establish TDM services for psychotropic drugs.

[The patient's satisfaction in relation with the treatment in hospital psychiatry: a comparison between Italy and Germany]. / Behandlungszufriedenheit und Einflussfaktoren in der stationären Psychiatrie: ein deutsch/italienischer Vergleich.

The aim of this study is to compare psychiatric patients' satisfaction with their treatment in Munich and in South Tirol. For this purpose, besides clinical and social-demographic factors, for each sample-group of patients, their general satisfaction, their valuation of the different aspects of hospital treatment and life quality were considered and compared. The relevance of these elements in the global satisfaction was examined with linear multiple regression models. The results of the research show a rather high level of global satisfaction in both sample-groups, even if statistically relevant differences occur in evaluations of several aspects of the treatment. In Munich's sample-group a higher rate of satisfaction emerged in relation with the treatment: the attitude of the medical staff, the psycho-pharmacological treatments, the clinic's image and the conduct of the nursing staff. In both groups the most relevant factor for patients' satisfaction, besides the positive results of the treatment, was the attitude of the doctor, and in particular way his empathy with the patient. In regard to the age, the diagnosis and the duration of the hospitalization, it was not possible to demonstrate, in both sample-groups, any statistically relevant connection with the general satisfaction rate, while a high rate of trust in the doctors and in the medicines was found to be, in each group, a significant condition for a positive evaluation of the treatment. The influence of the personal life-quality was proven statistically relevant but weak. Altogether, regardless of the medical structure that was examined, the results underline the predominant importance of the curing doctor's social and emotional skills for patients' satisfaction.

[Predicting risk of suicide in bipolar and unipolar depression: correlation between temperament and personality]. / Prädiktion des Suizidrisikos bei bipolar und unipolar depressiven Patienten: Wechselwirkung von Temperament und Persönlichkeit.

OBJECTIVE: The aim of this study was to evaluate the roles of personality and affective temperament traits in the prediction of suicide risk in mood disorders. METHODS: The participants were 147 psychiatric inpatients with bipolar disorders I and II and major depressive disorder. Patients undertook the Temperament Evaluation of Memphis, Pisa, Paris, and San Diego self-rating questionnaire, the Minnesota Multiphasic Personality Inventory-2 (MMPI-2), and the Beck Hopelessness Scale. RESULTS: Sixty-four subjects were diagnosed with increased suicidal risk based on the Mini International Neuropsychiatric Interview (MINI). Logistic regression analysis resulted in two models predictive of MINI-based suicidal risk: irritable temperament and the MMPI-2 scale. Multiple regression analysis further indicated that higher hyperthymic values are protective against hopelessness, while MINI-based suicidal intent is a predictor of hopelessness. CONCLUSIONS: Personality and affective temperament traits may have a role in the prediction of suicide.

ACEMD: Accelerating Biomolecular Dynamics in the Microsecond Time Scale.

The high arithmetic performance and intrinsic parallelism of recent graphical processing units (GPUs) can offer a technological edge for molecular dynamics simulations. ACEMD is a production-class biomolecular dynamics (MD) engine supporting CHARMM and AMBER force fields. Designed specifically for GPUs it is able to achieve supercomputing scale performance of 40 ns/day for all-atom protein systems with over 23 000 atoms. We provide a validation and performance evaluation of the code and run a microsecond-long trajectory for an all-atom molecular system in explicit TIP3P water on a single workstation computer equipped with just 3 GPUs. We believe that microsecond time scale molecular dynamics on cost-effective hardware will have important methodological and scientific implications.

Accuracy of the lattice-Boltzmann method using the Cell processor.

Accelerator processors like the new Cell processor are extending the traditional platforms for scientific computation, allowing orders of magnitude more floating-point operations per second (flops) compared to standard central processing units. However, they currently lack double-precision support and support for some IEEE 754 capabilities. In this work, we develop a lattice-Boltzmann (LB) code to run on the Cell processor and test the accuracy of this lattice method on this platform. We run tests for different flow topologies, boundary conditions, and Reynolds numbers in the range Re=6-350 . In one case, simulation results show a reduced mass and momentum conservation compared to an equivalent double-precision LB implementation. All other cases demonstrate the utility of the Cell processor for fluid dynamics simulations. Benchmarks on two Cell-based platforms are performed, the Sony Playstation3 and the QS20/QS21 IBM blade, obtaining a speed-up factor of 7 and 21, respectively, compared to the original PC version of the code, and a conservative sustained performance of 28 gigaflops per single Cell processor. Our results suggest that choice of IEEE 754 rounding mode is possibly as important as double-precision support for this specific scientific application.

The impact of accelerator processors for high-throughput molecular modeling and simulation.

The recent introduction of cost-effective accelerator processors (APs), such as the IBM Cell processor and Nvidia's graphics processing units (GPUs), represents an important technological innovation which promises to unleash the full potential of atomistic molecular modeling and simulation for the biotechnology industry. Present APs can deliver over an order of magnitude more floating-point operations per second (flops) than standard processors, broadly equivalent to a decade of Moore's law growth, and significantly reduce the cost of current atom-based molecular simulations. In conjunction with distributed and grid-computing solutions, accelerated molecular simulations may finally be used to extend current in silico protocols by the use of accurate thermodynamic calculations instead of approximate methods and simulate hundreds of protein-ligand complexes with full molecular specificity, a crucial requirement of in silico drug discovery workflows.

Suicide methods in Europe: a gender-specific analysis of countries participating in the "European Alliance Against Depression".

OBJECTIVE: To identify the most frequent gender-specific suicide methods in Europe. DESIGN: Proportions of seven predominant suicide methods utilised in 16 countries participating in the European Alliance Against Depression (EAAD) were reported in total and cross-nationally. Relative risk (RR) relating to suicide methods and gender was calculated. To group countries by pattern of suicide methods, hierarchical clustering was applied. SETTING AND PARTICIPANTS: Data on suicide methods for 119,122 male and 41,338 female cases in 2000-4/5 from 16 EAAD countries, covering 52% of European population were obtained. RESULTS: Hanging was the most prevalent suicide method among both males (54.3%) and females (35.6%). For males, hanging was followed by firearms (9.7%) and poisoning by drugs (8.6%); for females, by poisoning by drugs (24.7%) and jumping from a high place (14.5%). Only in Switzerland did hanging rank as second for males after firearms. Hanging ranked first among females in eight countries, poisoning by drugs in five and jumping from a high place in three. In all countries, males had a higher risk than females of using firearms and hanging and a lower risk of poisoning by drugs, drowning and jumping. Grouping showed that countries might be divided into five main groups among males; for females, grouping did not yield clear results. CONCLUSIONS: Research on suicide methods could lead to the development of gender-specific intervention strategies. Nevertheless, other approaches, such as better identification and treatment of mental disorders and the improvement of toxicological aid should be put in place.

Structural transitions and arrest of domain growth in sheared binary immiscible fluids and microemulsions.

We investigate spinodal decomposition and structuring effects in binary immiscible and ternary amphiphilic fluid mixtures under shear by means of three-dimensional lattice Boltzmann simulations. We show that the growth of individual fluid domains can be arrested by adding surfactant to the system, thus forming a bicontinuous microemulsion. We demonstrate that the maximum domain size and the time of arrest depend linearly on the concentration of amphiphile molecules. In addition, we find that for a well-defined threshold value of amphiphile concentration, the maximum domain size and time of complete arrest do not change. For systems under constant and oscillatory shear we analyze domain growth rates in directions parallel and perpendicular to the applied shear. We find a structural transition from a sponge to a lamellar phase by applying a constant shear and the occurrence of tubular structures under oscillatory shear. The size of the resulting lamellae and tubes depends strongly on the amphiphile concentration, shear rate, and shear frequency.

Hybrid method coupling fluctuating hydrodynamics and molecular dynamics for the simulation of macromolecules.

We present a hybrid computational method for simulating the dynamics of macromolecules in solution which couples a mesoscale solver for the fluctuating hydrodynamics (FH) equations with molecular dynamics to describe the macromolecule. The two models interact through a dissipative Stokesian term first introduced by Ahlrichs and Dunweg [J. Chem. Phys. 111, 8225 (1999)]. We show that our method correctly captures the static and dynamical properties of polymer chains as predicted by the Zimm model. In particular, we show that the static conformations are best described when the ratio sigma/b=0.6, where sigma is the Lennard-Jones length parameter and b is the monomer bond length. We also find that the decay of the Rouse modes' autocorrelation function is better described with an analytical correction suggested by Ahlrichs and Dunweg. Our FH solver permits us to treat the fluid equation of state and transport parameters as direct simulation parameters. The expected independence of the chain dynamics on various choices of fluid equation of state and bulk viscosity is recovered, while excellent agreement is found for the temperature and shear viscosity dependence of center of mass diffusion between simulation results and predictions of the Zimm model. We find that Zimm model approximations start to fail when the Schmidt number Sc < or approximately 30. Finally, we investigate the importance of fluid fluctuations and show that using the preaveraged approximation for the hydrodynamic tensor leads to around 3% error in the diffusion coefficient for a polymer chain when the fluid discretization size is greater than 50 A.

A Monte Carlo study of amphiphilic dendrimers: spontaneous asymmetry and dendron separation.

We study via Monte Carlo simulation the conformation of amphiphilic dendrimers for which terminal monomers (t) and internal monomers (i) interact differently with the solvent (s). Specifically, we have studied g = 3,6 dendrimers as a function of chi(it), chi(is), and chi(ts) (chi is the differential contact energy between the different particles) for parameter values chi(it) = 0, +/-1 and -1 < chi(is), chi(ts) < 1. We have allowed negative chi values in order to model attractive polar interactions (e.g., hydrogen bonding) which are believed to be important in many dendrimer/solvent systems. We find the "phase diagram" of dendrimer conformations to be extremely rich and to be a strong function of g, chi(is), and chi(ts) but only a weak function of chi(it), For chi(is), chi(ts) > 0, we observe dendrimer conformations, such as unimolecular normal micelles and inverted loopy micelles. However, for chi(is) < 0 or chi(ts) < 0, we observe more exotic molecular conformations, for example, the spontaneous development of asymmetry and dendron separation. These properties are analyzed in terms of snapshots as well as more quantitatively in terms of the radii of gyration, radial density profiles, pair-correlation functions, degree of asymmetry, and dendron overlap factor. By exploiting the dramatic conformational changes under different solvent conditions, we suggest the possibility of using amphiphilic dendrimers as stimuli-responsive smart materials.

Monte Carlo simulation of dendrimers in variable solvent quality.

We study via lattice Monte Carlo simulation and Flory theory the properties of g=1-6 dendrimers in variable solvent quality. For all the generations studied, we find that the radius of gyration R(g) collapses significantly (factor of 2) going from athermal to extreme poor solvent conditions, indicating that varying solvent quality is an effective means of controlling dendrimer size. We also find that in athermal, theta, and extreme poor solvent conditions, the radius of gyration of dendrimers scales with the total number of monomers roughly as R(g) approximately N(1/3). However, a more careful analysis shows that in athermal and theta solvents, there is, in fact, a small but systematic deviation of R(g) from R(g) approximately N(1/3) scaling and the simulation data is described better by the Flory theory prediction of R(g) approximately N(1/5)[(g+1)m](2/5) in athermal solvents and R(g) approximately N(1/4)[(g+1)m](1/4) in theta solvents. We also find for our simulation data that stronger deviations from constant density scaling are possible, with scaling behavior as shallow as R(g) approximately N(0.26) possible for solvent conditions in between theta and the completely collapsed state. It is evident therefore that dendrimers do not obey (or even approximately obey) R(g) approximately N(1/3) scaling under all solvent conditions. Under all solvent conditions, we find that the intramolecular density is dense corelike (i.e., the density maximum is in the interior of the dendrimer) and terminal groups are delocalized throughout the dendrimer.

Intravenous valproate loading in acutely manic and depressed bipolar I patients.

Recently, valproate has emerged as a drug of primary choice for the treatment of acute mania, especially mixed mania and, partially, rapid cycling. Because of its relative safety, it can be administered in high doses as an oral loading therapy, with approximately 60% to 70% of patients showing a favorable response. Here we report on seven bipolar I patients, two of which have euphoric mania, three have a mixed manic state (including one patient with ultra-rapid cycling and one with very prominent depressed features), and two have solely depressed mood. All but one of the manic patients showed a rapid and favorable response to intravenous valproate loading, which built up sufficient blood levels that were maintained by subsequent oral treatment. Of the two patients with solely depressed mood, however, one experienced only minor benefits and the other showed no change in the depressive symptomatology. Intravenous valproate was tolerated without problems and also led to a drastic reduction in and eventual withdrawal of benzodiazepine treatment in two cases. All of the patients showed a drastic remission of mania with valproate blood levels at or only slightly above 50 microg/mL (blood drawn 12 hours after last application). It is interesting to note that one patient who was previously nonresponsive to oral valproate loading responded well to intravenous valproate. Besides the obvious efficacy and safety of this treatment regimen, these findings may also imply that a difference in pharmacokinetics with intravenous loading may result in a quick saturation of plasma-binding proteins, and hence, peak concentrations of valproate may be reached rapidly, which could contribute to the beneficial action, even in patients previously nonresponsive to oral valproate.