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Phenotype Prediction Scores (PPS) might be powerful tools to predict traits or the efficacy of treatments based on combinations of Single-Nucleotide Polymorphism (SNPs) in large samples. We developed a novel method to produce PPS models for small samples sizes. The set of SNPs is first filtered on those known to be relevant in biological pathways involved in a clinical condition, and then further filtered repeatedly in a survival strategy to select stabile positive/negative risk alleles. This method is applied on Female Sexual Interest/Arousal Disorder (FSIAD), for which two subtypes has been proposed: 1) a relatively insensitive excitatory system in the brain for sexual cues, and 2) a dysfunctional activation of brain mechanisms for sexual inhibition. A double-blind, randomized, placebo-controlled cross-over experiment was conducted on 129 women with FSIAD. The women received three different on-demand drug-combination treatments during 3 two-week periods: testosterone (0.5 mg) + sildenafil (50 mg), testosterone (0.5 mg) + buspirone (10 mg), or matching placebos. The resulted PPS were independently validated on patient-level and group-level. The AUC scores for T+S of the derivation set was 0.867 (95% CI = 0.796–0.939; p<0.001) and was 0.890 (95% CI = 0.778–1.000; p<0.001) on the validation set. For T+B the AUC of the derivation set was 0.957 (95% CI = 0.921–0.992; p<0.001) and 0.869 (95% CI = 0.746–0.992; p<0.001) for the validation set. Both formulas could reliably predict for each drug who benefit from the on-demand drugs and could therefore be useful in clinical practice. [ABSTRACT FROM AUTHOR]

Data from clinical trials investigating on-demand medication often consist of an intentionally varying number of measurements per patient. These measurements are often observations of discrete events of when the medication was taken, including for example data on symptom severity. In addition to the varying number of observations between patients, the data have another important feature: they are characterized by a hierarchical structure in which the events are nested within patients. Traditionally, the observed events of patients are aggregated into means and subsequently analyzed using, for example, a repeated measures ANOVA. This procedure has drawbacks. One drawback is that these patient means have different standard errors, first, because the variance of the underlying events differs between patients and second, because the number of events per patient differs. In this paper, we argue that such data should be analyzed by applying a multilevel analysis using the individual observed events as separate nested observations. Such a multilevel approach handles this drawback and it also enables the examination of varying drug effects across patients by estimating random effects. We show how multilevel analyses can be applied to on-demand medication data from a clinical trial investigating the efficacy of a drug for women with low sexual desire. We also explore linear and quadratic time effects that can only be performed when the individual events are considered as separate observations and we discuss several important statistical topics relevant for multilevel modeling. Taken together, the use of a multilevel approach considering events as nested observations in these types of data is advocated as it is more valid and provides more information than other (traditional) methods. [ABSTRACT FROM AUTHOR]

Aim The aim was to compare the pharmacokinetic profiles of two formulations of a combination drug product containing 0.5 mg testosterone and 50 mg sildenafil for female sexual interest/arousal disorder. The prototype (formulation 1) consists of a testosterone solution for sublingual administration and a sildenafil tablet that is administered 2.5 h later. The dual route/dual release fixed dose combination tablet (formulation 2) employs a sublingual and an oral route for systemic uptake. This tablet has an inner core of sildenafil with a polymeric time delay coating and an outer polymeric coating containing testosterone. It was designed to increase dosing practicality and decrease potential temporal non-adherence through circumventing the relatively complex temporal dosing scheme. Methods Twelve healthy premenopausal subjects received both formulations randomly on separate days. Blood was sampled frequently to determine the pharmacokinetics of free testosterone, total testosterone, dihydrotestosterone, sildenafil and N-desmethyl-sildenafil. Results Formulation 2 had a higher maximum concentration ( Cmax) for testosterone, 8.06 ng ml-1 (95% confidence interval [CI] 6.84, 9.28) and higher area under the plasma concentration-time curve (AUC), 7.69 ng ml-1 h (95% CI 6.22, 9.16) than formulation 1, 5.66 ng ml-1 (95% CI 4.63, 6.69) and 5.12 ng ml-1 h (95% CI 4.51, 5.73), respectively. Formulation 2 had a lower Cmax for sildenafil, 173 ng ml-1 (95% CI 126, 220) and a lower AUC, 476 ng ml-1 h (95% CI 401, 551) than formulation 1, 268 ng ml-1 (95% CI 188, 348) and 577 ng ml-1 h (95% CI 462, 692), respectively. Formulation 2 released sildenafil after 2.75 h (95% CI 2.40, 3.10). Conclusions The dual route/dual release fixed dose combination tablet fulfilled its design criteria and is considered suitable for further clinical testing. What is Already Known about this Subject Female sexual interest/arousal disorder (FSIAD) is a significant problem impacting psychological well-being, but the pharmacotherapeutic options for this problem are lacking., The combined, on-demand, sublingual administration of low dose sublingual testosterone and oral administration of sildenafil is a novel pharmacotherapeutic option under development for FSIAD., In proof-of-concept trials, these compounds were successfully administered via different dosage forms (sublingual and oral) at different time points (separated by 2.5 h) because of their markedly different pharmacokinetic-pharmacodynamic profiles. For future larger scale studies and the clinical practice, this raises obvious adherence issues., What this Study Adds A newly developed dual route/dual release fixed dose combination tablet containing testosterone and sildenafil mimics the pharmacokinetic profile of these components when they are administered as different dosage forms, 2.5 h apart., This combination tablet is a suitable final pharmaceutical drug product that will be used in future studies. [ABSTRACT FROM AUTHOR]

The study aimed to compare the kinetics of two novel combination drug products for Female Sexual Interest/Arousal Disorder (FSIAD). Thirteen women received testosterone via the sublingual route followed 2.5 hours later by a buspirone tablet, versus a single combination tablet swallowed at once. The first clinical prototype consisted of a sublingual solution containing testosterone (0.5 mg) complexed with cyclodextrin and a tablet containing 10 mg buspirone, in a gelatin capsule to ensure blinding during the clinical studies. The innovative fixed-combination tablet consists of an inner-core component of 10 mg buspirone coated with a polymeric time-delay coating and an outer polymeric coating containing testosterone with hydroxypropyl-beta cyclodextrin. We observed an immediate testosterone pulse absorption from both formulations. We also demonstrated that there was adequate absorption of buspirone (>80 % relative to the conventional tablet) and a time delay in release of buspirone of 3.3 hours, close to the 3.0 hours of the reference formulation that showed clinical efficacy in early proof-of-principle studies. The newly developed combination tablet fulfils its design criteria and is a convenient tablet for further clinical studies in FSIAD. [ABSTRACT FROM AUTHOR]

In two experiments selective attention to angry faces was investigated in relation to trait anger and anxiety. A pictorial emotional Stroop task comparing colour-naming latencies for neutral and angry faces was employed. In Experiment 1 using an unmasked task, individuals scoring high on trait anger showed an attentional bias for angry faces. In Experiment 2, unmasked and masked versions of the task were used. Individuals were selected on low and high trait anxiety, but there was no indication of a relation between attentional bias scores and anxiety. When individuals were subsequently reallocated to groups on the basis of trait anger scores, the high anger group showed an attentional bias for angry faces in the unmasked and the masked task. Results are discussed in relation to recent neurobiological findings from our laboratory, as reflecting an evolutionary-evolved, content-specific response to the facial expression of anger. [ABSTRACT FROM AUTHOR]

Background: The assumption that testosterone is involved in human female sexual functioning is mainly based on results of studies of women with hypogonadotropic hypogonadism. This study sought to determine the effect of testosterone administration on physiological and subjective sexual arousal in sexually functional women. Methods: In a double-masked, randomly assigned, placebo-controlled crossover design, we examined whether administration of a single dose of testosterone to sexually functional women increases vaginal and subjective sexual arousal when they are exposed to erotic visual stimuli. To search for a time lag in the effect of testosterone therapy, we exposed 8 healthy women to 6 erotic film excerpts depicting intercourse. The first and second excerpts were shown immediately before and 15 minutes after, respectively, intake of placebo or testosterone; the last 4 excerpts were then shown at 1½-hour intervals. Results: Sublingual intake of testosterone caused a sharp increase in plasma testosterone levels within 15 minutes; these levels declined to baseline values within 90 minutes. Three to 4½ hours after reaching peak testosterone level, we found a statistically significantly increase in genital responsiveness (P = .04). Furthermore, on the day of testosterone treatment, there also was a strong and statistically significant association between the increase in genital arousal and subjective reports of "genital sensations" (P = .02) and "sexual lust" (P = .01) after 4½ hours. Conclusions: There is a time lag in the effect of sublingually administered testosterone on genital arousal in women. In addition, a consecutive increase in vaginal arousal might cause higher genital sensations and sexual lust. [ABSTRACT FROM AUTHOR]