Two novel combined drug treatments for women with hypoactive sexual desire disorder

Low sexual desire is the most common sexual complaint in women. As a result, many women suffer from sexual dissatisfaction which often negatively interferes with their quality of life. These complaints have been classified as the condition Hypoactive Sexual Desire Disorder (HSDD), and have recently been merged with the condition Female Sexual Arousal Disorder (FSAD) into the diagnosis Female Sexual Interest/Arousal Disorder (FSIAD) in the DSM-5. To date, no drug treatment approved by the U.S. Food & Drug Administration (FDA)/European Medicines Agency (EMA) is available to treat women with HSDD/FSIAD. As a result, there is an unmet need for a drug treatment for HSDD/FSIAD. In our search for an adequate treatment we followed a different approach compared to other pharmaceutical companies. Based on a personalized sexual medicine approach we proposed that different mechanisms cause low sexual desire in women, namely an insensitive system for sexual cues or dysfunctional activation of sexual inhibitory mechanisms. Subsequently we developed two new on-demand drug treatments for women with HSDD/FSIAD based on these different causal mechanisms. One treatment (testosterone combined with a phosphodiesterase type 5 inhibitor) has been developed for women with HSDD/FSIAD due to a relatively insensitive system for sexual cues, while the second treatment (testosterone combined with a 5-HT₁A receptor agonist) has been developed for women with HSDD/FSIAD due to dysfunctional activation of sexual inhibitory mechanisms

Pharmacokinetics of a prototype formulation of sublingual testosterone and a buspirone tablet, versus an advanced combination tablet of testosterone and buspirone in healthy premenopausal women

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

Validation and IMRT/VMAT delivery quality of a preconfigured fast-rotating O-ring linac system

PURPOSE: A fast-rotating O-ring dedicated intensity modulated radiotherapy (IMRT)/volumetric modulated arc therapy (VMAT) delivery system, the Halcyon, is delivered by default with a fully preconfigured photon beam model in the treatment planning system (TPS). This work reports on the validation and achieved IMRT/VMAT delivery quality on the system. METHODS: Acceptance testing followed the vendor's installation product acceptance and was supplemented with mechanical QA. The dosimetric calibration was performed according to the IAEA TRS-398 code-of-practice, delivering 600 cGy/min at 10 cm depth, a 90 cm source-surface distance, and a 10 × 10 cm² field size. The output factors, multileaf collimator (MLC) transmission and dosimetric leaf gap (DLG) were validated by comparing measurements with the modeled values in the TPS. Validation of IMRT/VMAT was conducted following AAPM reports (MPPG 5.a, TG-119). Next, dose measurements were performed for end-to-end (E2E) checks in heterogeneous anthropomorphic phantoms using radiochromic film in multiple planes and using ionization chambers (IC) point measurements. E2E checks were performed for VMAT (cranial, rectum, spine, and head and neck) and IMRT (lung). Additionally, IROC Houston mailed dosimetry audits were performed for the beam calibration and E2E measurements using a thorax phantom (IMRT) and a head and neck phantom (VMAT). Lastly, extensive patient-specific QA was performed for the first patients of each new indication, 26 in total (nrectum = 2, nspine = 5, nlung = 5, nesophagus = 2, nhead and neck = 7, ncranial = 5), treated on the fast-rotating O-ring linac. The patient-specific QA followed the AAPM TG-218 guidelines and comprised of portal dosimetry, ArcCHECK diode array, radiochromic film dosimetry in a MultiCube phantom, and IC point measurements. RESULTS: The measured output factors showed an agreement 25 cm). TG-119's confidence limits were achieved for the VMAT point dose measurements and for both the IMRT and VMAT radiochromic film measurements. The TG-119 confidence limits were not achieved for IMRT point dose measurements in both the target (5.9%) and the avoidance structure (6.4%). All E2E tests had point differences below 2.3% and gamma agreement scores above 90.6%. The IROC beam calibration audit showed agreement of <1%. The IROC lung IMRT audit and head and neck VMAT audit had results compliant with the IROC Houston's credentialing criteria. All IMRT and VMAT plans selected for patient-specific QA were within the action limits suggested by TG-218. CONCLUSIONS: The fast-rotating O-ring linac and its preconfigured TPS are compliant with the international commissioning criteria of AAPM MPPG 5.a and AAPM TG-119. E2E measurements on heterogeneous anthropomorphic phantoms were within clinically acceptable tolerances. IROC Houston's audits satisfied the credentialing criteria. This work comprises the first extensive dataset reporting on the preconfigured fast-rotating O-ring linac.status: publishe