MY-T study: Symptom-based titration decisions when using testosterone nasal gel, Natesto®.

INTRODUCTION: Natesto®, testosterone nasal gel (TNG), is a testosterone therapy (TTh) indicated for adult male hypogonadism. This study allowed titration decisions to be based on physicians' assessment of patient symptoms. METHODS: Hypogonadal males on active topical testosterone therapy (TThE) or naive to any form of testosterone therapy (TThN) were treated with 22 mg TNG daily (11 mg twice daily) for 90 days. Titration was determined by the physician at day 90 wherein the dose was increased to 33 mg daily if symptoms were not properly managed. Total testosterone (TT) levels were collected at day 90 and 120 and the quantitative Androgen Deficiency in the Aging Male (qADAM) symptom questionnaire was administered on days 0, 30, 60, 90, and 120. RESULTS: At study endpoint, 77.0% of all patients were in the normal TT range. Mean qADAM scores increased from 30.8 at baseline to 35.5 (6.6) at day 90. Physician assessments resulted in 37% patients being up-titrated for an additional 30 days, however, qADAM scores did not change significantly at the higher dose. CONCLUSIONS: The majority of patients achieved the normal range of testosterone with TNG when physicians based their titration decision on an assessment of symptoms. Sexual function and energy-related symptoms were predictive of improvements resulting from treatment. These symptoms were the most relevant indicators for physicians in making decisions relating to titration.

Efficacy of Nasal Testosterone Gel (Natesto®) Stratified by Baseline Endogenous Testosterone Levels.

OBJECTIVE: Pharmacokinetic and efficacy data from a phase 3 testosterone nasal gel (TNG) study were stratified by baseline endogenous testosterone level in patients with testosterone deficiency. Total testosterone (TT), LH, and FSH levels, as well as erectile function, mood, and lean body mass for each group were compared. In a subset of patients with very low baseline endogenous testosterone levels (<100 ng/dL), we investigated whether TNG is a suitable treatment option. MATERIALS AND METHODS: Patients with testosterone deficiency (serum TT <300 ng/dL) were treated with TNG for 3 months, followed by safety extension periods of 90 and/or 180 days. Pharmacokinetic parameters were calculated from serum hormone levels on days 30 and 90, along with efficacy measurements, which were analyzed by comparison with baseline values. Baseline and/or predose TT values were used for patient stratification. RESULTS: Prestudy and predose endogenous testosterone concentrations correlated. The maximal concentration of TT was nearly identical across all cohorts at days 30 and 90, whereas the average concentration over 24 hours had a slight positive dependence relative to predose levels. LH levels remained in the normal range but were decreased more in patients with higher starting baseline levels. These findings indicate that TNG works with an active hypothalamic-pituitary-gonadal axis that responds to each dose of TNG throughout the treatment period. Patients with the lowest endogenous testosterone levels received maximum exposure impact from each TNG dose. Patients with severe testosterone deficiency had similar efficacy improvements as the remainder of the study population. CONCLUSION: All testosterone-deficient cohorts were successfully treated with TNG.

Incorporation of multi-walled carbon nanotubes to PMMA bone cement improves cytocompatibility and osseointegration.

Acrylic bone cement (ABC) has been used as a grouting agent in joint replacement surgery for over 50 years. In particular, ABC is irreplaceable for high-load joint replacement such as total hip joint replacements (THJRs) and total knee joint replacements because of its excellent mechanical properties. However, the bioactivity of ABC needs to be improved. In this study, we attempted to enhance cytocompatibility and osseointegration of polymethyl methacrylate (PMMA) bone cement via the incorporation of multi-walled carbon nanotube (MWCNT) powders. The results of in vitro rat bone marrow mesenchymal stem cells (rBMSCs) culture on the specimens of PMMA containing different levels of MWCNT loading demonstrated that MWCNT addition improved cell adhesion and proliferation. Furthermore, it was shown from both gene and protein expression levels that MWCNT addition promoted the osteogenic differentiation. For the animal model study, PMMA specimens at different levels of MWCNT loading were implanted into a New Zealand rabbit bone defect model. The results showed that new bone formation occurred inside the bone cement and the integration between the bone cement and bone tissue were significantly enhanced with an increase in MWCNT loading level at 12 weeks post-surgery. Moreover, when the loading of MWCNT was only 1 wt%, the bone ingrowth ratio was up to 42.2% at 12 weeks, and a large number of osteoblasts congregated and new bone formed within the bone cement. In conclusion, cytocompatibility and osseointegration of the bone cements can be controlled by adjusting the MWCNT loading. The whole collection of the present results suggests that MWCNT-incorporated PMMA bone cement may have promise for use in certain orthopedic applications.

The My-T study: Patient satisfaction and preference comparing topical and nasal testosterone therapies.

INTRODUCTION: Natesto®, testosterone nasal gel (TNG) is an intranasal testosterone therapy (TTh) used to restore testosterone levels and improve symptoms of hypogonadism. Treatment requires application two (bid) or three (tid) times daily. The Treatment Satisfaction Questionnaire for Medication (TSQM) and a Patient Preference and Use (PPU) Questionnaire were used to obtain patient feedback on the use of TNG and compare to experience with topical TTh. METHODS: The study enrolled 24 TTh-naive (TThN) and 93 TTh-experienced (TThE) hypogonadal men. Treatment lasted up to 120 days, with titration at day 90 to determine the most appropriate dose for restoration of testosterone levels (11 mg bid or tid). Patient satisfaction and symptom changes were measured at days 0, 30, 60, 90, and 120. The PPU Questionnaire was performed at study entry and study completion. RESULTS: Symptoms improved from baseline (30.6) to day 90 (35.1) (p<0.0001; +15%), consistent with testosterone replacement. TNG increased scores for effectiveness (+20%), convenience (+30%), and global satisfaction (+3%) as compared to their previous topical TTh. TThE patients reported ease of use, convenience, efficacy/effectiveness, and travel friendliness as "likes" of TNG therapy. Overall, 67.2% of patients agreed or strongly agreed that they preferred TNG over topical TTh and 59% sought a prescription to continue treatment with TNG. CONCLUSIONS: Patients switching from topical TTh to TNG reported significant improvements in symptoms and patient satisfaction compared to their previous topical TTh. Patients also reported a significant improvement in convenience with TNG despite two to three times daily application. Preference, satisfaction, and convenience may translate to better treatment compliance.

Carboxyl functionalised MWCNT/polymethyl methacrylate bone cement for orthopaedic applications.

The incorporation of carboxyl functionalised multi-walled carbon nanotube (MWCNT-COOH) into a leading proprietary grade orthopaedic bone cement (Simplex P™) at 0.1 wt% has been investigated. Resultant static and fatigue mechanical properties, in addition to thermal and polymerisation properties, have been determined. Significant improvements (p ≤ 0.001) in bending strength (42%), bending modulus (55%) and fracture toughness (22%) were demonstrated. Fatigue properties were improved (p ≤ 0.001), with mean number of cycles to failure and fatigue performance index being increased by 64% and 52%, respectively. Thermal necrosis index values at ≥44℃ and ≥55℃ were significantly reduced (p ≤ 0.001) (28% and 27%) versus the control. Furthermore, the onset of polymerisation increased by 58% (p < 0.001), as did the duration of the polymerisation reaction (52%). Peak energy during polymerisation increased by 672% (p < 0.001). Peak area of polymerisation increased by 116% (p < 0.001) indicating that the incorporation of MWCNT-COOH reduced the rate of polymerisation significantly. A non-significant reduction (8%) in percentage monomer conversion was also recorded. Raman spectroscopy clearly showed that the addition of MWCNT-COOH increased the ratio between normalised intensities of the G-Band and D-Band (IG/ID ), and also increased the theoretical compressive strain (-1.72%) exerted on the MWCNT-COOH by the Simplex P™ cement matrix. Therefore, demonstrating a level of chemical interactivity between the MWCNT-COOH and the Simplex P™ bone cement exists and consequently a more effective mechanism for successful transfer of mechanical load. The extent of homogenous dispersion of the MWCNT-COOH throughout the bone cement was determined using Raman mapping.

Fatigue and biocompatibility properties of a poly(methyl methacrylate) bone cement with multi-walled carbon nanotubes.

Composites of multi-walled carbon nanotubes (MWCNT) of varied functionality (unfunctionalised and carboxyl and amine functionalised) with polymethyl methacrylate (PMMA) were prepared for use as a bone cement. The MWCNT loadings ranged from 0.1 to 1.0 wt.%. The fatigue properties of these MWCNT-PMMA bone cements were characterised at MWCNT loading levels of 0.1 and 0.25 wt.% with the type and wt.% loading of MWCNT used having a strong influence on the number of cycles to failure. The morphology and degree of dispersion of the MWCNT in the PMMA matrix at different length scales were examined using field emission scanning electron microscopy. Improvements in the fatigue properties were attributed to the MWCNT arresting/retarding crack propagation through the cement through a bridging effect and hindering crack propagation. MWCNT agglomerates were evident within the cement microstructure and the degree of agglomeration was dependent on the level of loading and functionality of the MWCNT. The biocompatibility of the MWCNT-PMMA cements at MWCNT loading levels upto 1.0 wt.% was determined by means of established biological cell culture assays using MG-63 cells. Cell attachment after 4h was determined using the crystal violet staining assay. Cell viability was determined over 7 days in vitro using the standard colorimetric MTT assay. Confocal scanning laser microscopy and SEM analysis was also used to assess cell morphology on the various substrates.

Incorporation of multiwalled carbon nanotubes to acrylic based bone cements: effects on mechanical and thermal properties.

Polymethyl methacrylate (PMMA) bone cement-multiwalled carbon nanotube (MWCNT) nanocomposites with a weight loading of 0.1% were prepared using 3 different methods of MWCNT incorporation. The mechanical and thermal properties of the resultant nanocomposite cements were characterised in accordance with the international standard for acrylic resin cements. The mechanical properties of the resultant nanocomposite cements were influenced by the type of MWCNT and method of incorporation used. The exothermic polymerisation reaction for the PMMA bone cement was significantly reduced when thermally conductive functionalised MWCNTs were added. This reduction in exotherm translated in a decrease in thermal necrosis index value of the respective nanocomposite cements, which potentially could reduce the hyperthermia experienced in vivo. The morphology and degree of dispersion of the MWCNTs in the PMMA matrix at different scales were analysed using scanning electron microscopy. Improvements in mechanical properties were attributed to the MWCNTs arresting/retarding crack propagation through the cement by providing a bridging effect into the wake of the crack, normal to the direction of crack growth. MWCNT agglomerations were evident within the cement microstructure, the degree of these agglomerations was dependent on the method used to incorporate the MWCNTs into the cement.

Influence of multiwall carbon nanotube functionality and loading on mechanical properties of PMMA/MWCNT bone cements.

Poly (methyl methacrylate) (PMMA) bone cement-multi walled carbon nanotube (MWCNT) nanocomposites with weight loadings ranging from 0.1 to 1.0 wt% were prepared. The MWCNTs investigated were unfunctionalised, carboxyl and amine functionalised MWCNTs. Mechanical properties of the resultant nanocomposite cements were characterised as per international standards for acrylic resin cements. These mechanical properties were influenced by the type and wt% loading of MWCNT used. The morphology and degree of dispersion of the MWCNTs in the PMMA matrix at different length scales were examined using field emission scanning electron microscopy. Improvements in mechanical properties were attributed to the MWCNTs arresting/retarding crack propagation through the cement by providing a bridging effect and hindering crack propagation. MWCNTs agglomerations were evident within the cement microstructure, the degree of these agglomerations was dependent on the weight fraction and functionality of MWCNTs incorporated into the cement.