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Results from randomized clinical trials of psilocybin in depressive disorders highlight the therapeutic potential of serotonergic psychedelic compounds in mental health disorders. The synthetic 5-hydroxytryptamine 2A receptor agonist 4-hydroxy-N,N-diisopropyltryptamine (4-OH-DiPT) is structurally similar to psilocin but is reported to have a shorter duration (2-3 h) of psychedelic effects, suggesting the potential for psilocybin-like therapeutic activity with reduced clinical resource burden. Here, we describe the preclinical and translational characterization of RE104, a 4-OH-DiPT prodrug comprising a glutarate moiety designed to cleave rapidly in situ and thus provide reasonable bioavailability of the active drug. Plasma concentration of 4-HO-DiPT over time in PK experiments in rats was correlated with head-twitch intensity. The half-life of 4-OH-DiPT was 40 min after subcutaneous administration of RE104 in rats. In a forced swim test, a single dose of RE104 (1 mg/kg) significantly reduced mean immobility time at 1 week compared with vehicle (P < 0.001), confirming translational antidepressant potential. Taken together, these data with RE104 show that the glutarate ester can act as an efficient prodrug strategy for 4-HO-DiPT, a unique short-duration psychedelic with potential in depressive disorders.
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Alucinógenos , Pró-Fármacos , Ratos Sprague-Dawley , Animais , Pró-Fármacos/farmacologia , Pró-Fármacos/síntese química , Alucinógenos/farmacologia , Alucinógenos/síntese química , Masculino , Ratos , Triptaminas/farmacologia , Triptaminas/síntese química , Triptaminas/química , Antidepressivos/farmacologia , Antidepressivos/síntese químicaRESUMO
INTRODUCTION: Testosterone (T) replacement therapy causes suppression of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) that can lead to decrease in semen parameters and possible infertility. Different T formulations may have varying suppression on FSH and LH. OBJECTIVE: To study whether shorter-acting T (multiple daily dosing) has less suppression on FSH and LH serum levels compared with longer-acting T (transdermal gel, injectable). METHODS: A systematic literature search was conducted by following the protocol based on Preferred Reporting Items for Systematic Reviews and Meta-Analysis protocols. We comprehensively reviewed the literature by systematically searching manuscripts indexed in PubMed from 1995 to March 13, 2019 to identify studies reporting changes in FSH and LH in hypogonadal men treated with exogenous T which evaluated the effect of exogenous T on FSH and LH. RESULTS: A total of 8 studies reported the effect of T on FSH and LH in 793 hypogonadal men: 2 used long-acting injectables (enanthate or undecanoate) in a total of 16 men, 5 used intermediate-acting daily topical gels or patches in a total of 471 men, and 1 used short-acting intranasal T (125 µL/nostril, twice a day or three times a day) in 306 men. Long-acting injectables decreased FSH by 86.3%, intermediate-acting daily gels/patches decreased FSH by 60.2%, and short-acting intranasal gel decreased FSH by 37.8%. Long-acting injectables decreased LH by 71.8%, intermediate-acting daily gels/patches decreased LH by 59.2%, and short-acting intranasal gel decreased LH by 47.3%. CONCLUSIONS: Our findings suggest that short-acting T preparations do not decrease serum FSH or LH to the same extent as longer-acting transdermal gels and injectables. However, further clinical trial data are necessary to determine whether the effect of short-acting TRT on gonadotropins translates into similar changes in semen parameters and fertility. Masterson TA, Turner D, Vo D, et al. The Effect of Longer-Acting vs Shorter-Acting Testosterone Therapy on Follicle Stimulating Hormone and Luteinizing Hormone. Sex Med Rev 2021;9:143-148.
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Hormônio Foliculoestimulante , Testosterona , Humanos , Hormônio Luteinizante , MasculinoRESUMO
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.
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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.
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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.
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INTRODUCTION: NATESTO® testosterone nasal gel (TNG) is a liquid gel that is applied in the nose for the treatment of male hypogonadism. There is a reasonable concern that administration of TNG to patients with active rhinitis could modify absorption. Results from two clinical studies are reported wherein subjects with allergic rhinitis (AR) subjects are treated with TNG. METHODS: The 24-hour pharmacokinetics (PK) and relative bioavailability of serum total testosterone (sTT) from TNG (11 mg tid ) were determined using a phase 1 Latin-square design with 18 eugonadal AR subjects crossed over between asymptomatic, symptomatic-untreated, and symptomatic-treated (oxymetazoline) conditions. Allergy symptoms, assessed using Total Nasal Symptom Score (TNSS), were induced using grass pollen in an allergy challenge chamber (ACC) prior to administration of TNG. The data are discussed in relation to results from a phase 3 study in 306 hypogonadal patients which compare clinical outcomes of AR and non-AR patients treated with TNG. RESULTS: PK analysis (Tmax, maximum observed concentration [Cmax], area under the curve [AUC]) of sTT showed no difference in the rate or extent of absorption of exogenous testosterone from TNG as a function of allergy symptoms. The relative bioavailability also showed all three conditions to be equivalent. However, pre-dose mean sTT in AR patients was 21-25% lower when symptomatic vs. asymptomatic, which is attributed to the allergic reaction. A large phase 3 study, based predominantly on PK measures of sTT, showed that clinical outcomes for AR and non-AR patients treated with TNG were identical, including the percentage of patients in the eugonadal range, hormone profiles, and adverse events. CONCLUSIONS: AR does not affect absorption of TNG. Patient outcomes for long-term treatment with TNG for up to one year are not dependent on AR history.