A phase III, single-arm, 6-month trial of a wide-dose range oral testosterone undecanoate product.

Background: Oral testosterone undecanoate (TU) formulations may provide effective, safe, and easily titratable testosterone replacement therapy. Objective: Demonstrate efficacy and safety of a novel oral TU formulation. Design: An open-label, single-arm, multi-center trial treated 155 hypogonadal men for 180 days. Treatment began at 200 mg TU twice daily with meals; doses were titrated over two 28-day cycles to between 100 and 800 mg TU daily, measuring average testosterone (T Cavg) after 90 days. Ambulatory blood pressure monitoring (ABPM) occurred at baseline, 120, and 180 days. Methods: Titrations used a randomized blood sample taken 3-, 4-, or 5-h post-morning dose. Outcomes used sodium fluoride/ethylenediaminetetraacetate plasma testosterone (T) values; serum results were also reported. Blood pressure (ABPM and in-clinic) was evaluated for change from baseline. Results: After titration, 87.8% of KYZATREX™ treated participants (worse-case scenario) and 96.1% of 90-day completers achieved eugonadal mean plasma T values. Serum T Cavg was 452 ng/dL and maximum T concentrations (T Cmax) met all FDA criteria. Participant eugonadal percentages were comparable across subgroups for age, weight, and body mass index. Diet had no effect on participant eugonadal percentages. KYZATREX was well tolerated, with no drug-related serious adverse events (SAE) and one adverse drug reaction (hypertension) observed in 2% or more of participants. Systolic ambulatory blood pressure increased 1.7 mmHg (95% confidence interval: 0.3-3.1). At baseline, 36% of 155 participants were receiving anti-hypertensive medication and 22% were diabetic. No dose increases occurred in existing anti-hypertensive medication; five participants (3.2%) started anti-hypertensive medication. Conclusion: KYZATREX provided safe and effective testosterone levels within the normal range in hypogonadal male study participants. Clinical trial registration: URL: https://clinicaltrials.gov/ unique identifier NCT04467697, conducted under NCT03198728. Post-completion, clinicaltrials.gov requested creation of the separate NCT04467697 identifier. All subjects were recruited under NCT03198728.

Frailty and Erectile Dysfunction: An Understudied Correlation

The area of geriatrics and the study of the aged are gaining prominence all over the world. In the US, the population of peopleover 65 years old is expected to reach 71 million in 10 years. Men are projected to account for approximately 43% of thepopulation. Owing to their more complex physiological and pathological state, elderly men face many challenges. Erectile functionmay diminish in elderly and vulnerable people owing to ageing, physical conditions, psychological stress, or a combinationof these factors. This propensity is more common in elderly men. This article reviews the literature on frailty syndrome anderectile dysfunction (ED) to better understand them. Complete MEDLINE/PubMed review of non-systematic literature from1990 to May 2023 was included. This topic is thoroughly researched using “frailty”, “low muscle mass”, “erectile dysfunction”,and “elderly”. Individuals with frailty tend to experience more pronounced instances of ED compared with those who are ingood health primarily owing to the anomalies present in their physiological composition. This poses challenges for individualswith physical vulnerabilities to engage in intimate relationships. ED may potentially exert a substantial influence on the mentalwell-being of older individuals or those who are otherwise vulnerable. Research demonstrates that implementing testosterone replacementtherapy (TRT) can effectively enhance erectile function among elderly individuals. This phenomenon persists despitethe knowledge that TRT is not devoid of potential adverse effects. The present investigation has revealed a significant association of frailty, exacerbated by advancing age, with the occurrence of ED. Our findings lead to the conclusion that the condition of frailty becomes more pronounced as individuals advance in age. (AU)

Oral testosterone therapy: past, present, and future.

INTRODUCTION: Testosterone replacement therapy (TRT) remains a commonly utilized treatment for men with testosterone deficiency (TD). Despite the recent FDA approval of new oral TRT medications, concerns remain regarding their efficacy and safety, and prescription rates for these medications have decreased compared to those for TD medications with other routes of administration. OBJECTIVE: In this study we sought to investigate the efficacy and safety of oral testosterone undecanoate (oTU), a new oral TRT medication. METHODS: A comprehensive review of the literature was performed using the Medline, EMBASE, and Cochrane Library databases; 1269 articles were identified, with 44 articles included in the final review and 12 used to perform meta-analyses to investigate the change in serum total testosterone (TT) and risk of adverse effects following oral testosterone undecanoate (oTU) use. Articles were also reviewed to investigate the reported effects of oTU on body composition, liver function, hematologic assays, lipid profiles, hormone assays, prostate growth, hypertension, and symptoms of TD. RESULTS: Across placebo-controlled randomized trials, there was no significant increase in TT for those receiving oTU vs placebo (mean difference, -0.26 [95% CI, -1.26 to 0.73]). On subanalysis, when eugonadal participants received oTU, a significant decrease in TT was demonstrated (mean difference -0.86 [95% CI, -1.28 to 0.43]). When participants who were hypogonadal at baseline received oTU, a significant increase in TT compared to placebo was seen (mean difference 1.25 [95% CI, 0.22-2.29]). There was no significant risk of adverse effects (RR, -0.03 [95% CI, -0.08 to 0.03]) or serious adverse effects (RR, 0.15 [95% CI, -0.66 to 0.96]) in the oTU groups compared to placebo. CONCLUSION: oTU was found to be well tolerated in hypogonadal patients, resulting in improved testosterone levels, height velocity, and sexual symptoms, without significant hepatotoxicity, prostatic enlargement, or worsening hypertension. There was no consensus regarding the effect of oTU on lean and fat mass percentages, hematologic assays, lipid profiles, mood, and general well-being.

Frailty and Erectile Dysfunction: An Understudied Correlation.

The area of geriatrics and the study of the aged are gaining prominence all over the world. In the US, the population of people over 65 years old is expected to reach 71 million in 10 years. Men are projected to account for approximately 43% of the population. Owing to their more complex physiological and pathological state, elderly men face many challenges. Erectile function may diminish in elderly and vulnerable people owing to ageing, physical conditions, psychological stress, or a combination of these factors. This propensity is more common in elderly men. This article reviews the literature on frailty syndrome and erectile dysfunction (ED) to better understand them. Complete MEDLINE/PubMed review of non-systematic literature from 1990 to May 2023 was included. This topic is thoroughly researched using "frailty", "low muscle mass", "erectile dysfunction", and "elderly". Individuals with frailty tend to experience more pronounced instances of ED compared with those who are in good health primarily owing to the anomalies present in their physiological composition. This poses challenges for individuals with physical vulnerabilities to engage in intimate relationships. ED may potentially exert a substantial influence on the mental well-being of older individuals or those who are otherwise vulnerable. Research demonstrates that implementing testosterone replacement therapy (TRT) can effectively enhance erectile function among elderly individuals. This phenomenon persists despite the knowledge that TRT is not devoid of potential adverse effects. The present investigation has revealed a significant association of frailty, exacerbated by advancing age, with the occurrence of ED. Our findings lead to the conclusion that the condition of frailty becomes more pronounced as individuals advance in age.

A comprehensive UHPLC-MS/MS method for the analysis of endogenous and exogenous steroids in serum for anti-doping purposes.

In the context of steroid analyses, the use of blood could represent a valuable complement to urine. While the blood steroid profile is currently being established to aid unveiling testosterone (T) doping, this matrix is also well suited for detection of exogenous anabolic steroids and steroid esters. In this study, a method to determine a simplified blood steroid profile in combination with the direct detection of exogenous anabolic steroids and steroid esters using just one serum aliquot was developed to obtain a comprehensive analytical workflow. Following the first chromatographic analysis of endogenous and exogenous steroids, samples were derivatised with Girard's reagent T (GT) to improve the ionisation of steroid esters and re-injected. The quantitative performance for T, androstenedione (A4) and 5α-dihydrotestosterone (DHT) was evaluated and the method was validated for qualitative analysis of exogenous analogues with estimated limits of detection (LOD) between 50 and 500 pg/ml. To demonstrate the applicability of the method, samples collected from a clinical study with an oral administration of testosterone undecanoate (TU) to 19 male volunteers were then analysed. The individual serum steroid profiles with the endogenous markers T, A4 and DHT were established as well as the concentrations of TU. TU was detected in all 19 volunteers up to 24 h, while DHT represented the most promising biomarker in endogenous steroid profile for the detection of oral TU administration. These results showed that the selected approach to combine exogenous and endogenous steroid analysis has the potential to strengthen T doping detection in the future.

Considerations when treating male pubertal delay pharmacologically.

INTRODUCTION: Delayed puberty , usually affects psychosocial well-being. Patients and their parents show concern about genital development and stature. The condition is transient in most of the patients; nonetheless, the opportunity should not be missed to diagnose an underlying illness. AREAS COVERED: The etiologies of pubertal delay in males and their specific pharmacological therapies are discussed in this review. EXPERT OPINION: High-quality evidence addressing the best pharmacological therapy approach for each etiology of delayed puberty in males is scarce, and most of the current practice is based on small case series or unpublished experience. Male teenagers seeking attention for pubertal delay most probably benefit from medical treatment to avoid psychosocial distress. While watchful waiting is appropriate in 12- to 14-year-old boys when constitutional delay of growth and puberty (CGDP) is suspected, hormone replacement should not be delayed beyond the age of 14 years . When hypogonadism is diagnosed, hormone replacement should be proposed by the age of 12 years . Testosterone replacement has been used for decades and is fairly standardized. Aromatase inhibitors have arisen as an interesting alternative . Gonadotrophin therapy seems more physiological in patients with central hypogonadism, but its efficacy and timing still need to be established.

Two-Year Analysis of a New Oral Testosterone Undecanoate (TU) Formulation in Hypogonadal Men: Efficacy, Impact on Psychosexual Function, and Safety.

BACKGROUND: Long-term data evaluating the efficacy and safety of oral testosterone undecanoate (oral TU; JATENZO) in adult hypogonadal men provides important information for healthcare professionals who prescribe testosterone replacement therapy (TRT). AIM: To determine the efficacy and safety of long-term oral TU therapy, including its impact on total testosterone (T) levels and psychosexual functioning. METHODS: Hypogonadal men, between 18 and 75 years old, (mean age 56.2; 87.2% white) who completed a 12-month, open-label, multicenter, randomized, active-controlled trial were given the opportunity to enroll in a 12-month extension study. Among the 129 eligible TU-treated subjects, 86 chose this option, and 69 completed 24 months of uninterrupted oral TU therapy. OUTCOMES: The efficacy of oral TU was documented by measuring total serum T concentrations; sexual function was measured using the Psychosexual Daily Questionnaire (PDQ). For safety, liver function tests, cardiovascular endpoints, and prostate health were measured. RESULTS: Over 2 years, total serum T concentrations for patients treated with oral TU were in the eugonadal range (300-1,000 ng/dL [10-35 nmol/L]; mean ± SD: 617 ± 427 ng/dL [21 ± 15 nmol/L]) and increased significantly from baseline (P < .0001). For sexual function, mean score changes versus baseline for all PDQ domains at all time points were significantly improved (P < .0011 for all). For the sexual activity and sexual desire components, patient scores were consistently greater than validated thresholds for clinically meaningful change. Typical T-induced safety changes were observed, including a 3-6 mm Hg increase in systolic blood pressure (P < .05); a slight increase in hematocrit (P < .0001) that stayed <48% throughout the study; no clinically significant changes in prostate-specific antigen levels; and decreased high-density lipoprotein cholesterol (-9.8 ± 0.9 mg/dL from baseline; P < .0001). There were no clinically significant changes from baseline in liver function tests. CLINICAL IMPLICATIONS: Over 2 years of treatment, this novel oral TU formulation maintained total T concentrations in mideugonadal ranges, with improvements in sexual function and no clinically significant changes in liver function or other safety concerns previously associated with oral TRT. STRENGTHS & LIMITATIONS: These are the first long-term data to evaluate the efficacy and safety of a novel formulation of oral TU; the comparative long-term safety of oral TU would be strengthened by confirmatory studies versus other TRT formulations. CONCLUSION: Oral TU offers a safe and effective long-term treatment option for men with hypogonadism. Honig S, Gittelman M, Kaminetsky J, et al. Two-Year Analysis of a New Oral Testosterone Undecanoate (TU) Formulation in Hypogonadal Men: Efficacy, Impact on Psychosexual Function, and Safety. J Sex Med 2022;19:1750-1758.

Nandrolone decanoate and testosterone undecanoate differently affect stress hormones, neurotransmitter systems, and general activity in the male rat.

Anabolic androgenic steroids (AAS) are frequently used to improve physical appearance and strength. AAS are known to affect muscle growth, but many AAS-users also experience psychiatric and behavioral changes after long-term use. The AAS-induced effects on the brain seem to depend on the type of steroid used, but the rationale behind the observed effect is still not clear. The present study investigated and compared the impact of nandrolone decanoate and testosterone undecanoate on body weight gain, levels of stress hormones, brain gene expression, and behavioral profiles in the male rat. The behavioral profile was determined using the multivariate concentric squared field test (MCSF-test). Blood plasma and brains were collected for further analysis using ELISA and qPCR. Nandrolone decanoate caused a reduction in body weight gain in comparison with both testosterone undecanoate and control. Rats receiving nandrolone decanoate also demonstrated decreased general activity in the MCSF. In addition, nandrolone decanoate reduced the plasma levels of ACTH in comparison with the control and increased the levels of corticosterone in comparison with testosterone undecanoate. The qPCR analysis revealed brain region-dependent changes in mRNA expression, where the hypothalamus was identified as the region most affected by the AAS. Alterations in neurotransmitter systems and stress hormones may contribute to the changes in behavior detected in the MCSF. In conclusion, both AAS affect the male rat, although, nandrolone decanoate has more pronounced impact on the physiological and the behavioral parameters measured.

Testosterone therapy reduces hepatic steatosis in men with type 2 diabetes and low serum testosterone concentrations.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is highly prevalent in people with diabetes with no available treatment. AIM: To explore the effect of testosterone treatment on liver. Testosterone therapy improves insulin resistance and reduces total body fat, but its impact on the liver remains poorly studied. METHODS: This secondary analysis of a 40 wk, randomised, double-blinded, placebo-controlled trial of intramuscular testosterone undecanoate in men with type 2 diabetes and lowered serum testosterone concentrations evaluated the change in hepatic steatosis as measured by liver fat fraction on magnetic resonance imaging (MRI). RESULTS: Of 88 patients enrolled in the index study, 39 had liver MRIs of whom 20 received testosterone therapy and 19 received placebo. All patients had > 5% hepatic steatosis at baseline and 38 of 39 patients met diagnostic criteria for NAFLD. Median liver fat at baseline was 15.0% (IQR 11.5%-21.1%) in the testosterone and 18.4% (15.0%-28.9%) in the placebo group. Median ALT was 34units/L (26-38) in the testosterone and 32units/L (25-52) in the placebo group. At week 40, patients receiving testosterone had a median reduction in absolute liver fat of 3.5% (IQR 2.9%-6.4%) compared with an increase of 1.2% in the placebo arm (between-group difference 4.7% P < 0.001). After controlling for baseline liver fat, testosterone therapy was associated with a relative reduction in liver fat of 38.3% (95% confidence interval 25.4%-49.0%, P < 0.001). CONCLUSION: Testosterone therapy was associated with a reduction in hepatic steatosis in men with diabetes and low serum testosterone. Future randomised studies of testosterone therapy in men with NAFLD focusing on liver-related endpoints are therefore justified.

A new oral testosterone (TLANDO) treatment regimen without dose titration requirement for male hypogonadism.

BACKGROUND: Male hypogonadism (testosterone level < 300 ng/dl) is a clinical syndrome that results from failure of the testis to produce physiological levels of testosterone. Most marketed testosterone replacement therapy products often require multiple dose adjustment clinic visits to achieve the desired, eugonadal testosterone levels. OBJECTIVE: To evaluate the efficacy and safety of a novel oral testosterone undecanoate therapy for the treatment of hypogonadism. MATERIAL AND METHODS: Ninety-five (N = 95) hypogonadal men were enrolled in this open-label, single-arm, multicenter study in the United States (NCT03242590). Subjects received 225 mg of oral testosterone undecanoate (TLANDO) twice a day for 24 days without dose adjustment. Primary efficacy was percentages of subjects who achieved mean 24-h testosterone levels within the eugonadal range and secondary efficacies were evaluated based on the upper limit of lab normal range of testosterone concentration. RESULTS: Subjects enrolled were on average age of 56 years, with about 17% of subjects older than 65 years. The mean body mass index was 32.8 kg/m2 . The baseline mean total testosterone values were below the normal range (202 ± 74 ng/dl). Post-treatment with 450 mg testosterone undecanoate daily dose without dose adjustment, 80% of subjects (95% confidence interval of 72%-88%) achieved a testosterone Cavg in the normal range and restored testosterone levels to mean testosterone Cavg of 476 ± 184 ng/dl at steady state. Testosterone restoration was comparable to other approved testosterone replacement therapy products. TLANDO was well tolerated with no deaths, no drug-related serious adverse events, and no hepatic adverse events. DISCUSSION AND CONCLUSIONS: TLANDO restored testosterone levels to the normal range in the majority of hypogonadal males. This new oral testosterone replacement therapy can provide an option for no-titration oral testosterone replacement therapy. This therapy has the potential to improve patient compliance in testosterone replacement therapy.

Testosterone Replacement Therapy: A Narrative Review with a Focus on New Oral Formulations.

Male hypogonadism affects 10-30% of the male population and is often under-recognized and under-treated. Different replacement formulations exist, each with specific benefits and limitations. These replacements include gels, patches and short- and long-acting injectables. JATENZO® (oral testosterone undecanoate; Clarus Therapeutics Inc., Northbrook, IL, US) is the first oral formulation of testosterone approved by the US Food and Drug Administration. TLANDO® (oral testosterone undecanoate; Lipocine Inc., Salt Lake City, UT, US), another oral testosterone formulation, has also recently been approved by the US Food and Drug Administration. Based on unique chemistry using a self-emulsifying drug delivery system and lymphatic absorption, JATENZO and TLANDO address some of the limitations of other dosing routes while providing a safe option without evidence of liver dysfunction. This review discusses various testosterone treatment options, focusing on the role and pharmacokinetics of the new oral formulations.

Long-term testosterone undecanoate treatment in the elderly testosterone deficient male: An observational cohort study.

BACKGROUND: Quarterly intramuscular injections with long-acting testosterone undecanoate (TU) provide stable serum testosterone concentrations over time and are therefore preferred by many testosterone-deficient patients. However, the use of long-acting TU in elderly patients is limited due to lack of safety and feasibility studies. OBJECTIVE: To investigate long-acting TU pharmacokinetics and assess differences in treatment regimens and risk of adverse outcomes in younger versus elderly testosterone-deficient patients. MATERIALS AND METHODS: Single-center longitudinal observational study. Patients who initiated long-acting TU treatment between 2005 and 2010 were included. Elderly patients were born before 1956 and younger patients between 1965 and 1985. TU dose was adjusted yearly through shortening or prolongation of time between injections. Treatment targets were as follows: (1) free testosterone between 0 and -1 SD from the age-adjusted mean, (2) no symptoms of testosterone deficiency, and (3) hematocrit within the normal range. RESULTS: The study population consisted of 63 elderly and 63 younger patients. Median follow-up time during testosterone replacement was 12.1 years. Increasing intervals between TU injections were performed 44% more often in the elderly compared to younger patients and time between TU injections were prolonged 4% more in the elderly patients. The hematocrit, as well as the hematocrit for a given serum testosterone (hematocrit: testosterone ratio), increased with treatment time but did not differ between age groups. During follow-up, 40% of patients-both elderly and younger-experienced polycythemia. Risk of polycythemia did not differ with age. DISCUSSION AND CONCLUSION: An increased number of adjustments of TU dose are necessary in elderly patients in order to reach treatment targets. TU treatment in elderly testosterone-deficient patients is not associated with an increased risk of polycythemia compared to younger patients if age-adjusted treatment targets are reached.

Correction of Androgen Deficiency in Men with Type 2 Diabetes.

BACKGROUND: In men with low levels of testosterone in the blood, it is believed that the symptoms can be regarded as an association between testosterone deficiency syndrome and related comorbidities. AIM: To investigate the effectiveness of testosterone therapy in patients with type 2 diabetes (T2D) and androgen deficiency. MATERIALS AND METHODS: Testosterone replacement therapy was carried out in 26 men with T2D and clinically or laboratory-confirmed androgen deficiency. The age of the subjects ranged from 35 to 69 years old. Laboratory studies included determinations of the concentration of the hormones estradiol, luteinizing hormone (LH), and prostate-specific antigen (PSA). The observation period was 9 months. RESULTS: The average level of total blood testosterone in the subjects before treatment was 9.4 mol/l and was likely lower than that of the control group (19.3 ± 1.6 nmol/l). The levels of total testosterone in the subjects ranged from 3.9 nmol/l to 10.7 nmol/l, and hormone levels measuring less than 8.0 nmol/l were observed in only 11 patients. After a course of testosterone replacement therapy, a stabilization in total testosterone levels at the level of reference values (as compared to the start of treatment) was observed in the blood of men with T2D after 9 months of observation and the administration of the fourth injection (16.83 ± 0.75 nmol/l). CONCLUSION: The use of long-acting injectable testosterone undecanoate leads to normalization of total testosterone levels in the blood of men with T2D and androgen deficiency, and LH levels in these patients are unlikely to change.

Exploring the efficacy of testosterone undecanoate in male children with 5α-reductase deficiency.

IMPORTANCE: Children with 5-alpha-reductase deficiency (5α-RD) and hypospadias present with micropenis, which makes it difficult to obtain sufficient tissue for urethral reconstruction. OBJECTIVE: We investigated the therapeutic effects of oral testosterone undecanoate and established a standard androgen treatment protocol for patients with 5α-RD with micropenis. METHODS: Patients with 5α-RD were treated with oral testosterone undecanoate for 3 months as a course. All patients were treated with no more than 3 courses. If the penile length (PL) reached 2.5 cm (the minimum criterion for surgery) or greater than or equal to -2.5 standard deviations (SDs) (lower limit of normal), testosterone undecanoate was considered to be effective. RESULTS: The median age of 90 patients with 5α-RD was 1.7 years (0.9, 3.1 years). The baseline PL was 1.9 ± 0.6 cm before treatment. At the end of the first course, the PL of 63 patients (70%) reached 2.5 cm, and 49 patients (54%) reached greater than or equal to -2.5 SDs. After two treatment courses, the PL of 81 patients (90%) reached 2.5 cm, and 90 patients (100%) reached greater than or equal to -2.5 SDs. After three courses, the PL of all patients reached 2.5 cm, and all patients reached a PL greater than or equal to -2.5 SDs. No abnormal increase was observed in height-SD score, weight-SD score, or ratio of bone age to chronological age during the 1-3-year follow-up. INTERPRETATION: After 3-9 months of treatment, PL increased to the target length. No severe adverse reactions were observed during follow-up. Testosterone undecanoate was safe and effective in children with 5α-RD with micropenis.

Effect of testosterone replacement therapy and mate tea (Ilex paraguariensis) on biochemical, functional and redox parameters of saliva in orchiectomized rats.

OBJECTIVE: Evaluate the effects of testosterone replacement therapy (TRT) and mate tea (MT) [Ilex paraguariensis] on biochemical, functional, and redox parameters of saliva in orchiectomized rats (ORX) DESIGN: Sixty young adult male Wistar rats (3 months old) were either castrated bilaterally or underwent fictitious surgery (SHAM) and were distributed into 5 groups: SHAM, ORX, TU (castrated rats that received a single intramuscular injection of testosterone undecanoate 100 mg/kg), MT (castrated rats that received MT 20 mg/kg, via intragastric gavage, daily), and TU + MT. All treatments started 4 weeks after castration (4 months old) and lasted 4 weeks (5 months old). At the end of treatment, pilocarpine-induced salivary secretion was collected to analyze salivary flow rate (SFR) and biochemistry composition through determination of total protein (TP), amylase (AMY), electrolyte, and biomarkers of oxidative stress. RESULTS: ORX increased SFR, salivary buffering capacity, calcium, phosphate, chloride, total antioxidant capacity, thiobarbituric acid reactive substances (TBARs), and carbonyl protein, reduced TP and AMY activity, and did not change pH, sodium, and potassium compared to SHAM. TU and TU+MT restored all salivary parameters to values of SHAM, while only TBARs and AMY returned to SHAM levels in the MT group. CONCLUSIONS: TRT with long-acting TU restored the biochemical, functional, and redox parameters of saliva in orchiectomized rats. Although MT did not have a TRT-like effect on salivary gland function, the more effective reduction in lipid oxidative damage in the MT and TU + MT groups could be considered as adjuvant to alleviate the salivary oxidative stress induced by orchiectomy.

An update on oral drug delivery via intestinal lymphatic transport.

Orally administered drug entities have to survive the harsh gastrointestinal environment, penetrate the enteric epithelia and circumvent hepatic metabolism before reaching the systemic circulation. Whereas the gastrointestinal stability can be well maintained by taking proper measures, hepatic metabolism presents as a formidable barrier to drugs suffering from first-pass metabolism. The pharmaceutical academia and industries are seeking alternative pathways for drug transport to circumvent problems associated with the portal pathway. Intestinal lymphatic transport is emerging as a promising pathway to this end. In this review, we intend to provide an updated overview on the rationale, strategies, factors and applications involved in intestinal lymphatic transport. There are mainly two pathways for peroral lymphatic transport-the chylomicron and the microfold cell pathways. The underlying mechanisms are being unraveled gradually and nowadays witness increasing research input and applications.

Development and Comparison of Intramuscularly Injected Long-acting Testosterone Undecanoate Nano-/Microcrystal Suspensions with Three Different Particle Size.

The aim of this study was to develop and compare the pharmacokinetic property of testosterone undecanoate (TU) nano-/microcrystal suspension with three different particle sizes after intramuscular (i.m.) administration. TU nano-/microcrystal suspensions were prepared by high pressure homogenization method and the mean particle size was 0.30 ± 0.11 µm (A), 1.21 ± 0.37 µm (B), and 4.83 ± 0.60 µm (C), respectively. Scanning electron microscope (SEM) was employed to observe the morphology of nano-/microcrystal suspensions after operation. X-ray Powder diffraction (XRPD) confirmed the crystalline state of TU in nano-/microcrystal suspension. After storage at 4 °C and 25 °C under mechanical shaking for 2 months, physical and chemical stabilities of nano-/microcrystal suspensions were measured by particle size analyzer and high performance liquid chromatography. There was no obvious change in particle size distribution and content of TU. After i.m. administration of suspension C to rats, the concentration of TU in plasma lasted for nearly 12 days that was comparative with the commercial testosterone undecanoate injection. The results showed that microcrystal C with a larger particle size had long-acting effect comparing with other two suspensions. The muscle irritation test in rabbits showed that the local irritation of TU nano-/microcrystal suspensions was lower than that of commercial testosterone undecanoate injection. It can be concluded that appropriate particle size of nano-/microcrystal suspensions for i.m. administration of TU was important to achieve better therapeutic effect.

Effects of a Novel Oral Testosterone Undecanoate on Ambulatory Blood Pressure in Hypogonadal Men.

BACKGROUND: Testosterone replacement therapies may increase blood pressure (BP) with chronic use but the mechanism is not clear. TLANDO™ is a new oral testosterone undecanoate (TU) under development for the treatment of male hypogonadism. METHODS: We studied the effects of the TU at 225 mg twice daily on ambulatory BP (ABP) and heart rate, in 138 men with hypogonadism (mean age, 54 years, 79% white, 48% with hypertension). Ambulatory BP and heart rate and hematologic assessments were obtained at baseline and following 4-months of therapy. RESULTS: Changes from baseline in ambulatory 24-hour, awake, and sleep systolic BP (SBP) of 3.8 (P < 0.001), 5.2 (P < 0.001), and 4.3 mmHg (P = 0.004) were observed post-treatment, respectively. Lesser changes in the diastolic BP (DBP) were observed (1.2 (P = 0.009), 1.7 (P = 0.004), and 1.7 mmHg (P = 0.011) for 24-hour, awake, and sleep, respectively). Hematocrit and hemoglobin were increased by 3.2% and 0.9 g/dL (P < 0.001), respectively. In those men in the top quartile of changes in hematocrit (range of 6% to 14%), the largest increases in ambulatory SBP (mean, 8.3 mmHg) were observed, whereas the changes in ambulatory SBP in the lower 3 quartiles were smaller (mean, 1.9, 3.3, and 2.1 mmHg in 1st, 2nd and 3 rd quartiles, respectively). CONCLUSION: These data demonstrate that small increases in ABP occurred following 4 months of the oral TU. For those men whose hematocrit rose by >6%, BP increases were of greater clinical relevance. Hence, hematocrit may aid in predicting the development of BP increases on testosterone therapy. CLINICALTRIALS.GOV IDENTIFIER: NCT03868059.

Effects of the oral testosterone undecanoate Kyzatrex™ on ambulatory blood pressure in hypogonadal men.

Testosterone replacement therapies have been shown to increase blood pressure (BP) in hypogonadal men. We studied the effects of a new formulation of testosterone undecanoate (Kyzatrex™) on ambulatory blood pressure (ABP) and heart rate, in 155 men with hypogonadism (mean age, 50.5 years, 76.8% white, 36.1% on antihypertensive therapy). The ABP, heart rate and clinical assessments were obtained at baseline and following 120 and 180 days of therapy. Mean changes from baseline in 24-h ambulatory systolic BP of 1.7 mmHg (95% CI, 0.3, 3.1) at day 120 and 1.8 mmHg (95% CI, 0.3, 3.2) at day 180 were observed post-treatment. For those men on antihypertensive drug therapy, increases in mean 24-h systolic BP were greater than those not taking antihypertensive drugs (3.4 vs 0.7 mmHg at day 120 and 3.1 vs 1.0 mmHg at day 180, respectively). Changes from baseline in 24-h diastolic BP and heart rate at day 120 were smaller (<1 mmHg and <1 beat/min, respectively). There were no relationships observed between testosterone concentration or hemoglobin levels with ABP. Multivariable analyses showed that baseline ambulatory BP and antihypertensive therapy were significantly correlated with BP changes. These data demonstrate small increases in ambulatory BP following 120 days on this oral testosterone undecanoate with no further changes at 180 days. Changes in ambulatory BP were minimal in patients not taking antihypertensive therapy.

Effects of Long-Acting Testosterone Undecanoate on Behavioral Parameters and Na + , K+-ATPase mRNA Expression in Mice with Alzheimer`s Disease.

Previous studies have shown that testosterone attenuates stress-induced mood dysfunction and memory deterioration. However, the exact mechanism is still unknown. This study was conducted to investigate the role of long-term testosterone undecanoate on the behavioral responses in AD induced by AlCl3 + D-galactose administration and the possible alteration of the gene expression level of the Na/K ATPase pump. Adult male mice received AlCl3 in drinking water (10 mg/kg/day) and (D-gal 200 mg/kg/day), subcutaneously for 90 consecutive days, then received a single intramuscular (I.M) injection of castor oil (vehicle) on day 91, while treated groups received a single I.M injection of either low (100 mg/kg/45 days) or high dose (500 mg/kg/45 days) respectively of long-acting testosterone undecanoate on day 91. The time spent in the interaction zone during the open field test, preference index to novel objects in the novel object recognition test, spontaneous alternation percentage (SAP) in Y-maze test, and escape latency time in the Morris water maze test were used to measure the locomotor activity, long-term memory, and spatial memory in mice, respectively. The results showed that testosterone undecanoate treatment improved locomotor activity, improved preference to novel objects, improved spatial memory, and reversed anxiety and depression induced by AlCl3 + D-galactose administration in male mice, suggesting the enhancement of behavioral and memory functions brought by testosterone treatment. Moreover, testosterone undecanoate treatment did alter gene expression levels of Na/K ATPase isoforms in the brain hippocampus. In most cases, altered gene expression was significant and correlated with the observed behavioral changes. Taken together, our findings provide new insight into the effects of long-acting testosterone undecanoate administration on locomotor activity, long-term memory, anxiety, and spatial memory in male mice with Alzheimer's disease.