RESUMEN
INTRODUCTION: Hair loss is driven by multiple factors, including genetics. Androgenetic alopecia (AGA) is a condition in which treatments necessitate prolonged compliance with prescribed medications. We have developed IVL3001, a long-acting injectable (LAI) formulation of finasteride encapsulated within poly lactic-co-glycolic acid microspheres, to enhance the efficacy of the finasteride and to achieve consistent positive outcomes in adults. An open-label, sequential, single-dose phase I clinical trial was designed to evaluate the safety, pharmacokinetic (PK), and pharmacodynamic (PD) of IVL3001. METHODS: A total of 40 non-smoking, healthy adult males were divided into three cohorts where the IVL3001 group received a single subcutaneous injection of 12-36 mg IVL3001 and 1 mg finasteride (Propecia®) once daily for 28 days. The plasma concentrations of finasteride, dihydrotestosterone (DHT), and testosterone were measured using liquid chromatography-tandem mass spectrometry. The tolerability of the injections was assessed, and compartment models were developed to predict the effective dose and assess PK/PD profiles. RESULTS: IVL3001 and finasteride 1 mg tablets were well tolerated. IVL3001 showed consistent plasma concentrations without bursts or fluctuations. Consistent with its mechanism of action, IVL3001 reduced DHT levels. Simulation data showed that the administration of 12-36 mg of IVL3001 every 4 weeks achieved plasma concentrations similar to finasteride, with comparable DHT reduction. CONCLUSION: The present study represents the first clinical trial to evaluate the safety, pharmacokinetic (PK), pharmacodynamic (PD), and tolerability of finasteride long-acting injectables (LAI) in adults. The rapid onset of action sustained effective drug concentration and the prolonged half-life of IVL3001 suggest that it offers multiple benefits over conventional oral formulations in terms of therapeutic response and compliance. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT04945226.
Asunto(s)
Inhibidores de 5-alfa-Reductasa , Alopecia , Finasterida , Humanos , Finasterida/farmacocinética , Finasterida/administración & dosificación , Finasterida/efectos adversos , Alopecia/tratamiento farmacológico , Masculino , Adulto , Inhibidores de 5-alfa-Reductasa/farmacocinética , Inhibidores de 5-alfa-Reductasa/administración & dosificación , Inhibidores de 5-alfa-Reductasa/efectos adversos , Inhibidores de 5-alfa-Reductasa/farmacología , Dihidrotestosterona/farmacocinética , Dihidrotestosterona/administración & dosificación , Dihidrotestosterona/sangre , Persona de Mediana Edad , Preparaciones de Acción Retardada , Testosterona/farmacocinética , Testosterona/sangre , Inyecciones Subcutáneas , Adulto Joven , MicroesferasRESUMEN
The purpose of this study was to compare the characteristics of testosterone polylactic-co-glycolic (PLGA) microspheres prepared by a paddle mixer or microfluidics device. The comparison was conducted by not only in vitro evaluation but also in vivo evaluation which has not been reported up to date. We discovered that, among the steps in microsphere preparation, the solvent removal process strongly impacted drug content, particle size and surface morphology. Spectroscopic measurements suggested that molecular interactions and crystallinity of the drug incorporated in the microspheres differed. For the drug release profile, although both mixer- and microfluidics-prepared samples showed similar sustained release of the incorporated drug for approximately one month in vitro, they exhibited different plasma concentration profiles in vivo. Together, our findings show that the preparation process, especially the solvent removal process, may affect the physicochemical characteristics of testosterone PLGA microspheres, leading to different in vivo performance.
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Liberación de Fármacos , Microesferas , Tamaño de la Partícula , Copolímero de Ácido Poliláctico-Ácido Poliglicólico , Testosterona , Testosterona/administración & dosificación , Testosterona/farmacocinética , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/química , Animales , Masculino , Ácido Láctico/química , Ácido Poliglicólico/química , Composición de Medicamentos/métodos , Dispositivos Laboratorio en un Chip , Microfluídica/métodos , Preparaciones de Acción RetardadaRESUMEN
CONTEXT: Injections with intramuscular (IM) testosterone esters have been available for almost 8 decades and not only result in predictable serum testosterone levels but are also the most inexpensive modality. However, they are difficult to self-administer and associated with some discomfort. Recently, subcutaneous (SC) administration of testosterone esters has gained popularity, as self-administration is easier with this route. Available data, though limited, support the feasibility of this route. Here we review the pharmacokinetics and safety of SC testosterone therapy with both long- and ultralong-acting testosterone esters. In addition, we provide guidance for clinicians on how to counsel and manage their patients who opt for the SC route. EVIDENCE ACQUISITION: Systematic review of available literature on SC testosterone administration including clinical trials, case series, and case reports. We also review the pharmacology of testosterone absorption after SC administration. EVIDENCE SYNTHESIS: Available evidence, though limited, suggests that SC testosterone therapy in doses similar to those given via IM route results in comparable pharmacokinetics and mean serum testosterone levels. With appropriate training, patients should be able to safely self-administer testosterone esters SC with relative ease and less discomfort compared with the IM route. CONCLUSION: Although studies directly comparing the safety of SC vs IM administration of testosterone esters are desirable, clinicians should consider discussing the SC route with their patients because it is easier to self-administer and has the potential to improve patient adherence.
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Hipogonadismo/tratamiento farmacológico , Procedimientos de Reasignación de Sexo/métodos , Testosterona/administración & dosificación , Estudios de Factibilidad , Femenino , Humanos , Hipogonadismo/sangre , Inyecciones Intramusculares , Inyecciones Subcutáneas , Masculino , Autoadministración/métodos , Procedimientos de Reasignación de Sexo/efectos adversos , Testosterona/efectos adversos , Testosterona/sangre , Testosterona/farmacocinética , Personas TransgéneroRESUMEN
CONTEXT: There is no licensed oral native testosterone (NT) because of challenges in the formulation. Licensed oral formulations of the ester, testosterone undecanoate (TU), require a meal for absorption and generate supraphysiological dihydrotestosterone (DHT) levels. OBJECTIVE: To develop an oral NT formulation. DESIGN AND METHODS: A lipid-based formulation of native testosterone filled into soft-gelatin capsules at 40 mg per capsule was designed with 2 years of stability at ambient temperature. Pharmacokinetic comparison studies of this oral lipidic NT formulation to oral TU were conducted in dogs and hypogonadal men. RESULTS: In dogs, 40 mg NT was well absorbed under fasted conditions whereas 40 mg TU required a high-fat meal: for NT, the mean fed/fasted AUC ratio was 1.63 and for TU 7.05. In hypogonadal men, fed and fasted NT had similar pharmacokinetics: Cmax mean 26.5 vs 30.4 nmol/L (769 vs 882 ng/dL), AUC0-10 h 87 vs 88.6 h nmol/L. NT (fed state) showed a testosterone AUC increase of 45% between 120 and 200 mg, and NT 200 mg gave a similar mean AUC0-10 h to TU 80 mg: 87 vs 64.8 h nmol/L. Serum TU levels were variable and on a molar basis were ~ten-fold higher than serum testosterone levels after TU 80 mg fed. The DHT: testosterone AUC0-10 h ratio was more physiological for NT than TU being 0.19 vs 0.36. There were no emerging safety concerns with NT. CONCLUSION: This novel oral lipidic native testosterone formulation has potential advantages over oral TU of dosing independently of food and a lower risk of supraphysiological DHT levels. Significance statement There is no licensed oral testosterone because of challenges in formulation, and the oral formulations of the ester, testosterone undecanoate, require a fatty meal for absorption and generate supraphysiological dihydrotestosterone levels. We have overcome the design challenges and formulated an oral native testosterone that can be taken with or without food and provides physiological levels of testosterone and dihydrotestosterone in hypogonadal men. This formulation, DITEST, has the potential advantage of being oral for patients who do not tolerate injections and less risk of adverse events that might theoretically be associated with elevated dihydrotestosterone levels. Future studies will need to define the dosing regimen for replacement in hypogonadal men.
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Interacciones Alimento-Droga , Lípidos/química , Testosterona/administración & dosificación , Testosterona/química , Administración Oral , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Animales , Área Bajo la Curva , Grasas de la Dieta , Perros , Composición de Medicamentos , Femenino , Alimentos , Humanos , Hipogonadismo/tratamiento farmacológico , Hipogonadismo/metabolismo , Absorción Intestinal , Masculino , Persona de Mediana Edad , Testosterona/farmacocinética , Adulto JovenRESUMEN
Intramuscular testosterone undecanoate is indicated as testosterone replacement in adult males with a deficiency in or absence of endogenous testosterone (hypogonadism). Intramuscular testosterone undecanoate 750 mg is approved to be administered at initiation and at 4 weeks, followed by a maintenance dose every 10 weeks. However, a more frequent maintenance regimen may improve symptom management of low testosterone at the end of each dosing interval. The current objective was to develop a population pharmacokinetic (PK) model for intramuscular testosterone undecanoate 750 mg and to perform PK simulations to assess the impact of an 8-week maintenance regimen on testosterone exposure. A 1-compartment model with first-order absorption and first-order elimination best described the PK of testosterone undecanoate. The model included time-dependent suppression and gradual recovery of endogenous testosterone production during testosterone undecanoate administration. Significant covariates included body weight and sex hormone-binding globulin level. With the final PK model, simulations were performed to evaluate the impact of an 8-week vs a 10-week maintenance regimen on testosterone exposure. The 8-week testosterone undecanoate regimen had a predicted 11% increase in average concentration and last observed concentration during a dosing interval before a subsequent dose and a 5% increase in maximum concentration. This translated into an ≈10% increase in the percentage of patients predicted to have a last observed concentration during a dosing interval before a subsequent dose >300 ng/dL, minimal change in the percentage of patients with average concentration in the normal range, and a low likelihood of maximum concentration >2500 ng/dL. These simulations suggest that more frequent administration of intramuscular testosterone undecanoate may be beneficial in some patients. Further clinical evaluation of an 8-week dose regimen is warranted.
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Hipogonadismo/tratamiento farmacológico , Testosterona/análogos & derivados , Adulto , Anciano , Peso Corporal , Humanos , Inyecciones Intramusculares , Masculino , Persona de Mediana Edad , Modelos Biológicos , Globulina de Unión a Hormona Sexual/análisis , Testosterona/administración & dosificación , Testosterona/farmacocinética , Factores de TiempoRESUMEN
5α-reductase inhibitors (5-ARIs) are considered by the World Anti-doping Agency as potential confounding factors in evaluating the athlete steroid profile, since they may interfere with the urinary excretion of several diagnostic compounds. We herein investigated 5α-reductase inhibitors from a different perspective, by verifying their influence on the carbon isotopic composition of 5α- and 5ß-reduced testosterone and nandrolone metabolites. The GC-C-IRMS analysis was performed on a set of urine samples collected from three male Caucasian volunteers after the acute and chronic administration of finasteride in combination with the intake of 19-norandrostenedione, a nandrolone precursor. The excretion and the isotopic profile of androsterone (A), etiocholanolone (Etio) 5α-androstane-3α,17ß-diol (5αAdiol), and 5ß-androstane-3α,17ß-diol (5ßAdiol) were determined as well as those of 19-norandrosterone (19-NA) and 19-noretiocholanolone (19-NE). Pregnanediol (PD) and pregnanetriol (PT) were also measured as endogenous reference compounds to define the individual endogenous isotopic profile. Our results confirmed the impact of finasteride, especially if chronically administered, on the enzymatic pathway of testosterone and nandrolone, and pointed out the influence of 5-ARIs on δ13 C values of the selected target compounds determined in the IRMS confirmation analysis.
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Inhibidores de 5-alfa-Reductasa/farmacología , Nandrolona/análisis , Detección de Abuso de Sustancias/métodos , Testosterona/análisis , Inhibidores de 5-alfa-Reductasa/administración & dosificación , Adulto , Doping en los Deportes/prevención & control , Finasterida/administración & dosificación , Finasterida/farmacología , Cromatografía de Gases y Espectrometría de Masas , Humanos , Masculino , Persona de Mediana Edad , Nandrolona/farmacocinética , Testosterona/farmacocinéticaRESUMEN
Investigations were performed on the determination of the main components in Berchemia lineata (L.) DC. (BL) and its metabolism with human liver microsomes (HLM). A total of 35 compounds were detected in BL extracts and 25 of them including 6 naphthopyrones, 10 flavonoids, 2 phenolic acids, 2 phenols, 4 fatty acids and 1 quinone were unambiguously or tentatively identified by UPLC-QTOF-MS/MS. Among them, naphthopyrones were first identified in BL extracts and labelled in chromatography. In addition, the weak inhibitory effects of BL extracts (IC50ï¼149.25 µg/mL) and rubrofusarin-6-O-α-L-rhamnosyl-(1-6)-O-ß-D-glu-copyranside (the main component of BL extracts, M0; IC50ï¼82.14 µM) on CYP3A4 were also proved using testosterone as specific probe drug. The main metabolic pathway of M0 by HLM was hydroxylation in its aglycone, the metabolite was tentatively identified as 10-hydroxy-rubrofusarin-6-O-α-L-rhamnosyl-(1-6)-O-ß-D-glucopyranside. Components characterisation and the metabolism with HLM could help the further development and application of BL.
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Inhibidores del Citocromo P-450 CYP3A/farmacología , Microsomas Hepáticos/efectos de los fármacos , Extractos Vegetales/química , Extractos Vegetales/farmacocinética , Rhamnaceae/química , Cromatografía Líquida de Alta Presión/métodos , Citocromo P-450 CYP3A/metabolismo , Inhibidores del Citocromo P-450 CYP3A/química , Flavonoides/análisis , Humanos , Microsomas Hepáticos/metabolismo , Fenoles/análisis , Plantas Medicinales/química , Espectrometría de Masas en Tándem/métodos , Testosterona/farmacocinéticaRESUMEN
PURPOSE: In both preclinical and clinical settings, testosterone treatment (TTh) of hypogonadism has shown beneficial effects on insulin sensitivity and visceral and liver fat accumulation. This prospective, observational study was aimed at assessing the change in markers of fat and liver functioning in obese men scheduled for bariatric surgery. METHODS: Hypogonadal patients with consistent symptoms (n = 15) undergoing 27.63 ± 3.64 weeks of TTh were compared to untreated eugonadal (n = 17) or asymptomatic hypogonadal (n = 46) men. A cross-sectional analysis among the different groups was also performed, especially for data derived from liver and fat biopsies. Preadipocytes isolated from adipose tissue biopsies were used to evaluate insulin sensitivity, adipogenic potential and mitochondrial function. NAFLD was evaluated by triglyceride assay and by calculating NAFLD activity score in liver biopsies. RESULTS: In TTh-hypogonadal men, histopathological NAFLD activity and steatosis scores, as well as liver triglyceride content were lower than in untreated-hypogonadal men and comparable to eugonadal ones. TTh was also associated with a favorable hepatic expression of lipid handling-related genes. In visceral adipose tissue and preadipocytes, TTh was associated with an increased expression of lipid catabolism and mitochondrial bio-functionality markers. Preadipocytes from TTh men also exhibited a healthier morpho-functional phenotype of mitochondria and higher insulin-sensitivity compared to untreated-hypogonadal ones. CONCLUSIONS: The present data suggest that TTh in severely obese, hypogonadal individuals induces metabolically healthier preadipocytes, improving insulin sensitivity, mitochondrial functioning and lipid handling. A potentially protective role for testosterone on the progression of NAFLD, improving hepatic steatosis and reducing intrahepatic triglyceride content, was also envisaged. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02248467, September 25th 2014.
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Hipogonadismo , Grasa Intraabdominal , Metabolismo de los Lípidos/efectos de los fármacos , Hígado , Enfermedad del Hígado Graso no Alcohólico , Obesidad , Testosterona , Adulto , Biopsia/métodos , Estudios Transversales , Humanos , Hipogonadismo/diagnóstico , Hipogonadismo/tratamiento farmacológico , Hipogonadismo/epidemiología , Resistencia a la Insulina , Grasa Intraabdominal/efectos de los fármacos , Grasa Intraabdominal/metabolismo , Grasa Intraabdominal/patología , Italia/epidemiología , Hígado/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Masculino , Persona de Mediana Edad , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Enfermedad del Hígado Graso no Alcohólico/patología , Obesidad/diagnóstico , Obesidad/tratamiento farmacológico , Obesidad/metabolismo , Sustancias Protectoras/administración & dosificación , Sustancias Protectoras/farmacocinética , Testosterona/administración & dosificación , Testosterona/farmacocinética , Resultado del TratamientoRESUMEN
OBJECTIVE: The current study aimed to investigate the potential of Solid Self-Emulsifying Drug Delivery Systems (solid SEDDS) loaded with Testosterone Undecanoate (TU) (solid TUSEDDS). The solid TU-SEDDS was composed of TU, Medium-Chain Triglycerides (MCT, oil), 2- Chloro-1-(chloromethyl) ethyl carbamate (EL-35, surfactant) and polyethylene glycol (PEG400, cosurfactant). It was expected to improve the dissolution and oral bioavailability of TU, as a result of investigating the feasibility of the clinical application of SEDDS. METHODS: First, a TU-SEDDS was developed by using rational blends of components with the good solubilizing ability for TU. Next, a ternary phase diagram was constructed to determine the self-emulsifying region, and the formulation was optimized. Then, the solid TU-SEDDS formulation was established by screening suitable solid adsorptions. Finally, the prepared SEDDS, TUSEDDS and solid TU-SEDDS formulations were evaluated in vitro and in vivo. RESULTS: The size of the solid TU-SEDDS was 189.1 ± 0.23 nm. The Transmission Electron Microscopy (TEM) results showed that the oil droplets were homogenous and spherical with good integrity. The Differential Scanning Calorimetry (DSC) and X-Ray Powder Dffraction (XRD) results indicated that the solid TU-SEDDS formulation almost preserves the amorphous state. Scanning Electron Microscopy (SEM) indicated that neusilin US2 successfully adsorbed the TU-SEDDS. Drug release indicated that the dissolution of the solid TU-SEDDS was faster than that of Andriol Testocaps ®. Furthermore, in vivo pharmacokinetic (PK) studies in Sprague-Dawley (SD) rats showed that the Area Under the Curve (AUC) of the solid TU-SEDDS (487.54±208.80 µg/L×h) was higher than that of Andriol Testocaps® (418.93±273.52 µg/L×h, P < 0.05). In beagles not fed a high-fat diet, the AUC of the solid TU-SEDDS (5.81±4.03 µg/L×h) was higher than that of Andriol Testocaps ® (5.53±3.43 µg/L×h, P > 0.05). In beagles fed a high-fat diet, the AUC of the solid TUSEDDS (38.18±21.90 µg/L×h) was higher than that of Andriol Testocaps® (37.17±13.79 µg/L×h, P > 0.05). CONCLUSION: According to the results of this research, oral solid TU-SEDDS is expected to be another alternative delivery system for the late-onset hypogonadism. This is beneficial to the transformation of existing drug delivery systems into preclinical and clinical studies.
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Sistemas de Liberación de Medicamentos , Testosterona/análogos & derivados , Administración Oral , Animales , Disponibilidad Biológica , Perros , Liberación de Fármacos , Emulsiones , Ratas , Ratas Sprague-Dawley , Solubilidad , Testosterona/química , Testosterona/farmacocinéticaRESUMEN
The current study investigated the use of synthetic membranes in developing a bio-predictive in vitro permeation testing (IVPT) method for 1.62% testosterone gel. The IVPT studies were carried out using both Franz (FC), and Flow-through (FTC) diffusion cells. The experimental variables included the type of synthetic membranes (hydrophilic polyamide nylon, polysulfone tuffryn and STRAT-M (SM) membrane) and the type of receiver media (phosphate buffer containing various concentrations of sodium lauryl sulfate). In vivo drug release rates were obtained from published reports for 1.62% testosterone gel applied to either abdominal area (treatment group A), upper arms/shoulders (treatment group B), or alternating between abdomen and arms/shoulders (treatment group C). The in vitro-in vivo correlations were established using GastroPlus software. The best IVPT method was selected based on establishing point-to-point correlation with the in vivo data of treatment group A with minimal prediction errors (%PE) of AUC0-24 and Cmax. The results showed that the IVPT method which employed the FTC diffusion system, SM membrane and phosphate buffer without surfactant established the best IVIVR model with a correlation coefficient (R2) of 0.9966 and an exponential function of Y = (1.35)5 × X3.6. The in vivo data obtained from treatment group A and B was used for internal validation of the prediction model. The validation data was acceptable, with %PE of less than 10% for both AUC0-24 and Cmax. In conclusion, these results suggest that bio-predictive IVPT methods for testosterone gels may be developed using synthetic membranes and diffusion apparatus by varying the composition of the receiver medium.
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Membranas Artificiales , Absorción Cutánea , Piel/metabolismo , Testosterona/administración & dosificación , Administración Cutánea , Área Bajo la Curva , Difusión , Liberación de Fármacos , Geles , Humanos , Técnicas In Vitro , Masculino , Permeabilidad , Ensayos Clínicos Controlados Aleatorios como Asunto , Testosterona/farmacocinéticaRESUMEN
INTRODUCTION: Testosterone deficiency (TD) is an increasing problem that can affect a man's physical and psychological health, and quality of life. Testosterone replacement therapy (TRT), combined with weight reduction, lifestyle advice, and the treatment of co-morbidities, is the treatment of choice in men who are not concerned about fertility. However, there remains an unmet need in this therapeutic area, relating to factors such as inconvenient or painful administration, fluctuations in testosterone levels, supra-physiologic testosterone levels, poor tolerability, and secondary safety issues, which may be associated with the current TRT options. Advances in transdermal delivery systems have resulted in the development of a new 2% transdermal testosterone gel, that may offer some additional features over the other currently available TRTs. AREAS COVERED: We performed a comprehensive review of the published and gray literature to identify randomized studies and non-randomized studies (NRS) involving adult men receiving treatment for low testosterone levels. EXPERT OPINION: Topical gels are often the most convenient first-line treatment for testosterone deficiency, but options are important as patient preference is more important than virtually any other clinical area of medicine. The chosen therapy must be convenient to use and reach reliable therapeutic levels to effectively and consistently relieve symptoms. Testavan, a new 2% testosterone gel, goes some way to achieving these goals.
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Terapia de Reemplazo de Hormonas/instrumentación , Testosterona/administración & dosificación , Administración Cutánea , Administración Tópica , Diseño de Equipo , Geles , Terapia de Reemplazo de Hormonas/efectos adversos , Humanos , Hipogonadismo/tratamiento farmacológico , Masculino , Ensayos Clínicos Controlados Aleatorios como Asunto , Testosterona/efectos adversos , Testosterona/farmacocinéticaRESUMEN
Male hypogonadism is notoriously associated with altered lipid metabolism. In this study, we performed an untargeted mass spectrometry-based profiling of plasma lipids from twenty healthy and twenty hypogonadal men before and after testosterone replacement therapy (TRT) for 60 days. Results demonstrated that hypogonadism was associated with a significant increase in sphingomyelin (SM), whereas phosphatidylcholine (PC) was mainly cleaved by activated phospholipase-A2 into lysophosphatidylcholine (LPC). In hypogonadal patients, arachidonic acid (AA), also produced through the latter cleavage, was prevalently bio-transformed into leukotriene B4 (LTB4) and not into endoperoxides from which prostaglandins and thromboxanes are derived. Interestingly, upon testosterone treatment SM, PC and LPC returned to levels similar to controls. Also, AA was newly converted into prostaglandin-A2, thromboxane-A2 and 5(S)-hydroxyeicosatetraenoic acid (HETE), suggesting that testosterone probably plays a role in controlling hypogonadal alterations above reported.
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Ácido Araquidónico/metabolismo , Terapia de Reemplazo de Hormonas , Hipogonadismo/tratamiento farmacológico , Hipogonadismo/metabolismo , Insulina/metabolismo , Metabolismo de los Lípidos/efectos de los fármacos , Fosfatidilcolinas/metabolismo , Testosterona/administración & dosificación , Estudios de Casos y Controles , Humanos , Hipogonadismo/sangre , Hipogonadismo/etiología , Lipidómica , Masculino , Fosfatidilcolinas/sangre , Testosterona/farmacocinética , Resultado del TratamientoRESUMEN
Two new Schiff base ligands (TE and TF) were prepared from conjugation of testosterone with 4-(4-ethylphenyl)-3-thiosemicarbazide and 4-(4-fluorophenyl)-3-thiosemicarbazide, respectively. Their nickel (NE and NF) and zinc (ZE and ZF) complexes were reported. X-ray crystallography revealed a distorted square planar geometry was adopted by NE. The compounds demonstrated excellent selectivity towards the colorectal carcinoma cell line HCT 116 despite their weak preferences towards the prostate cancer cell lines (PC-3 and LNCaP). Against HCT 116, all these compounds were able to arrest cell cycle at G0/G1 phase and induce apoptosis via mitochondria-dependent (TE, NE, and TF) and extrinsic apoptotic pathway (ZE, NF, and ZF). Moreover, only ZE was able to act as topoisomease I poison and halt its enzymatic reactions although all compounds presented excellent affinity towards DNA.
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Neoplasias Colorrectales , Complejos de Coordinación , Níquel , Testosterona , Tiosemicarbazonas , Zinc , Muerte Celular/efectos de los fármacos , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Complejos de Coordinación/síntesis química , Complejos de Coordinación/química , Complejos de Coordinación/farmacocinética , Complejos de Coordinación/farmacología , Células HCT116 , Humanos , Níquel/química , Níquel/farmacocinética , Níquel/farmacología , Testosterona/química , Testosterona/farmacocinética , Testosterona/farmacología , Tiosemicarbazonas/química , Tiosemicarbazonas/farmacocinética , Tiosemicarbazonas/farmacología , Zinc/química , Zinc/farmacocinética , Zinc/farmacologíaRESUMEN
Current challenges in accurately predicting intestinal metabolism arise from the complex nature of the intestine, leading to limited applicability of available in vitro tools as well as knowledge deficits in intestinal physiology, including enzyme abundance. In particular, information on regional enzyme abundance along the small intestine is lacking, especially for non-cytochrome P450 enzymes such as carboxylesterases (CESs), UDP-glucuronosyltransferases (UGTs), and sulfotransferases (SULTs). We used cryopreserved human intestinal mucosa samples from nine donors as an in vitro surrogate model for the small intestine and performed liquid chromatography tandem mass spectrometry-based quantitative proteomics for 17 non-cytochrome P450 enzymes using stable isotope-labeled peptides. Relative protein quantification was done by normalization with enterocyte marker proteins, i.e., villin-1, sucrase isomaltase, and fatty acid binding protein 2, and absolute protein quantification is reported as picomoles per milligram of protein. Activity assays in glucuronidations and sequential metabolisms were conducted to validate the proteomics findings. Relative or absolute quantifications are reported for CES1, CES2, five UGTs, and four SULTs along the small intestine: duodenum, jejunum, and ileum for six donors and in 10 segments along the entire small intestine (A-J) for three donors. Relative quantification using marker proteins may be beneficial in further controlling for technical variabilities. Absolute quantification data will allow for scaling factor generation and in vivo extrapolation of intestinal clearance using physiologically based pharmacokinetic modeling. SIGNIFICANCE STATEMENT: Current knowledge gaps exist in intestinal protein abundance of non-cytochrome P450 enzymes. Here, we employ quantitative proteomics to measure non-cytochrome P450 enzymes along the human small intestine in nine donors using cryopreserved human intestinal mucosa samples. Absolute and relative abundances reported here will allow better scaling of intestinal clearance.
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Carboxilesterasa/análisis , Glucuronosiltransferasa/análisis , Mucosa Intestinal/enzimología , Intestino Delgado/enzimología , Sulfotransferasas/análisis , Adulto , Carboxilesterasa/metabolismo , Clopidogrel/farmacocinética , Pruebas de Enzimas , Femenino , Glucuronosiltransferasa/antagonistas & inhibidores , Glucuronosiltransferasa/metabolismo , Humanos , Mesilato de Imatinib/farmacología , Irinotecán/farmacocinética , Masculino , Persona de Mediana Edad , Proteómica , Sulfotransferasas/metabolismo , Testosterona/farmacocinética , Adulto JovenRESUMEN
BACKGROUND: The aim of testosterone replacement therapy (TRT) is to improve symptoms and signs of testosterone deficiency including decreased libido, erectile dysfunction, depressed mood, anaemia, loss of muscle and bone mass, by increasing serum testosterone levels to physiologic range. TRT has been used in the last 70 years, and overtime, numerous preparations and formulations have been developed to improve pharmacokinetics (PKs) and patient compliance. The routes of delivery approved for use in the Western world include buccal, nasal, subdermal, transdermal and intramuscular (IM). OBJECTIVES: The aim of this narrative review was to describe and compare all available and approved testosterone preparations according to pharmacology, PKs and adverse effects. MATERIALS AND METHODS: We have performed an extensive PubMed review of the literature on TRT in clinical practice. Contraindications and monitoring of TRT were analyzed by comparing available guidelines released in the last five years. We provide a review of advantages and disadvantages of different modalities of TRT and how to monitor treatment to minimize the risks. RESULTS: TRT is associated with multiple benefits highly relevant to the patient. However, the recommendations given in different guidelines on TRT are based on data from a limited number of randomized controlled trials (RCTs), as well as non-randomized clinical studies and observational studies. This is the case for the safety of a long-term TRT in late-onset hypogonadism (LOH). No evidence is provided indeed on the effects of TRT on endpoints such as deterioration of heart failure suggesting a cautious approach to T replacement in older men with a history of heart failure. CONCLUSION: Clinicians must consider the unique characteristics of each patient and make the necessary adjustments in the management of LOH in order to provide the safest and most beneficial results.
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Eunuquismo/tratamiento farmacológico , Terapia de Reemplazo de Hormonas , Testosterona/administración & dosificación , Toma de Decisiones Clínicas , Formas de Dosificación , Vías de Administración de Medicamentos , Composición de Medicamentos , Eunuquismo/sangre , Eunuquismo/diagnóstico , Terapia de Reemplazo de Hormonas/efectos adversos , Humanos , Masculino , Medición de Riesgo , Factores de Riesgo , Testosterona/efectos adversos , Testosterona/deficiencia , Testosterona/farmacocinética , Resultado del TratamientoRESUMEN
BACKGROUND: Aging is associated with diminished testosterone (Te) secretion, which may be attributed to Leydig cell dysfunction, decreased pituitary stimulation, and altered Te feedback. OBJECTIVE: To study all regulatory nodes-gonadotropin-releasing hormone (GnRH), luteinizing hormone (LH) and Leydig cell-in the same cohort of healthy men. STUDY DESIGN: This was a placebo-controlled, blinded, prospectively randomized cross-over study in 40 men, age range 19 to 73 years, and body mass index (BMI) range 20 to 34.3 kg/m2. A submaximal dose of the GnRH antagonist ganirelix was used to assess outflow of GnRH, by calculating the difference between LH output during the control arm and ganirelix arm. Ketoconazole (a steroidogenic inhibitor) was used to estimate feedback, by the difference in LH output during the ketoconazole and control arm. High-dose ganirelix and repeated LH infusions were used to measure testicular responsivity. Blood sampling was performed at 10-minute intervals. RESULTS: There were age-related, but not body composition-related decreases in estimated GnRH secretion, the feedback strength of Te on LH, and Leydig cell responsivity to LH, accompanied by changes in approximate entropy. Bioavailable Te levels were negatively related to both age and computed tomography (CT)-estimated abdominal visceral mass (AVF), without interaction between these variables. The LH response to a submaximal dose of GnRH was independent of age and AVF. CONCLUSION: Advancing age is associated with (1) attenuated bioavailable Te secretion caused by diminished GnRH outflow and not by decreased GnRH responsivity of the gonadotrope, (2) diminished testicular responsivity to infused LH pulses, and (3) partial compensation by diminished Te feedback on central gonadotropic regulation.
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Factores de Edad , Envejecimiento/metabolismo , Composición Corporal/fisiología , Hormona Luteinizante/farmacocinética , Testosterona/farmacocinética , Adulto , Anciano , Disponibilidad Biológica , Índice de Masa Corporal , Estudios Cruzados , Hormona Liberadora de Gonadotropina/administración & dosificación , Hormona Liberadora de Gonadotropina/análogos & derivados , Voluntarios Sanos , Antagonistas de Hormonas/administración & dosificación , Humanos , Vida Independiente , Células Intersticiales del Testículo/metabolismo , Masculino , Persona de Mediana Edad , Método Simple Ciego , Testículo/metabolismo , Adulto JovenRESUMEN
Circulating levels of testosterone have been positively associated with impulsivity. The present study investigates the effect of testosterone administration on impulsivity in an intertemporal choice task, where participants are given a choice between smaller-sooner rewards and larger-later rewards. Healthy young male participants (n = 111) received a single-dose of 150 mg testosterone gel in a double-blind, placebo-controlled, between-subjects design. At 180 min post-administration, participants performed the decision-making task. Both model-free (i.e., higher indifference point) and model-based (i.e., steeper discounting rate) parameters revealed that testosterone administration increased impulsive choice. This finding supports the hypothesis that exogenous testosterone increases impulsivity among healthy young males in a laboratory task.
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Conducta de Elección/efectos de los fármacos , Toma de Decisiones/efectos de los fármacos , Conducta Impulsiva/efectos de los fármacos , Testosterona/administración & dosificación , Adolescente , Adulto , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Voluntarios Sanos , Humanos , Masculino , Placebos , Recompensa , Testosterona/farmacocinética , Factores de Tiempo , Adulto JovenRESUMEN
Skin models with efficient skin barrier function are required for percutaneous absorption studies. The contribution of media supplementation with n-3 and n-6 polyunsaturated fatty acids (PUFAs) to the development of the skin barrier function of in vitro skin models remains incompletely understood. To investigate whether PUFAs, alpha-linolenic acid (ALA, n-3 PUFA) and linoleic acid (LA, n-6 PUFA), could enhance the impermeability of a three-dimensional reconstructed human skin model, skin substitutes were produced according to the self-assembly method using culture media supplemented with either 10 µM ALA or 10 µM LA. The impact of PUFAs on skin permeability was studied by using a Franz cell diffusion system to assess the percutaneous absorption of testosterone and benzoic acid. Our findings showed that ALA supplementation induced a decrease in the absorption of testosterone, while LA supplementation did not significantly influence the penetration of testosterone and benzoic acid under present experimental conditions. Both ALA and LA were incorporated into phospholipids of the skin substitutes, resulting in an increase in n-3 total PUFAs or n-6 total PUFAs. Collectively, these results revealed the under-estimated impact of n-3 PUFA supplementation as well as the importance of the n-6 to n-3 ratio on the formation of the skin barrier of in vitro reconstructed human skin models.
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Ácidos Grasos/farmacología , Metabolismo de los Lípidos/efectos de los fármacos , Absorción Cutánea/efectos de los fármacos , Piel Artificial , Piel/efectos de los fármacos , Testosterona/farmacocinética , Ingeniería de Tejidos , Adolescente , Adulto , Células Cultivadas , Femenino , Humanos , Masculino , Persona de Mediana Edad , Permeabilidad/efectos de los fármacos , Piel/citología , Piel/metabolismo , Fenómenos Fisiológicos de la Piel/efectos de los fármacos , Técnicas de Cultivo de Tejidos , Donantes de Tejidos , Ingeniería de Tejidos/métodos , Adulto JovenRESUMEN
BACKGROUND: Testosterone is a driver of prostate cancer (PC) growth via ligand-mediated activation of the androgen receptor (AR). Tumors that have escaped systemic androgen deprivation, castration-resistant prostate cancers (CRPC), have measurable intratumoral levels of testosterone, suggesting that a resistance mechanism still depends on androgen-simulated growth. However, AR activation requires an optimal intracellular concentration of androgens, a situation challenged by low circulating testosterone concentrations. Notably, PC cells may optimize their androgen levels by regulating the expression of steroid metabolism enzymes that convert androgen precursors into androgens. Here we propose that testosterone entry into the cell could be another control point. METHODS: To determine whether testosterone enters cells via a transporter, we performed in vitro 3 H-testosterone uptake assays in androgen-dependent LNCaP and androgen and AR-independent PC3 cells. To determine if the uptake mechanism depended on a concentration gradient, we modified UGT2B17 levels in LNCaP cells and measured androgen levels by liquid-liquid extraction-mass spectrometry. We also analyzed CRPC metastases for expression of AKR1C3 to determine whether this enzyme that converts adrenal androgens to testosterone was present in the tumor stroma (microenvironment) in addition to its expression in the tumor epithelium. RESULTS: Testosterone uptake followed a concentration gradient but unlike in passive diffusion, was saturable and temperature-dependent, thus suggesting facilitated transport. Suppression of UGT2B17 to abrogate a testosterone gradient reduced testosterone transport while overexpression of the enzyme enhanced it. The facilitated transport suggests a paracrine route of testosterone uptake for maintaining optimal intracellular levels. We found that AKR1C3 was expressed in the tumor microenvironment of CRPC metastases in addition to epithelial cells and the pattern of relative abundance of the enzyme in epithelium vs stroma varied substantially between the metastatic sites. CONCLUSIONS: Our findings suggest that in addition to testosterone transport and metabolism by tumor epithelium, testosterone could also be produced by components of the tumor microenvironment. Facilitated testosterone uptake by tumor cells supports a cell nonautonomous mechanism for testosterone signaling in CRPC.