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Leuprolide, a gonadotropin-releasing hormone (GnRH) agonist widely used in androgen deprivation therapy for the treatment of advanced prostate cancer, suffers from a short circulating half-life like other peptide therapeutics. As an attempt to improve its pharmacokinetic properties, two PEGylated leuprolides with different molecular weight were synthesized utilizing N-hydroxysuccinimidyl (NHS) conjugation chemistry. The reaction conditions, including reaction temperature, reaction time and feed ratio of the reactants, were optimized to obtain a higher yield. Reverse-phase high performance liquid chromatography (RP-HPLC) characterization indicates a high purity of the resulting conjugates. Matrix-assisted laser desorption mass spectrometry (MALDI-MS) characterization suggests a 1:1 PEGylation. 1H NMR study reveals that the reaction occurs on the imidazolyl group on the histidine residue and the conjugates are stable in pH7.4 aqueous solutions. The in vitro bioactivity of the conjugates was evaluated using both hormone-sensitive and hormone-insensitive cell lines. It was found that the PEGylated peptides can still counteract the stimulatory action of androgens and the mitogenic action of epidermal growth factor on cell proliferation. The in vivo bioactivity of the conjugates was also tested. Like the unmodified peptide, administration of the conjugates to male rats leads to an initial testosterone surge, followed by a suppression of testosterone secretion. Pharmacokinetics of the drugs after i.v. and s.c. administrations were determined. In both cases, a prolonged circulating half-life, an increased AUC, and a decreased Cl_F were observed for the PEGylated drugs.
Gonadotropin-releasing hormone (GnRH) and its synthetic analog leuprolide acetate, a GnRH agonist, have neurotrophic properties. This study was designed to determine whether administration of leuprolide acetate can improve locomotor behavior, gait, micturition reflex, spinal cord morphology and the amount of microglia in the lesion epicenter after spinal cord injury in rats. Rats with spinal cord compression injury were administered leuprolide acetate or saline solution for 5 weeks. At the 5(th) week, leuprolide acetate-treated rats showed locomotor activity recovery by 38%, had improvement in kinematic gait and exhibited voiding reflex recovery by 60%, as compared with the 1(st) week. By contrast, saline solution-treated rats showed locomotor activity recovery only by 7%, but voiding reflex did not recover. More importantly, leuprolide acetate treatment reduced microglial immunological reaction and induced a trend towards greater area of white and gray matter in the spinal cord. Therefore, leuprolide acetate has great potential to repair spinal cord injury.
Methods. This prospective US multicenter trial of leuprolide acetate 1-month depot (7.5-15 mg) for central precocious puberty utilized an open-label treatment period, long-term follow-up, and adult callback. Forty-nine females <9 years old with Tanner breast stage ≥2 before 8 years and 6 males <10 years old with Tanner genital stage ≥2 before 9 years with stimulated LH ≥10 IU/L and bone age advance ≥1 year were enrolled. Results. Subjects were treated for 3.9 ± 2.0 years. Mean peak GnRH-stimulated LH and FSH were prepubertal after the first dose and remained suppressed throughout treatment. During treatment, mean estradiol decreased to the limit of detection and mean testosterone decreased but remained above prepubertal norms. During posttreatment follow-up (3.5 ± 2.2 years), all patients achieved a pubertal hormonal response within 1 year and menses were reported in all females ≥12 years old. No impairment of reproductive function was observed at adulthood (mean age: 24.8 years).
Poly(lactic-co-glycolic acid) PLGA (release controlling excipient) plays a dominant role on the performance of PLGA based long-acting parenterals. These types of drug products typically exhibit complex multi-phasic in vitro/in vivo release/absorption characteristics. In particular, owing to their large size, charged state, and hydrophilicity, peptide loaded microspheres can exhibit more complex release mechanisms. Accordingly, it is challenging to develop Level A in vitro-in vivo correlations (IVIVCs) for such complex long-acting parenterals. With the objective of gaining a better understanding of how to achieve IVIVCs for peptide loaded PLGA microspheres, formulations with similar as well as different release characteristics were prepared with PLGAs from different sources. Leuprolide acetate was selected as the model drug. Owning to the different physicochemical properties of the PLGAs (such as inherent viscosity, molecular weight and blockiness), the formulations exhibited significant differences in their critical quality attributes (such as particle size, porosity and pore size) and consequently had different in vitro and in vivo performance. Affirmative conventional IVIVCs were developed that were able to predict the in vivo performance using the corresponding in vitro release profiles. In addition, the developed conventional IVIVCs were able to discriminate between formulations with comparable in vitro/in vivo performance and those that had dissimilar in vitro/in vivo performance. The present work provides a comprehensive understanding of the influence of PLGA source variations on IVIVC development and predictability for peptide loaded PLGA microspheres.
A phospholipid-based injectable gel was developed for the sustained delivery of leuprolide acetate (LA). The gel system was prepared using biocompatible materials (SPME), including soya phosphatidyl choline (SPC), medium chain triglyceride (MCT) and ethanol. The system displayed a sol state with low viscosity in vitro and underwent in situ gelation in vivo after subcutaneous injection. An in vitro release study was performed using a dialysis setup with different release media containing different percentages of ethanol. The stability of LA in the SPME system was investigated under different temperatures and in the presence of various antioxidants. In vivo studies in male rats were performed to elucidate the pharmacokinetic profiles and pharmacodynamic efficacy. A sustained release of LA for 28 days was observed without obvious initial burst in vivo. The pharmacodynamic study showed that once-a-month injection of LA-loaded SPME (SPME-LA) led to comparable suppression effects on the serum testosterone level as observed in LA solution except for the onset time. These findings demonstrate excellent potential for this novel SPME system as a sustained release delivery system for LA.
This study optimized the preparation of electrosprayed microspheres containing leuprolide and developed an in vitro-in vivo correlation (IVIVC) model that enables mutual prediction between in vitro and in vivo dissolution. The pharmacokinetic (PK) and pharmacodynamic (PD) study of leuprolide was carried out in normal rats after subcutaneous administration of electrosprayed microspheres. The parameters of the IVIVC model were estimated by fitting the PK profile of Lucrin depot® to the release compartment of the IVIVC model, thus the in vivo dissolution was predicted from the in vitro dissolution. From this correlation, the PK profile of leuprolide was predicted from the results of in vivo dissolution. The IVIVC model was validated by estimating percent prediction error (%PE) values. Among prepared microspheres, an optimal formulation was selected using the IVIVC model. The maximum plasma concentration and the area under the plasma concentration-time curve from zero to infinity from the predicted PK profile were 4.01 ng/mL and 52.52 h·ng/mL, respectively, and from the observed PK profile were 4.14 ng/mL and 56.95 h·ng/mL, respectively. The percent prediction error values of all parameters did not exceed 15%, thus the IVIVC model satisfies the validation criteria of the Food and Drug Administration (FDA) guidance. The PK/PD evaluation suggests that the efficacy of OL5 is similar to Lucrin depot®, but the formulation was improved by reducing the initial burst release.
This study developed the pharmacokinetic (PK)-pharmacodynamic (PD) model of the testosterone-suppressive effect of leuprolide for evaluation of the sustained release (SR) depot and leuprolide solution in rats with or without prostate cancer. Six groups of rats were divided by the routes of administration (intravenous and subcutaneous injection) and kinds of formulation (vehicle, leuprolide solution, and SR depot). The PK profile after subcutaneous injection of leuprolide solution could be well-described by the one-compartment model. The absorption rate constant, the total body clearance, and the volume of distribution were estimated at 16.67 h-1, 514.46 mL/h, and 487.40 mL. Using PK parameters in the solution-administered group, the PK model for the SR depot was developed. The PK-PD model was constructed by describing the testosterone-suppressive effect of leuprolide using the feedback turnover model. The response of testosterone after administration of each formulation was well described using this PK-PD model for the estimation of PD parameters (EC50, Emax, h) and systemic parameters (kin, kout, kf on, kf off). The developed PK-PD model containing an inhibitory feedback system could successfully describe the testosterone-suppressive effect of leuprolide in the type of formulation. The PK-PD model developed would be useful for evaluating the formulation of similar drugs whose effect is regulated through the feedback mechanism.
It has been reported that the Gonadotropin-releasing hormone (GnRH) and its agonist leuprolide acetate (LA) can act as promoters of nerve regeneration. The aim of this study is to evaluate the effect of LA in a complete transection model. Sciatic nerve injury (SNI) was performed using a complete nerve transection and immediately repaired by epineural sutures. Rats were divided into three groups: SHAM, SNI treated with LA (SNI + LA) or saline solution (SNI + SS) for 5 weeks. Sciatic nerve regeneration was evaluated by kinematic gait analyzes, electrophysiological, morphological and biochemical tests. SNI + LA group had a functional recovery in kinematic gait, an increase in ankle angle value and a faster walking speed, compound muscle action potential amplitude, nerve conduction velocity (NCV). Furthermore, the number of myelinated axons and microtubule-associated protein 2 (MAP-2) expression were also higher compared to SS group. In conclusion, LA treatment improves of gait, walking speed, NCV, axons morphometry and MAP-2 expression in rats with sciatic nerve complete transection. These results suggest that LA can be a potential treatment for peripheral nerve injuries.
In this study, a GnRH agonist, leuprolide acetate (LA), was given as a single depot injection before 48 h of life to Wistar female rats allotted to prenatal (E16-18) and postnatal androgenization (day 5 of life) by the use of testosterone propionate, looking for reproductive endpoints. Remarkably, a single injection of LA increased the estrus cycles in the postnatal group (PostN) from 0% to 25% of the estrus cycles in the postnatal LA treated group (PostN L). LA also reduced the serum testosterone levels and cysts and atretic follicles in PostN L in contrast with rats (>100 days) from the PostN group (p = 0.04). Prenatally androgenized rats (PreN) exhibited significant modifications in the hypothalamic genes, such as Gnrh. To the best of our knowledge, this is the first study to show that blockage of the GnRH axis with leuprolide acetate depot prevented the development of typical features (anovulation, cysts, atretic follicles) in a postnatal testosterone propionate rat model of PCOS.
GnRH agonists have been used to halt the development of puberty in children with precocious puberty since the 1980s. Recently, drugs like Lupron Depot® (leuprolide acetate), have been used to suppress pubertal progression in adolescents who are questioning their gender identity. However, few preclinical studies have been conducted to investigate potential effects of using GnRH agonists in this context.
Leuprolide is a synthetic nonapeptide drug (pyroGlu-His-Trp-Ser-Tyr-d-Leu-Leu-Arg-Pro-NHEt) that acts as a gonadotropin-releasing hormone agonist. The continuous administration of therapeutic doses of leuprolide inhibits gonadotropin secretion, which is used in androgen-deprivation therapy for the treatment of advanced prostate cancer, central precocious puberty, endometriosis, uterine fibroids, and other sex-hormone-related conditions. To improve the pharmacokinetic properties of peptide drugs, a fatty acid was conjugated with leuprolide for long-term action. In this study, we developed a simple ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method for the simultaneous determination of leuprolide and leuprolide-oleic acid conjugate (LOC) levels. The developed method was validated in terms of linearity, precision, accuracy, recovery, matrix effect, and stability according to the US Food and Drug Administration guidelines, and the parameters were within acceptable limits. Subsequently, the pharmacokinetics of leuprolide and LOCs were evaluated. In vivo rat subcutaneous studies revealed that conjugation with fatty acids significantly altered the pharmacokinetics of leuprolide. After the subcutaneous administration of fatty-acid-conjugated leuprolide, the mean absorption time and half-life were prolonged. To the best of our knowledge, this is the first study showing the effects of fatty acid conjugates on the pharmacokinetics of leuprolide using a newly developed UPLC-MS/MS method for the simultaneous quantification of leuprolide and LOCs.
Leuprolide is an established luteinizing hormone-releasing hormone (LHRH) agonist used as first-line treatment in advanced prostate cancer. As different formulations and dosing schedules are likely to have economic implications, we aimed to evaluate their efficacy, safety, and costs in nine European countries: Austria, Belgium, Czech Republic, Hungary, Italy, Latvia, Netherlands, Poland, and Portugal.
Mild hypoxic-ischemic encephalopathy (HIE) is a condition that predisposes to negative outcomes such as neuroanatomical injury, mood disorders, and motor or cognitive disabilities. The neuroinflammation plays an important role in the neurological damage; therefore, reducing it could provide neuroprotection. The leuprolide acetate (LA) has shown to have neuroregenerative and immunomodulator properties in other nervous system injuries.
Cardiovascular (CV) events are the leading cause of death in prostate cancer. Men with prostate cancer are likely to have CV risk factors and use CV-related concomitant medications. In the phase 3 HERO study, a 54% lower incidence of major adverse cardiac events was reported in men treated with the oral gonadotropin-releasing hormone (GnRH) receptor antagonist, relugolix, vs leuprolide. Herein, we characterize the impact of concomitant CV therapies on efficacy and safety in the HERO study.
Conventionally, hCG is used as a 'faux' LH surge to bring final oocyte maturation due to structural similarity with LH. Although GnRH agonists induce a more physiological gonadotropin surge for follicular maturation, they have been associated with luteal phase deficiency. Our aim was to assess whether adding a gonadotropin-releasing hormone agonist (GnRHa) to hCG trigger improves oocyte maturation and the number of high-grade embryos in GnRH antagonist IVF cycles.
Limited data from controlled clinical trials are available for men who experience biochemical recurrence after definitive therapy for prostate cancer. In the absence of overt metastases, patients with non-metastatic castration-sensitive prostate cancer (nmCSPC) often receive androgen deprivation therapy (ADT). There is no standard-of-care consensus on optimal ADT timing, although most men are treated prior to metastases, especially those with high-risk features (Gleason score 8-10 or prostate-specific antigen doubling time (PSADT) <9-12 months). Given data that ADT plus novel hormonal agents improve survival in men with metastatic CSPC, there is a desire to evaluate these agents earlier in the disease course. The main objective of EMBARK is the comparative assessment of enzalutamide plus leuprolide (luteinising hormone-releasing hormone agonist (LHRHa)) or enzalutamide monotherapy versus monotherapy LHRHa to improve metastasis-free survival (MFS) in patients with high-risk nmCSPC PSA recurrence after definitive therapy.
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