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  • Efficacy and safety of Leuprorelin acetate for subjects with spinal and bulbar muscular atrophy: pooled analyses of two randomized-controlled trials.
    Journal of Neurology, 2019
    Co-Authors: Atsushi Hashizume, Masahisa Katsuno, Keisuke Suzuki, Haruhiko Banno, Yu Takeuchi, Motoshi Kawashima, Noriaki Suga, Tomoo Mano, Amane Araki, Yasuhiro Hijikata
    Abstract:

    Spinal and bulbar muscular atrophy (SBMA) is an adult-onset, hereditary neuromuscular disease characterized by muscle atrophy, weakness, contraction fasciculation, and bulbar involvement. Although the causative gene, androgen receptor, has been identified, the development of novel therapeutics for SBMA is incomplete. In this study, the efficacy and safety of Leuprorelin acetate administration for patients with SBMA, using the pooled data of two randomized-controlled trials, was studied. Two randomized double-blinded studies (JASMITT-06DB and JASMITT-11DB) were done as multicentric, investigator-initiated clinical trials in Japan. In both studies, eligible patients were randomly assigned 1:1 to receive Leuprorelin acetate administration once per 12 weeks for 48 weeks. The primary endpoint was the longitudinal change of pharyngeal barium residues from the baseline data measured with videofluorographic swallowing analyses. The pooled analysis plan was decided upon after the 06B study was finished and before the 11DB study began. The primary endpoint difference between the Leuprorelin group and the placebo group was pharyngeal barium residue after initial swallowing, − 4.12% (95% CI, − 8.40–0.15; p = 0.058). The primary endpoint of this study does not reach significant results, although inter-group differences of pharyngeal barium residues after the initial swallowing indicated that Leuprorelin acetate may be effective at each assessment point in both study groups. The efficacy of Leuprorelin acetate for patients with SBMA was statistically similar in two randomized-controlled trials, and suggested that Leuprorelin acetate may be effective and safe. Further investigations are needed to clarify the promising efficacy of the drug.

  • Long-term treatment with Leuprorelin for spinal and bulbar muscular atrophy: natural history-controlled study.
    Journal of Neurology Neurosurgery & Psychiatry, 2017
    Co-Authors: Atsushi Hashizume, Masahisa Katsuno, Keisuke Suzuki, Haruhiko Banno, Yasuhiro Hijikata, Akihiro Hirakawa, Shinichiro Yamada, Tomonori Inagaki, Sobue
    Abstract:

    Objective To evaluate the prognosis and progression of spinal and bulbar muscular atrophy (SBMA), a rare X-linked motor neuron disorder caused by trinucleotide repeat expansion in the AR (androgen receptor) gene, after long-term androgen suppression with Leuprorelin acetate treatment. Methods In the present natural history-controlled study, 36 patients with SBMA treated with Leuprorelin acetate for up to 84 months (Leuprorelin acetate-treated group; LT group) and 29 patients with SBMA with no specific treatment (non-treated group; NT group) were analysed. Disease progression was evaluated by longitudinal quantitative assessment of motor functioning using the revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R), and the modified Norris score. In addition, we selected two major clinical endpoint events, namely the occurrence of pneumonia requiring hospitalisation and death, to evaluate disease prognosis following long-term Leuprorelin acetate treatment. Results In our analysis of the longitudinal disease progression using the random slope model, we observed a significant difference in the ALSFRS-R total score, the Limb Norris Score, and the Norris Bulbar Score (p=0.005, 0.026 and 0.020, respectively), with the LT group exhibiting a slower per-12-months decline compared with the NT group. As for the event analysis, the prognosis of the LT group was better in comparison to the NT group as for the event-free survival period (p=0.021). Conclusion Long-term treatment with Leuprorelin acetate appears to delay the functional decline and suppress the incidence of pneumonia and death in subjects with SBMA.

  • efficacy and safety of Leuprorelin in patients with spinal and bulbar muscular atrophy jasmitt study a multicentre randomised double blind placebo controlled trial
    Lancet Neurology, 2010
    Co-Authors: Masahisa Katsuno, Keisuke Suzuki, Haruhiko Banno, Yu Takeuchi, Motoshi Kawashima, Ichiro Yabe, Hidenao Sasaki, Masashi Aoki, Mitsuya Morita, Imaharu Nakano
    Abstract:

    Summary Background Spinal and bulbar muscular atrophy is a hereditary motor neuron disease caused by the expansion of a polyglutamine tract in the androgen receptor. At present there are no treatments for spinal and bulbar muscular atrophy, although Leuprorelin suppressed the accumulation of pathogenic androgen receptors in a phase 2 trial. We aimed to assess the efficacy and safety of Leuprorelin for spinal and bulbar muscular atrophy. Methods The Japan SBMA Interventional Trial for TAP-144-SR (JASMITT) was a 48-week, randomised, double-blind, placebo-controlled trial done at 14 hospitals between August, 2006, and March, 2008. Patients with spinal and bulbar muscular atrophy were randomly assigned (1:1) by minimisation to subcutaneous 11·25 mg Leuprorelin or identical placebo every 12 weeks. Patients and investigators were masked to treatment allocation. The primary endpoint was pharyngeal barium residue, which indicates incomplete bolus clearance, measured at week 48 by videofluorography. All patients who were randomly assigned and who were assessed with videofluorography at least once were included in the analyses. This study is registered with the JMACCT clinical trials registry, number JMA-IIA00009, and the UMIN clinical trials registry, number UMIN000000465. Findings 204 patients were randomly assigned and 199 started treatment: 100 with Leuprorelin and 99 with placebo. At week 48, the pharyngeal barium residue after initial swallowing had changed by −5·1% (SD 21·0) in the Leuprorelin group and by 0·2% (18·2) in the placebo group (difference between groups −5·3%; 95% CI −10·8 to 0·3; p=0·063). The mean difference in pharyngeal barium residue after piecemeal deglutition at week 48 was −3·2% (−6·4 to 0·0; p=0·049), but there was no significant difference between the groups after covariate adjustment for the baseline data (−4·1 to 1·6; p=0·392). In a predefined subgroup analysis, Leuprorelin treatment was associated with a greater reduction in barium residue after initial swallowing than was placebo in patients with a disease duration less than 10 years (difference between groups −9·8, −17·1 to −2·5; p=0·009). There were no significant differences in the number of drug-related adverse events between groups (57 of 100 in the Leuprorelin group and 54 of 99 in the placebo group; p=0·727). Interpretation 48 weeks of treatment with Leuprorelin did not show significant effects on swallowing function in patients with spinal and bulbar muscular atrophy, although it was well tolerated. Disease duration might influence the efficacy of Leuprorelin and thus further clinical trials with sensitive outcome measures should be done in subpopulations of patients. Funding Large Scale Clinical Trial Network Project, Japan and Takeda Pharmaceuticals.

  • phase 2 trial of Leuprorelin in patients with spinal and bulbar muscular atrophy
    Annals of Neurology, 2009
    Co-Authors: Haruhiko Banno, Masahisa Katsuno, Keisuke Suzuki, Yu Takeuchi, Motoshi Kawashima, Noriaki Suga, Motoko Takamori, Tomohiko Nakamura, Koji Matsuo, Shinichi Yamada
    Abstract:

    Objective: Spinal and bulbar muscular atrophy (SBMA) is a hereditary motor neuron disease caused by the expansion of a polyglutamine tract in the androgen receptor (AR). Animal studies have shown that the pathogenesis of SBMA is dependent on serum testosterone level. This study is aimed at evaluating the efficacy and safety of androgen deprivation by Leuprorelin acetate in patients with SBMA. Methods: Fifty SBMA patients underwent subcutaneous injections of Leuprorelin acetate or placebo in a randomized, placebocontrolled trial for 48 weeks, followed by an open-label trial for an additional 96 weeks, in which 19 patients of the Leuprorelin group and 15 of the placebo group received Leuprorelin acetate. The patients who did not participate in the open-label trial were also followed up for the 96-week period (UMIN000000474). Results: Leuprorelin acetate significantly extended the duration of cricopharyngeal opening in videofluorography and decreased mutant AR accumulation in scrotal skin biopsy. The patients treated with Leuprorelin acetate for 144 weeks exhibited significantly greater functional scores and better swallowing parameters than those who received placebo. Autopsy of one patient who received Leuprorelin acetate for 118 weeks suggested that androgen deprivation inhibits the nuclear accumulation or stabilization, or both, of mutant AR in the motor neurons of the spinal cord and brainstem. Interpretation: These observations suggest that administration of Leuprorelin acetate suppresses the deterioration of neuromuscular impairment in SBMA by inhibiting the toxic accumulation of mutant AR. The results of this phase 2 trial support the start of large-scale clinical trials of androgen deprivation for SBMA. Ann Neurol 2009;65:140 –150 Spinal and bulbar muscular atrophy (SBMA), also known as Kennedy’s disease, is the first of the neurodegenerative diseases for which the molecular basis was discovered to be the expansion of a trinucleotide CAG repeat in the gene of the causative protein. SBMA is an adult-onset, motor neuron disease characterized by muscle atrophy, weakness, contraction fasciculations, and bulbar involvement. 1– 4 Its prevalence has been estimated to be 1 to 2 per 100,000, although a considerable number of patients may be misdiagnosed with other neuromuscular diseases such as amyotrophic lateral sclerosis (ALS). 5,6 The progression of SBMA is usually slow, but life-threatening respiratory tract infections often occur in the advanced stage of the disease, resulting in death. 7 Laboratory tests show increased serum levels of creatine kinase and liver enzymes in most cases. The expanded CAG triplet repeat sequence, which encodes a polyglutamine tract, is found in the androgen receptor gene (AR). 8 The CAG repeat numbers range from 38 to 62 in SBMA patients, whereas healthy individuals have 9 to 36 CAGs. 5,8 –10 The number of CAGs is correlated with disease severity and inversely correlated with the age of onset, as observed in other polyglutamine-related neurodegenerative dis

  • Leuprorelin rescues polyglutamine dependent phenotypes in a transgenic mouse model of spinal and bulbar muscular atrophy
    Nature Medicine, 2003
    Co-Authors: Masahisa Katsuno, Hiroaki Adachi, Manabu Doyu, Makoto Minamiyama, Chen Sang, Yasushi Kobayashi, Akira Inukai, Gen Sobue
    Abstract:

    Spinal and bulbar muscular atrophy (SBMA) is an adult-onset motor neuron disease that affects males. It is caused by the expansion of a polyglutamine (polyQ) tract in androgen receptors. Female carriers are usually asymptomatic. No specific treatment has been established. Our transgenic mouse model carrying a full-length human androgen receptor with expanded polyQ has considerable gender-related motor impairment. This phenotype was abrogated by castration, which prevented nuclear translocation of mutant androgen receptors. We examined the effect of androgen-blockade drugs on our mouse model. Leuprorelin, a lutenizing hormone-releasing hormone (LHRH) agonist that reduces testosterone release from the testis, rescued motor dysfunction and nuclear accumulation of mutant androgen receptors in male transgenic mice. Moreover, Leuprorelin treatment reversed the behavioral and histopathological phenotypes that were once caused by transient increases in serum testosterone. Flutamide, an androgen antagonist promoting nuclear translocation of androgen receptors, yielded no therapeutic effect. Leuprorelin thus seems to be a promising candidate for the treatment of SBMA.

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  • Leuprorelin
    Drugs, 1994
    Co-Authors: Greg L. Plosker, Rex N. Brogden
    Abstract:

    Synopsis Leuprorelin (leuprolide acetate) is a gonadotrophin-releasing hormone (GnRH) analogue used to treat a wide range of sex hormone-related disorders including advanced prostatic cancer, endometriosis and precocious puberty. It acts primarily on the anterior pituitary, inducing a transient early rise in gonadotrophin release. With continued use, Leuprorelin causes pituitary desensitisation and/or down-regulation, leading to suppressed circulating levels of gonadotrophins and sex hormones. Clinical trials in men with advanced prostatic cancer demonstrate that Leuprorelin (usually monthly depot injections of 3.75 or 7.5mg) is less likely to cause serious adverse cardiovascular effects than diethylstilbestrol, and has comparable efficacy to bilateral orchiectomy or other GnRH analogues. Therefore, the choice between Leuprorelin and orchiectomy may be made on the basis of the patients treatment preference, along with specific patient characteristics and cost implications. Monthly intramuscular or subcutaneous administration of depot Leuprorelin 3.75mg was superior to placebo, and comparable to oral danazol 800 mg/day or intranasal buserelin 900 μg/day, in achieving objective and subjective responses in women with endometriosis. Thus, Leuprorelin is an effective alternative to other treatments for women with endometriosis, but the recommended duration of its use in this clinical setting is limited to 6 months because it reduces bone mineral density. In children with central precocious puberty, Leuprorelin (usually monthly intramuscular or subcutaneous injections of depot Leuprorelin 3.75 to 15mg) decreases mean growth velocity and signs of sexual maturation and increases predicted adult height compared with baseline measurements. Although effects on final adult height are predicted from available data and require confirmation in long term follow-up studies, the absence of effective alternatives to GnRH analogues makes Leuprorelin a first-line therapy for children with this rare disease. In women with uterine leiomyomata, monthly intramuscular administration of depot Leuprorelin 3.75mg for 6 months markedly reduces uterine volume and fibroid-related symptoms, but, as with other GnRH analogues, these effects dissipate following discontinuation of the drug. As adjuvant therapy in women undergoing in vitro fertilisation or gamete intrafallopian transfer, Leuprorelin (usually 0.5 to 1 mg/day subcutaneously) reduces the risk of cancelled cycles for oocyte retrieval by preventing premature luteinisation. While some studies demonstrate an improvement in intermediate end-points such as increased number of mature oocytes retrieved and embryos available for transfer, a significant effect has not been demonstrated on the rate of live births per stimulated cycle. The tolerability profile of Leuprorelin varies somewhat depending on the patients gender and/or disease state because most adverse effects associated with Leuprorelin result from changes in levels of circulating sex hormones. In men with prostatic cancer receiving Leuprorelin, impotence and decreased libido occur almost universally, hot flushes are reported by 35 to 71 % of men and exacerbation of symptoms (disease flare) occurs in approximately 10%. Hot flushes occur in approximately 80% of women receiving Leuprorelin for endometriosis and other common adverse events include headache, vaginitis/vaginal dryness, insomnia and emotional lability. Children with precocious puberty appear to tolerate Leuprorelin well, although long term effects on the reproductive system are unknown. The most frequently reported problem in this patient population is local reaction at the injection site, which develops in approximately 5% of children receiving Leuprorelin. In general, few notable differences have been demonstrated between Leuprorelin and other GnRH analogues in the limited number of comparative clinical trials conducted in patients with sex hormone-related disorders. While monthly injections of depot Leuprorelin may be preferable to daily administration of other GnRH analogues in some patients, other GnRH analogues are also available in depot formulations. Thus, Leuprorelin offers effective therapy for a number of sex hormone-related disorders with daily subcutaneous administration of the aqueous solution or convenient monthly injections of the depot formulation. Pharmacodynamic Properties Leuprorelin (leuprolide acetate) is a potent agonist analogue of gonadotrophin-releasing hormone (GnRH) which initially induces release of gonadotrophins [luteinising hormone (LH) and follicle-stimulating hormone (FSH)] from the anterior pituitary, but with continued use causes pituitary desensitisation and/or down-regulation. Since gonadotrophins control release of testosterone from testicular Leydig cells in males and estrogens from the ovaries in females, Leuprorelin effectively suppresses circulating sex hormone levels within about 2 to 4 weeks (after an initial transient rise in levels) and these remain suppressed for the duration of treatment. Thus, Leuprorelin has been used in the treatment of various sex hormone-related diseases such as prostatic cancer, endometriosis, precocious puberty and uterine leiomyomata. Leuprorelin has also been used as adjunctive therapy, primarily to prevent LH surge before satisfactory oocyte maturation, in women undergoing in vitro fertilisation. Histological evaluations have demonstrated that long term (up to 24 months) subcutaneous administration of Leuprorelin 1 to 10 mg/day to men with prostatic cancer markedly suppressed spermatogenesis and Leydig cell activity and caused peritubular membrane thickening. In a rat model of endometriosis, transplanted endometrial tissue growth was suppressed by Leuprorelin in a dose-dependent manner, and appeared to be associated with suppression of serum estradiol levels. Monthly subcutaneous administration of depot Leuprorelin 1 mg/kg for up to 12 months in the rat significantly reduced vertebral bone mineral density, but was at least partially reversible after administration ceased. While the principal mechanism of action of Leuprorelin is pituitary desensitisation resulting in decreased serum levels of gonadotrophins and sex hormones, it is not clear whether this is a result of reduced GnRH receptor binding sites, uncoupling of receptors from intracellular processes, non-GnRH receptor mediated mechanisms, or a combination of these. In vitro data suggest some direct effects of Leuprorelin on smooth muscle of the reproductive tract, specific human breast cancer cell lines and possibly ovarian function. It is unclear from pharmacodynamic studies whether Leuprorelin has direct antitumour activity in prostatic cancer. Pharmacokinetic Properties After oral administration, Leuprorelin is almost completely inactivated by in-testinal enzymes, and the drug is therefore administered parenterally in the clinical setting. Single dose administration of Leuprorelin 1mg subcutaneously in healthy volunteers and patients with prostatic cancer achieved mean peak plasma drug concentrations of 32 to 35 μg/L within 30 to 60 minutes after administration; bioavailability was 94% compared with intravenous administration, elimination half-life was 3.6 hours and total body clearance was 9.1 L/h. The sustained release depot formulation releases Leuprorelin from biodegradable microspheres at a constant daily rate of 2.8% of the dose for approximately 1 month after subcutaneous or intramuscular administration. Some Leuprorelin is apparently leached from microsphere surfaces, resulting in transient peak plasma concentrations of 13.1 and 47.4 μg/L achieved within 3 hours of subcutaneous administration of depot Leuprorelin 3.75 and 7.5mg, respectively. However, mean plasma drug concentrations decreased markedly within the first 24 hours and remained between approximately 0.4 and 0.6 μg/L with continued monthly subcutaneous or intramuscular injections. On the basis of available animal and human data, Leuprorelin is metabolised to a (5–9) pentapeptide metabolite and probably other peptide metabolites, but is thought to be predominantly excreted in the urine. Therapeutic Use Noncomparative studies of men with advanced prostatic cancer treated with monthly depot injections of Leuprorelin 3.75 or 7.5mg (or in older studies, daily subcutaneous injections of Leuprorelin 1 or 10mg) demonstrated that few patients achieved complete response (usually ⪯ 5%). Partial response and stable disease rates both ranged widely from approximately 20 to 70% and were generally associated with improvements in subjective responses and performance status. Combined therapy with subcutaneous Leuprorelin 1 mg/day plus oral administration of the antiandrogen flutamide, 250mg 3 times daily, significantly increased median length of survival (35.6 vs 28.3 months) and progression-free survival (16.5 vs 13.9 months) compared with Leuprorelin monotherapy in a large double-blind study of 603 evaluable patients. Data available from the limited number of randomised comparative trials in men with prostatic cancer demonstrated that therapy with monthly subcutaneous injections of depot Leuprorelin 3.75mg had equivalent efficacy but was better tolerated than oral administration of fosfestrol 100mg 3 times daily. Daily subcutaneous administration of Leuprorelin 1mg achieved comparable response and survival rates to those seen with oral diethyl-stilbestrol 3 mg/day, although Leuprorelin was better tolerated. Women with endometriosis had significant improvements from baseline laparoscopic measurements of mean (revised) American Fertility Society endometriosis classification scores following monthly injections of depot Leuprorelin 3.75mg (or in older studies, daily subcutaneous administration of Leuprorelin lmg) for up to 2 years. Subjective symptom scores for dysmenorrhoea, pelvic pain, pelvic tenderness and dyspareunia also improved significantly from baseline or compared with placebo after 6 months of depot Leuprorelin 3.75mg administered intramuscularly each month. In comparative studies improvements in objective and subjective responses with Leuprorelin (usually 3.75mg monthly by depot intramuscular or subcutaneous injection) were similar to those achieved with oral danazol 800 mg/day or intranasal buserelin 900 μg/day. Concomitant ‘add-back’ therapy with estrogen/progesterone or progesterone alone did not influence the efficacy of Leuprorelin and helped preserve vertebral bone mineral density. In a study of 62 children with central precocious puberty, daily subcutaneous administration of Leuprorelin 4 to 50 μg/kg for 3.5 to 24.9 months decreased mean growth velocity significantly, from 11.5 cm/year at baseline to 7.4 cm/year during treatment. Predicted adult height of these children increased by 3.5cm with Leuprorelin. Similar results were achieved in smaller studies using intramuscular or subcutaneous injections of depot Leuprorelin in monthly dosages generally ranging from 3.75 to 15mg. Leuprorelin effectively suppressed levels of gonadotrophins and sex steroids, and usually prevented progression of Tanner staging for breast, genital and pubic hair development. In studies of women with uterine leiomyomata, monthly intramuscular administration of depot Leuprorelin 3.75mg for 6 months markedly reduced uterine volume and improved fibroid-related symptoms in the majority of women. However, as with other GnRH analogues, these effects are transient, as demonstrated by regrowth of fibroids and a return to baseline uterine volume within approximately 24 weeks of discontinuing treatment. In women receiving controlled ovarian stimulation with menotropins (FSH plus LH) for in vitro fertilisation (IVF) or gamete intrafallopian transfer (GIFT), adjunctive treatment with subcutaneous Leuprorelin 0.5 or 1 mg/day was associated with similar or increased numbers of mature oocytes retrieved per cycle and embryos available for transfer compared with cycles in which women did not receive Leuprorelin. Pregnancy rates ranged from approximately 15 to 26% of cycles treated with Leuprorelin compared with approximately 15 to 22% of cycles not treated with Leuprorelin, and were not significantly different between treatment groups. Cycles in which Leuprorelin was used usually required a higher total dose of menotropins, but were less likely to be cancelled (for oocyte retrieval) because of premature luteinisation or other factors. In studies comparing outcomes in women receiving adjuvant therapy with Leuprorelin 0.25 to 1 mg/day subcutaneously versus Clomifene 50 to 100 mg/day orally, buserelin 300 μg/day subcutaneously or nafarelin 400 μg/day intranasally, no significant differences were noted between treatment groups for pregnancy rates or total number of live births. Tolerability The tolerability profile of Leuprorelin depends, to some extent, on the patient’s gender and/or clinical condition, since most adverse events are related to changes in circulating levels of sex hormones. Impotence and decreased libido occur in virtually all sexually active men receiving Leuprorelin for prostatic cancer, usually within 3 months of initiating treatment. Hot flushes occur in 35 to 71% of men during therapy and approximately 10% experience increased prostatic cancer symptoms (disease flare), usually manifested as bone pain, during the first 2 weeks of treatment. Patients with spinal cord compression should not receive GnRH analogues and those with urinary tract obstruction may not be able to tolerate a transient increase in symptoms associated with an initial increase in serum testosterone levels. Disease flare may be reduced by coadministration of an antiandrogen 1 week before and 1 to 4 weeks after the initial Leuprorelin dose. In a large study comparing subcutaneous Leuprorelin 1 mg/day with oral diethyl-stilbestrol 3 mg/day in men with prostatic cancer, Leuprorelin recipients more frequently experienced flushing (52 vs 11% of patients), but had significantly fewer episodes of gynaecomastia/breast tenderness (3 vs 49%), nausea/vomiting (5 vs 16%) and peripheral oedema (2 vs 16%), and a trend toward fewer serious complications of thrombosis, pulmonary embolus or myocardial infarction (1 vs 7%). Leuprorelin induces a hypoestrogenic state and suppresses menses in women with endometriosis or uterine leiomyomata. Flushing or vasodilation develops in approximately 80% of women receiving monthly depot injections of Leuprorelin 3.75mg. Other adverse events reported frequently among this patient population include headache (͌ 35% of patients), vaginitis/vaginal dryness (29 to 37%), insomnia (17 to 55%) and emotional lability (16 to 45%). In a large study of women with endometriosis, monthly administration of depot Leuprorelin 3.75mg caused a significantly lower incidence of weight gain (13 vs 27% of patients) and oedema (5 vs 18%) than oral danazol 800 mg/day, but a higher incidence of hot flushes (84 vs 54%), insomnia (17 vs 6%) and decreased libido (13 vs 4%). Reduction in bone mineral density can occur in women receiving Leuprorelin. Although reversible after shorter courses of Leuprorelin (e.g. 6 months), sustained bone loss may occur after long term administration (e.g. 2 years). Some protection against this problem can be provided with concomitant ‘add-back’ therapy consisting of estrogen/progesterone or progesterone only. Adverse events appear to be much less common in children treated with Leuprorelin for precocious puberty, although long term effects of Leuprorelin on the reproductive system are unknown. The most frequently reported adverse event is a local reaction at the injection site (pain, induration, erythema or abscess) which occurs in about 5% of children receiving daily subcutaneous injections or monthly subcutaneous or intramuscular injections of depot Leuprorelin. Dosage and Administration In men with prostatic cancer, the recommended dosage of depot Leuprorelin is 3.75mg (Europe and Japan) or 7.5mg (US) administered intramuscularly or sub-cutaneously once monthly. As an alternative to the depot formulation, the aqueous formulation of Leuprorelin may be administered subcutaneously at a dosage of 1 mg/day. The recommended dosage of depot Leuprorelin for women with endometriosis is 3.75mg intramuscularly or subcutaneously once monthly for 6 months. Treatment for longer periods, or retreatment after recurrence of endometriosis, is not recommended because of potentially irreversible adverse effects on bone mineral density. Leuprorelin dosage in women with uterine leiomyomata is the same as for endometriosis. The recommended dosage of Leuprorelin in children with precocious puberty varies between countries. In the US, depot Leuprorelin is initiated at a dosage of 0.3 mg/kg (minimum 7.5mg) or 7.5mg in children weighing ⪯25kg, 11.25mg in those weighing 25 to 37.5kg and 15mg in those weighing >37.5kg. Leuprorelin dosage is titrated upwards by increments of 3.75mg at monthly intervals based on clinical and laboratory assessments. However, in some European countries, the initial recommended dosage of depot Leuprorelin is 1.88mg in children weighing ⪯20kg and 3.75mg in those weighing >20kg, administered at monthly intervals. In Japan, the usual monthly dosage of depot Leuprorelin is 30 μg/kg which may be increased up to 90 μg/kg depending on the patient’s clinical status. Intramuscular or subcutaneous injection have both been recommended. As adjuvant therapy in women undergoing in vitro fertilisation (IVF) or gamete intrafallopian transfer (GIFT), Leuprorelin dosage varies according to various parameters of response, and is usually administered from the midluteal phase of the previous cycle or the follicular phase of the stimulated cycle until human chorionic gonadotrophin (hCG) administration. In clinical trials, Leuprorelin 0.5 to 1 mg/day subcutaneously was commonly used.

  • Leuprorelin. A review of its pharmacology and therapeutic use in prostatic cancer, endometriosis and other sex hormone-related disorders.
    Drugs, 1994
    Co-Authors: Greg L. Plosker, Rex N. Brogden
    Abstract:

    Leuprorelin (leuprolide acetate) is a gonadotrophin-releasing hormone (GnRH) analogue used to treat a wide range of sex hormone-related disorders including advanced prostatic cancer, endometriosis and precocious puberty. It acts primarily on the anterior pituitary, inducing a transient early rise in gonadotrophin release. With continued use, Leuprorelin causes pituitary desensitisation and/or down-regulation, leading to suppressed circulating levels of gonadotrophins and sex hormones. Clinical trials in men with advanced prostatic cancer demonstrate that Leuprorelin (usually monthly depot injections of 3.75 or 7.5 mg) is less likely to cause serious adverse cardiovascular effects than diethylstilbestrol, and has comparable efficacy to bilateral orchiectomy or other GnRH analogues. Therefore, the choice between Leuprorelin and orchiectomy may be made on the basis of the patient's treatment preference, along with specific patient characteristics and cost implications. Monthly intramuscular or subcutaneous administration of depot Leuprorelin 3.75 mg was superior to placebo, and comparable to oral danazol 800 mg/day or intranasal buserelin 900 micrograms/day, in achieving objective and subjective responses in women with endometriosis. Thus, Leuprorelin is an effective alternative to other treatments for women with endometriosis, but the recommended duration of its use in this clinical setting is limited to 6 months because it reduces bone mineral density. In children with central precocious puberty, Leuprorelin (usually monthly intramuscular or subcutaneous injections of depot Leuprorelin 3.75 to 15mg) decreases mean growth velocity and signs of sexual maturation and increases predicted adult height compared with baseline measurements. Although effects on final adult height are predicted from available data and require confirmation in long term follow-up studies, the absence of effective alternatives to GnRH analogues makes Leuprorelin a first-line therapy for children with this rare disease. In women with uterine leiomyomata, monthly intramuscular administration of depot Leuprorelin 3.75 mg for 6 months markedly reduces uterine volume and fibroid-related symptoms, but, as with other GnRH analogues, these effects dissipate following discontinuation of the drug. As adjuvant therapy in women undergoing in vitro fertilisation or gamete intrafallopian transfer, Leuprorelin (usually 0.5 to 1 mg/day subcutaneously) reduces the risk of cancelled cycles for oocyte retrieval by preventing premature luteinisation. While some studies demonstrate an improvement in intermediate end-points such as increased number of mature oocytes retrieved and embryos available for transfer, a significant effect has not been demonstrated on the rate of live births per stimulated cycle.(ABSTRACT TRUNCATED AT 400 WORDS)

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