Pharmacokinetics and metabolism of lhrh agonists, clinical aspects

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Four adult female stumptailed macaque monkeys with regular menstrual cycles and one with irregular cycles and dysfunctional uterine bleeding were treated with a single implant containing 2.6 mg of the GnRH agonist buserelin in a matrix of polylactide/ glycolide copolymer (75:25). The implant was used as a cylindrical rod of 0.8 \m=x\ 0.12 cm and implanted sc in the abdominal wall. The insertion of the implant was followed by a modest rise in serum concentrations of LH and FSH lasting 3\ p=n-\ 4 days before falling to basal values. The release profile of buserelin from the implant was measured in urine by a radioimmunoassay detecting the intact molecule and its major metabolites. Immunoreactive buserelin in urine was high between days 1 \ p = n -\ 3 after implant after which there was a rapid decline to form a plateau between days 15\ p=n-\ 70 followed by a further gradual decline. This prolonged release of buserelin suppressed ovulation for a mean of 148 days (range 105\p=n-\182 days) as indicated by absence of serum progesterone rises. Serum FSH concentrations were low for at least 75 days and during this time serum oestradiol concentrations were uniformly suppressed in all monkeys. Once the buserelin release from the implant declined serum FSH concentrations began to rise. There was a variable delay of 7\ p=n-\ 60 days before this rise in FSH was associated with stimulation of ovarian oestradiol secretion followed by rises in serum progesterone concentrations indicative of ovulation. Apart from the first menses after insertion of implant, 4 of the monkeys became amenorrhoeic for the period of anovulation. The remaining monkey had dysfunctional uterine bleeding prior to treatment and this gradually decreased before disappearing 7 weeks after implant.These results show that this buserelin implant can provide sustained release of peptide to suppress pituitary-ovarian function in the macaque for at least 3 months. Such an implant should provide an important addition to the currently available modes of administration for the clinical use of GnRH agonists.

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

An implant of a gonadotropin releasing hormone agonist (buserelin) which suppresses ovarian function in the macaque for 3–5 months

Fraser

Sandow²,

Seidel³

et al. 1987

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“…It follows that degradation of buserelin also occurs in stored milk within the breast, but this would be difficult to demonstrate because it is uncertain as to whether the buserelin entering the breast milk is intact or already partially degraded. Buserelin is primarily degraded in the liver and kidneys, the degradation products being excreted in the urine (Sandow et al 1984(Sandow et al , 1985a. The addition of bacitracin to the breast milk samples ensures that further degradation cannot occur in vitro before the samples are assayed.…”

Section: Discussionmentioning

confidence: 99%

“…Buserelin levels in urine and breast milk were deter¬ mined by double antibody radio-immunoassays using a rabbit antibody (R104) raised against buserelin con¬ jugated to human serum albumin (Fraser et al 1983) in Edinburgh, and in Frankfurt using antibody 636 (Sandow et al 1981(Sandow et al , 1984(Sandow et al , 1985. The antibodies are C-terminal specific, detecting intact buserelin and its metabolites.…”

Section: Radioimmunoassaysmentioning

confidence: 99%

LRH agonist buserelin as a post-partum contraceptive: lack of biological activity of buserelin in breast milk

Dewart

McNeilly

Smith

et al. 1987

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To evaluate the possibility of using the LRH agonist buserelin as a contraceptive for lactating women we have investigated the passage of buserelin into breast milk and explored possible biological activity in the infant. Eleven mothers received 600 \ g=m\ gbuserelin by nasal spray. Buserelin was measured by radioimmunoassay in the breast milk of these mothers, and values ranged from undetectable levels (less than 15 pg/ml) to 8800 pg/ml. The maximum amount of buserelin that an infant could ingest during an average feed would be 1\p=n-\2\g=m\g.In adult men ingestion of 600 \ g=m\ g buserelin dissolved in cows milk was without biological effect upon both serum and urinary levels of luteinizing hormone. There was no change in the levels of LH found in the urine of infants fed by women who had received 600 \g=m\g buserelin by nasal spray. We conclude that the small amount of buserelin passing into the breast milk of these volunteers was without biological activity when ingested by the infant.The choice of contraceptive methods presently available to lactating mothers is limited. There is a need for a reliable, acceptable and easily admini¬ stered method of contraception which does not interfere with lactation and is non-steroidal. To this end we are currently evaluating the effective¬ ness of luteinizing hormone releasing hormone agonist (LRH agonist), buserelin, as a contracep¬ tive for lactating women. This report outlines the investigations that have been carried out prior to regular administration of buserelin to breast feeding mothers.Breast feeding is nutritionaly good for the infant (Buchanan 1975). The contraceptive effects of breast feeding have been investigated (Howie & McNeilly 1982;Short 1984), and it has been shown that while full breast feeding is asso¬ ciated with the suppression of ovarian activity in women post-partum when supplementary feeds are given (Howie et al. 1981) or when suckling activity declines to less than 50 min/day nursing (McNeilly et al. 1983), follicular development and ovulation resume. Steroidal forms of contracep¬ tion are the most practical method currently avail¬ able but are not ideal. Combined oral contracep¬ tives may have an adverse effect upon breast milk production (Koetswang 1982). The progestogen only pill is commonly prescribed to lactating women in developed countries, but troublesome side effects include irregular vaginal bleeding, nausea, vomiting and headache.Numerous studies have demonstrated that daily adinistration of LRH agonist to women with nor¬ mal menstrual cycles is a reliable and reversible method of suppressing ovulation (e.g. Bergquist et al. 1979; Schmidt-Gollwitzer et al. 1981). Our hypothesis is that buserelin administered to breast feeding women will reliably suppress ovulation

“…These therapeutic advances have been made despite the fact that GnRH analogues cannot be administered by mouth as they are inac¬ tivated when taken orally. Studies using daily in¬ jections were followed by the development of nasal sprays for clinical application (2,3). Although nasal administration has the advantage of long-term self-medication, it has a low efficiency of absorp¬ tion and there are variations in the dose require¬ ments for ovarian suppression between individ¬ uals.…”

mentioning

confidence: 99%

Controlled release of a GnRH agonist from a polyhydroxybutyric acid implant: reversible suppression of the menstrual cycle in the macaque

Fraser

Sandow²,

Seidel³

et al. 1989

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The use of polyhydroxybutyric acid as a matrix for delivery of the GnRH agonist buserelin was studied in adult stumptailed macaques with regular menstrual cycles. This material contained 5.0 mg buserelin in a disk of 0.6 cm diameter and 0.15 cm thickness. The effects on pituitary-ovarian function were examined and buserelin release profiles from 30 000 and 150 000 molecular weight polyhydroxybutyric acid matrices were compared. In an attempt to reduce the high initial release rate of buserelin from these disks, and to prolong the effective period of release, implants of 30 000 molecular weight were coated with cyanoacrylate. The implants were removed after 28, 35 or 42 days for the 30 000, the 150 000 and the coated implants, respectively. The urinary excretion profile for the agonist revealed a high initial release of buserelin from these implants followed by a rapid decline. The coated disks released significantly less (p < 0.05) buserelin over the first 3 days than did either of the uncoated implants, but maintained release of the agonist over a longer period. Inhibition of ovulation and suppression of estradiol secretion lasted for the duration of treatment in 3 of 5 macaques receiving the 30 000 implant, and in 5 of 5 receiving the 150 000 or the coated implant. In 3 macaques in whom the coated implant was left in situ, ovulation was suppressed for 104 \ m=+-\ 3.7 days. These results demonstrate that a polyhydroxybutyric acid matrix can be used as a depot formulation for a GnRH agonist and that improved control of release of the agonist can be achieved by coating such implants with cyanoacrylate. This approach may be useful in experimental and clinical situations and may be applicable for delivery of other peptide hormones.The ability of agonist analogues of gonadotropinreleasing hormone to suppress pituitary-ovarian function by inducing desensitization of the pitui¬ tary gonadotrope has been studied extensively for evaluation as a potential contraceptive and in treatment of sex hormone-dependent disorders (reviewed in 1). These therapeutic advances have been made despite the fact that GnRH analogues cannot be administered by mouth as they are inac¬ tivated when taken orally. Studies using daily in¬ jections were followed by the development of nasal sprays for clinical application (2,3). Although nasal administration has the advantage of long-term self-medication, it has a low efficiency of absorp¬ tion and there are variations in the dose require¬ ments for ovarian suppression between individ¬ uals. Furthermore, multiple daily injections or nasal spray administration are generally unsuit¬ able for application to animal studies. Administra¬ tion of GnRH and its agonists by long-term infu¬ sion shows that continued exposure is most effec¬ tive in suppressing pituitary-gonadal function; pi¬ tuitary receptors and gonadotropin content in ex¬ perimental animals are more suppressed than after daily injections (4)(5)(6)(7)(8).Initially, such experiments involved infusion of peptide via osmotic minipumps or portable...