Pharmacokinetics and Bioavailability of the GnRH Analogs in the Form of Solution and Zn2+-Suspension After Single Subcutaneous Injection in Female Rats.

BACKGROUND AND OBJECTIVES: Although many synthetic gonadoliberin analogs have been developed, only a few of them, including buserelin, were introduced into clinical practice. Dalarelin, which differs from buserelin by just one aminoacid in the position 6 (D-Ala), is not widely used so far. Gonadotropin-releasing hormone (GnRH) analogs are used to treat many different illnesses and are available in different forms like solution for injection, nasal spray, microspheres, etc. Unfortunately, none of the above drug formulations can release the hormones for 24 h. We assumed that classical suspension could solve this problem. METHODS: Two sets of experiments were performed. In the first one, buserelin and dalarelin were injected into mature female rats in two forms: suspension, in which the analogs are bounded by Zn2+ ions and solution. The pharmacokinetic parameters and bioavailability of the analogs were calculated, based on their concentration in the plasma measured by high-performance liquid chromatography method (HPLC). In the second experiment, the hormones in two different forms were injected into superovulated immature female rats and then the concentration of Luteinizing hormone (LH), Follicle-stimulating hormone (FSH) and 17ß-estradiol in the serum was measured by radioimmunological method. RESULTS: The Extent of Biological Availability (EBA), calculated on the base of AUC0-∞, showed that in the form of solution buserelin and dalarelin display, respectively, only 13 and 8 % of biological availability of their suspension counterparts. Comparing both analogs, the EBA of dalarelin was half (53 %) that of buserelin delivered in the form of solution and 83 % when they were delivered in the form of suspension. The injection of buserelin or dalarelin, in the form of solution or suspension, into superovulated female rats increased LH, FSH and estradiol concentration in the serum. However, after injection of the analogs in the form of suspension, the high concentration of LH and FSH in the serum persisted longer. CONCLUSION: Performed studies indicate that GnRH analogs in the form of suspension have higher bioavailability than their solution counterparts. It influences the effects of their action, especially in relation to LH and FSH.

Assessment of effective absorbed dose of (111)In-DTPA-Buserelin in human on the basis of biodistribution rat data.

In this study, the effective absorbed dose to human organs was estimated, following intra vascular administration of (111)In-DTPA-Buserelin using biodistribution data from rats. Rats were sacrificed at exact time intervals of 0.25, 0.5, 1, 2, 4 and 24 h post injections. The Medical Internal Radiation Dose formulation was applied to extrapolate from rats to humans and to project the absorbed radiation dose for various human organs. From rat data, it was estimated that a 185-MBq injection of (111)In-DTPA-Buserelin into the human might result in an estimated absorbed dose of 24.27 mGy to the total body and the highest effective absorbed dose was in kidneys, 28.39 mSv. The promising results of this study emphasises the importance of absorbed doses in humans estimated from data on rats.

Recomendaciones para la dosificación de medicamentos en pacientes con insuficiencia hepática crónica / Drug dosage recommendations in patients with chronic liver disease

La insuficiencia hepática crónica produce alteraciones que afectan a la cinética de los medicamentos y a pesar de que su ajuste se basa en el índice Child-Pugh, no se disponen de recomendaciones y/o algoritmos de referencia que faciliten su dosificación. Se realizó una revisión bibliográfica de la dosificación en insuficiencia hepática crónica de los medicamentos de la guía del hospital incluidos en el listado de fármacos que la OMS recomienda no utilizar o utilizar con precaución en pacientes con enfermedad hepática, añadiendo las novedades terapéuticas de los últimos años. Para ello se revisaron las fichas técnicas, base DrugDex- Micromedex, recomendaciones de la OMS y artículos de revisión de los últimos 10 años en Medline; además, se calcularon los parámetros cinéticos de cada fármaco con el objeto de establecer una recomendación teórica basada en la propuesta de Delcò y Huet. Se presentan recomendaciones para 186 medicamentos, según lo indicado en la ficha técnica (49,5%), DrugDex-Micromedex (26,3%) y OMS (18,8%); 6 recomendaciones se realizaron en base a publicaciones específicas y en 4 fármacos se propuso la recomendación teórica basada en los parámetros farmacocinéticos. Las recomendaciones finales para el manejo clínico fueron de: modificación de dosis (26,9%), monitorización hepática/analítica del paciente (8,6%), contraindicación (18,8%), emplear con precaución (19,3%) y no requerir ajuste (26,3%). En esta revisión se presentan recomendaciones específicas para el manejo práctico del paciente con insuficiencia hepática crónica, obtenida mediante una síntesis de la bibliografía publicada y completada con aplicación de una metodología teórica(AU)

Chronic liver diseases (CLD) alter the kinetics of drugs. Despite dosage adjustment is based on Child-Pugh scores, there are no available recommendations and/or algorithms of reference to facilitate dosage regimens. A literature review about dose adjustment of the drugs from the hospital guide -which are included in the list of the WHO recommended drugs to be avoided or used with caution in patients with liver disease- was carried out. The therapeutic novelties from the last few years were also included. In order to do so, the summary of product characteristics (SPC), the database DrugDex- Micromedex, the WHO recommendations and the review articles from the last 10 years in Medline were reviewed. Moreover, the kinetic parameters of each drug were calculated with the aim of establishing a theoretical recommendation based on the proposal of Delcò and Huet. Recommendations for 186 drugs are presented according to the SPC (49.5%), DrugDex-Micromedex (26.3%) and WHO (18.8%) indications; six recommendations were based on specific publications; the theoretical recommendation based on pharmacokinetic parameters was proposed in four drugs. The final recommendations for clinical management were: dosage modification (26.9%), hepatic/analytical monitoring of the patient (8.6%), contraindication (18.8%), use with caution (19.3%) and no adjustment required (26.3%). In this review, specific recommendations for the practical management of patients with chronic liver disease are presented. It has been elaborated through a synthesis of the published bibliography and completed by following a theoretical methodology(AU)

Cytotoxic effects of nasal buserelin on nasal mucosal tissue in rabbits.

To investigate the cytotoxic effects of nasal buserelin on rabbit nasal mucosal tissue, twenty-four female rabbits were studied prospectively. The rabbits were divided into 4 groups including 6 rabbits. The rabbits' left noses were included in the all study groups: 150 µg/puff/day of buserelin acetate was administered topically twice daily during 21, 42 and 63 days. Saline was administered topically twice daily to the left nasal cavity in the control group. The nasal septal mucosal stripe tissue was carefully removed from underlaying cartilage after sedation. HE staining, Masson's trichrome, toluidine blue and TUNEL staining were used to evaluate mucosal changes. Each preparation was investigated via apoptotic cells, and they were accounted. Kruskal-Wallis test was used to evaluate nonparametric comparison of apoptotic cells. Mononuclear cells have been raised in the sub-epithelial connective tissue, nucleuses of epithelial cells in the apical region were pyknotic, and apoptotic cells were determined on 21-day group. In the 42-day group, nasal epithelial tissue was similar to 21-day group and epithelial cells including pyknotic nucleus were present in this group, too. In the 63-day group, epithelial cells were light colored. Venous sinuses in the sub-epithelial connective tissue were wide but not congested and not raised collagen filaments. In the intra-epithelial tissue, some of cells were TUNEL (+). Apoptotic cells were fewer in the control group according to 21-day group. In 42- and 63-day groups, these cells were fewer than in 21-day group. Numerical difference was present between the groups, but statistical significance was not found between the groups. We concluded that nasal buserelin cytotoxicity was not potent in the nasal cavity in rabbits. We use nasal buserelin in all indications with confidence.

Using a GnRH agonist to obtain an index of testosterone secretory capacity in the cockatiel (Nymphicus hollandicus) and sulphur-crested cockatoo (Cacatua galerita).

OBJECTIVE: Validation of a stimulation test for determining the steroidogenic capacity of the parrot testis. The major aim was to characterise testosterone secretion after injection of a gonadotropin-releasing hormone agonist (GnRHa), then use the test to investigate seasonal reproduction in the male cockatiel. PROCEDURE: A synthetic GnRHa (buserelin; 8.0 microg of peptide/kg bodyweight) was injected IM into male cockatiels (n = 7) and sulphur-crested cockatoos (n = 3) and serial blood samples collected at 0, 30, 60, 90 and 120 min after administration. Once validated, the technique was subsequently used to examine seasonal changes (23 months) in the testosterone profile of a captive cockatiel population. RESULTS: Injection of buserelin resulted in a significant increase in the testosterone concentration of cockatiel plasma, with maximal concentrations occurring at approximately 60 (1.33 +/- 0.08 ng/mL) to 90 min (1.22 +/- 0.08 ng/mL) after injection. Although no clear pattern of seasonal variation in testosterone secretion was detected in cockatiel plasma, samples taken 60 and 90 min after administration showed a significant increase in all seasons. Injection of buserelin in the sulphur-crested cockatoo also resulted in increased testosterone secretion, with maximal concentrations obtained after 90 min. CONCLUSION: Buserelin can be used to obtain a reliable index of the prevailing testosterone capacity of the cockatiel and cockatoo testis. With further studies, this test may be incorporated into clinical assessment of reproductive status.

Conformational effects of Lys191 in the human GnRH receptor: mutagenesis and molecular dynamics simulations studies.

In the present study, we analyzed the role of Lys191 on function, structure, and dynamic behavior of the human GnRH receptor (hGnRHR) and the formation of the Cys14-Cys200 bridge, which is essential for receptor trafficking to the plasma membrane. Several mutants were studied; mutants lacked either the Cys14-Cys200 bridge, Lys191 or both. The markedly reduced expression and function of a Cys14Ser mutant lacking the 14-200 bridge, was nearly restored to wild-type/DeltaLys191 levels upon deletion of Lys191. Lys191 removal resulted in changes in the dynamic behavior of the mutants as disclosed by molecular dynamics simulations: the distance between the sulfur- (or oxygen-) sulfur groups of Cys (or Ser)14 and Cys200 was shorter and more constant, and the conformation of the NH(2)-terminus and the exoloop 2 exhibited fewer fluctuations than when Lys191 was present. These data provide novel information on the role of Lys191 in defining an optimal configuration for the hGnRHR intracellular trafficking and function.

Evidence for LHRH-receptor expression in human airway epithelial (Calu-3) cells and its role in the transport of an LHRH agonist.

PURPOSE: To determine whether LHRH-receptor is expressed in Calu-3, a human bronchial epithelial cell line, and to further determine whether this receptor plays a role in the transport of deslorelin, an LHRH agonist. METHODS: Using cultured monolayers of Calu-3 grown at air-interface, the presence and localization of LHRH-receptors in Calu-3 cells was determined using immunochemical methods. To determine the mechanisms of deslorelin transport, the directionality [apical-basolateral (A-B) and basolateral-apical (B-A)] of deslorelin transport across Calu-3 monolayers and the effects of temperature (37 degrees C and 4 degrees C) and an energy depletor (2,4-dinitrophenol) were investigated. To determine the role of LHRH-receptor in deslorelin transport across Calu-3 monolayers, the influence of an LHRH-receptor antisense oligonucleotide on the LHRH-receptor expression and deslorelin transport was studied. Also, the effect of a competing LHRH agonist, buserelin, on deslorelin transport was determined. RESULTS: Immunofluorescence studies indicated the predominance of LHRH-receptor in Calu-3 cells at the apical and lateral surfaces. Western blot and RT-PCR studies further confirmed the expression of LHRH-receptor in Calu-3 cells. Deslorelin transport across Calu-3 monolayers was vectorial, with the cumulative A-B transport (1.79 +/- 0.29%) at the end of 240 min being higher than the B-A transport (0.34 +/- 0.11%). Low temperature as well as 2,4-dinitrophenol abolished this directionality. LHRH-receptor antisense oligonucleotide decreased the receptor expression at the mRNA and protein level and reduced the A-B deslorelin transport by 55 +/- 4%, without affecting the B-A transport, suggesting a role for LHRH-receptor in the vectorial transport of deslorelin. In addition, buserelin reduced the A-B deslorelin transport by 56 +/- 5% without affecting the B-A transport. CONCLUSIONS: Taken together, our results provide evidence that deslorelin is transported across the respiratory epithelium via the LHRH-receptor.

In vitro and in vivo correlation of buserelin release from biodegradable implants using statistical moment analysis.

Here we investigated the possibility to develop different levels of correlation between in vitro drug release profiles and in vivo pharmacokinetic parameters for three Buserelin implant formulations. The in vitro and in vivo data were analyzed using model-independent and model-dependent methods. Since diffusion, dissolution and erosion effects influence drug release in most cases a simple kinetic model is unlikely to explain the overall in vivo release behavior. Thus the in vitro drug release curves were analyzed according to the theoretical models of Higuchi and Korsmeyer-Peppas. For the formulation with predominant diffusion controlled release level A IVIVC could be established (R2=0.986). Independent on drug release mechanism, a level B correlation between the mean in vitro dissolution time (MDT) and mean in vivo residence time (MRT) was obtained with a correlation coefficient of 0.983. Finally, level C correlation were observed when single in vitro parameters, e.g. T50% (time required to release 50% of drug in vitro) where compared with single in vivo parameters like AUC. This study suggests that a level B correlation could be achieved even when drug release occurs by a combination of diffusion and erosion processes. More sophisticated in vitro models mimicking drug release under in vivo conditions are clearly desirable for parenteral depot formulations.

Peroral delivery systems based on superporous hydrogel polymers: release characteristics for the peptide drugs buserelin, octreotide and insulin.

Novel peroral peptide drug delivery systems based on superporous hydrogel (SPH) and SPH composite (SPHC) have recently been developed in our laboratory. In this report the following issues were studied: release of the peptide drugs buserelin, octreotide and insulin from SPH and SPHC polymers and the developed delivery systems, stability of these peptides during the release and the integrity of insulin in the polymeric matrix of SPHC. Release studies from SPH and SPHC polymers revealed that buserelin, octreotide and insulin were released almost completely from the polymers. Peptide release rates from SPH were faster than from SPHC, due to the more porous structure of SPH polymer. All peptides studied in contact with SPHC polymer were stable under different environmental conditions (ambient temperature, 37 degrees C, light and darkness and at pH values 3.2 and 7.2). FTIR studies demonstrated that no covalent binding occurred between insulin and the polymeric SPHC matrix. Release profiles of all peptides from the developed delivery systems showed a time-controlled release profile: after a short lag time of 10-15 min, a burst release of peptides occurred during which more than 80% of peptide was released within 30-45 min. In conclusion, the present delivery systems based on SPH and SPHC show appropriate in vitro properties for application in peroral peptide drug delivery of buserelin, octreotide and insulin, and are therefore promising for further in vivo evaluation.

N-trimethylated chitosan chloride (TMC) improves the intestinal permeation of the peptide drug buserelin in vitro (Caco-2 cells) and in vivo (rats).

PURPOSE: To evaluate N-trimethyl chitosan chloride (TMC) of high degrees of substitution as intestinal permeation enhancers for the peptide drug buserelin in vitro using Caco-2 cell monolayers, and to investigate TMCs as enhancers of the intestinal absorption of buserelin in vivo, in rats. METHODS: TMCs were tested on Caco-2 cells for their efficiency to increase the paracellular permeability of the peptide buserelin. For the in vivo studies male Wistar rats were used and buserelin was administered with or without the polymers intraduodenally. Both types of experiments were performed at pH 7.2. RESULTS: Transport studies with Caco-2 cell monolayers confirmed that the increase in buserelin permeation is dependent on the degree of trimethylation of TMC. In agreement with the in vitro results, in vivo data revealed highly increased bioavailability of buserelin following intraduodenal co-administration with 1.0% (w/v) TMCs. Intraduodenally applied buserelin resulted in 0.8% absolute bioavailability, whereas co-administrations with TMCs resulted in mean bioavailability values between 6 and 13 %. Chitosan HCl (1.0%; pH = 7.2) did not significantly increase the intestinal absorption of buserelin. CONCLUSIONS: Both the in vitro and in vivo results indicate that TMCs are potent mucosal permeation enhancers of the peptide drug buserelin at neutral pH values.

Gender-specific exacerbation of murine lupus by gonadotropin-releasing hormone: potential role of G alpha(q/11).

We have previously demonstrated that GnRH and its analogues modulate the severity of murine systemic lupus erythematosus. In the present study, we demonstrate that GnRH alters disease severity in a sexually dimorphic fashion, even in gonadectomized mice. GnRH administration leads to an exacerbation of lupus in ovariectomized females, whereas it exerts no effect in castrated males. We initially hypothesized that gender differences in lymphocytic expression of GnRH receptor might explain these observations. Using competitive RT-PCR and binding studies to quantitate GnRH receptor expression in lymphoid organs, we found that GnRH administration led to decreased expression of GnRH receptor messenger RNA (mRNA) and GnRH binding, compared with vehicle, in spleens of ovariectomized females after 2 weeks of treatment. These decreases occurred concurrently with increased expression of interleukin-2 receptor mRNA and protein in females. GnRH administration did not alter GnRH receptor or interleukin-2 receptor mRNA or protein in castrated males. GnRH exerts actions on the pituitary through G protein signal transduction, specifically through G alpha(q/11). Competitive RT-PCR revealed that GnRH administration was associated with increases in the expression of G alpha(q/11) mRNA, compared with vehicle, in spleens in ovariectomized females but not in castrated males. Immunoblot analysis revealed a similar pattern. We conclude that gender differences in expression of G alpha(q/11) may contribute to gender differences in immunity and/or autoimmune disease.

Mucoadhesive polymers in peroral peptide drug delivery. VI. Carbomer and chitosan improve the intestinal absorption of the peptide drug buserelin in vivo.

PURPOSE: To evaluate the effect of the crosslinked poly(acrylate) carbomer 934P (C934P) and its freeze-dried neutralized sodium salt (FNaC934P) as well as chitosan hydrochloride on the intestinal absorption of the peptide drug buserelin. METHODS: Buserelin was applied intraduodenally in control buffer, 0.5% (w/v) C934P, 0.5% (w/v) FNaC934P, 1.5% (w/v) chitosan hydrochloride or FNaC934P/chitosan hydrochloride (1:1 (v/v)) mixture in rats. RESULTS: All polymer preparation showed a statistically significant improvement of buserelin absorption compared to the control solution. The absolute bioavailabilities for the different polymer preparations were: control, 0.1%; 0.5% FNaC934P, 0.6%; 0.5% C934P, 2.0%; chitosan hydrochloride, 5.1% and FNaC934P/chitosan hydrochloride (1:1 (v/v)) mixture, 1.0%. The higher bioavailability with chitosan hydrochloride compared to C934P and FNaC934P indicates that for buserelin the intestinal transmucosal transport enhancing effect of the polymer plays a more dominant role than the protection against proteases such as alpha-chymotrypsin. CONCLUSIONS: The mucoadhesive polymers carbomer 934P and chitosan hydrochloride are able to enhance the intestinal absorption of buserelin in vivo in rats, and may therefore be promising excipients in peroral delivery systems for peptide drugs.

Disposition of 3H-labelled buserelin continuously infused into rats.

The disposition of the gonadotropin-releasing hormone (GnRH) agonist buserelin was studied in male rats under conditions of long-term administration. Rats were continuously infused with about 30 pmole [3H]-buserelin/24 h subcutaneously by osmotic minipumps for 4-7 days. After killing the rats, the 3H-activity of the tissues was measured and was found to be highly concentrated (about 10-fold to plasma) only in the pituitary. The daily amounts of 3H-activity excreted in urine and faces were constant over the whole infusion period, suggesting steady state conditions. On a molar basis, of the infused dose of buserelin, 14.8% was found to be excreted into urine as intact peptide, and 16.5, 10.8 and 20.6% as the partial buserelin sequences 1-2, 1-3 and 5-9. It is concluded that the major elimination route of buserelin, constant with time, is glomerular filtration, followed by enzymatic degradation of part of the filtered peptide by kidney tubuli enzymes to the partial sequences 1-2, 1-3 and 5-9, which reflects the proteolytic breakdown of buserelin by kidney membrane peptidases in vitro. Based on the similarities in the pharmacokinetics, in vivo metabolities, and in vitro enzymatic degradabilities among the GnRH agonists that have the native GnRH sequence modified at position 6 with or without additional modification at the C-terminal, the elimination process as shown here for buserelin should also be valid for other GnRH agonists.

In vivo buccal delivery of the peptide drug buserelin with glycodeoxycholate as an absorption enhancer in pigs.

PURPOSE: To study the potential of buccal delivery of the peptide drug in pigs. METHODS: Intravenous administration and buccal delivery without and with 10 mM sodium glycodeoxycholate (GDC) as absorption enhancer were investigated as a randomised cross-over study in six pigs. The buccal delivery device consisted of an application chamber with a solution of buserelin and was attached to the buccal mucosa for 4 hours using an adhesive patch. RESULTS: Buccal administration of buserelin resulted in rapidly reached steady state plasma levels. The absolute bioavailability of the peptide after buccal delivery for 4 hours could be increased from 1.0 +/- 0.3 to 5.3 +/- 1.1% (mean +/- SD.) by co-administration of 10 mM GDC (0.45% w/v)). CONCLUSIONS: The results of this study demonstrate that buccal administration with the use of absorption enhancers is a useful approach for the delivery of peptide drugs such as buserelin.

Enhanced nasal delivery of luteinizing hormone releasing hormone agonist buserelin by oleic acid solubilized and stabilized in hydroxypropyl-beta-cyclodextrin.

The potential use of three 2-hydroxypropyl ether derivatives of cyclodextrins (HP-alpha-, HP-beta- and HP-gamma-CyDs) as biocompatible solubilizers and stabilizers for oleic acid, a lipophilic absorption enhancer, was assessed in the nasal absorption of buserelin, an agonist of luteinizing hormone-releasing hormone, in rats. HP-CyDs increased the aqueous solubility of oleic acid and protected it against oxidation through the formation of inclusion complexes with the efficacy increasing in the order: HP-gamma-CyD << HP-alpha-CyD < HP-beta- CyD. The bend structure due to a cis-double bond halfway along the acyl chain of oleic acid provided a better fit into the cavity of HP-beta-CyD, in which the double bond appears to be buried, and hence becomes less susceptible to oxidation. The rate and extent of nasal bioavailability of buserelin were remarkably increased by coadministration of oleic acid and HP-beta-CyD, compared with the sole use of the enhancer. This enhancement was ascribable to the lowering of both the enzymatic and physical barriers of the nasal epithelium to the peptide, probably through the facilitated transmucosal penetration of oleic acid solubilized in HP-beta-CyD.

Improvement of nasal bioavailability of luteinizing hormone-releasing hormone agonist, buserelin, by cyclodextrin derivatives in rats.

The effects of chemically modified cyclodextrins on the nasal absorption of buserelin, an agonist of luteinizing hormone-releasing hormone, were investigated in anesthetized rats. Of the cyclodextrins tested, dimethyl-beta-cyclodextrin (DM-beta-CyD) was the most effective in improving the rate and extent of the nasal bioavailability of buserelin. Fluorescence spectroscopic studies indicated that the cyclodextrins formed inclusion complexes with buserelin, which may reduce the diffusibility of buserelin across the nasal epithelium and may participate in the protection of the peptide against enzymatic degradation in the nasal mucosa. Additionally, the cyclodextrins increased the permeability of the nasal mucosa, which was the primary determinant based on the multiple regression analysis of the nasal absorption enhancement of buserelin. Scanning electron microscopic observations revealed that DM-beta-CyD induced no remarkable changes in the surface morphology of the nasal mucosa at a minimal concentration necessary to achieve substantial absorption enhancement. The present results suggest that DM-beta-CyD could improve the nasal bioavailability of buserelin and is well-tolerated by the nasal mucosa of the rat.

Bioavailability of buserelin and gonadorelin in suspensions.

There have been determined parameters defining biological availability of gonadorelin and buserelin marked 125 J. Hormonal preparations were hypodermically administered to the rats in suspensions containing zinc ions of the molar ratio of the hormone: zinc 1:5. It has been stated that buserelin in suspension is better available to an organism than gonadorelin .

The effects of buserelin microparticles on ovarian function in healthy women.

OBJECTIVE: To investigate the tolerance, pharmacokinetics and pharmacodynamics of the microparticle formulation of buserelin, when it was administered subcutaneously. DESIGN: A single-blind, randomised, parallel-group design was used to investigate the duration of suppression of ovarian function associated with doses of 1.8 3.6 and 7.2 mg buserelin administered subcutaneously as microparticles. SETTING: The study was carried out at the Hoechst Research Centre for Clinical Pharmacology, Department of Pharmacology, University of the Orange Free State, Bloemfontein. PATIENTS: Thirty-two health premenopausal female volunteers aged between 19 and 39 years and weighing between 52 and 85 kg completed the study. OUTCOME MEASURES: Serum progesterone and oestradiol concentrations were measured twice weekly until normal ovarian function resumed, i.e. when serum progesterone concentrations increased to at least 8 nmol/l (a sign of ovulation) and oestradiol concentrations increased to values above 300 pmol/l. Serum and urinary concentrations of buserelin were measured at the same times as those of progesterone and oestradiol. RESULTS: Doses of 1.8 3.6 and 7.2 mg elicited anovulation for mean periods of 52, 77 and 113 days and suppressed ovarian production of oestrogen for 19, 38 and 69 days. Resumption of normal ovarian function occurred when serum buserelin concentrations decreased to between 0.03 and 0.05 microgram/ml. The correlation coefficient between dose and duration of anovulation was 0.75; the correlation coefficient between dose and duration of suppression of oestrogen production was 0.76. CONCLUSION: Apart from minor side-effects such as hot flushes, vaginal spotting and acne, the compound was tolerated well. We conclude that a good relationship exists between dose and duration of suppression of ovarian function. Doses of 3.6 - 7.2 mg buserelin should suppress oestrogen production for approximately 6 - 9 weeks and ovulation for 11 - 16 weeks.

Impact of different GnRH analogs in benign gynecological disorders related to their chemical structure, delivery systems and dose.

This review addresses the question of whether the different gonadotropin releasing hormone (GnRH) agonists in clinical use might have different impacts, related to their chemical structure, delivery system and dose. Impact was investigated in benign gynecological disorders, i.e. endometriosis and leiomyoma. Arguments are presented indicating that a difference in impact of different analogs can be expected. All currently used intranasal, daily subcutaneous and depot preparations finally give rise to low levels of serum estradiol. The number of days before the first ovulatory menstruation after discontinuation of GnRH agonist treatment is remarkably constant. Four weeks after the last impact of the agonist, there is resumption of follicle growth. This phenomenon is independent of chemical structure, delivery system and dose. One should realize, however, that it generally takes about 30 days before the impact of a depot preparation disappears. Consequently, the impact of a depot preparation lasts 4 weeks longer than that of an otherwise applied agonist. Thus resumption of pituitary activity after discontinuation of a depot formulation takes 4 weeks longer than after discontinuation of non-depot formulations. All agonists have an impressive effect on endometriosis, independent of their chemical structure and delivery system. However, there are no studies comparing different agonists with the same delivery system in comparable endometriosis groups. Similarly, all agonists considerably reduce myoma volume, independently of their chemical structure and delivery system.(ABSTRACT TRUNCATED AT 250 WORDS)