42 research outputs found
Evidence that exclusive use of Follistim may produce better pregnancy results than the use of Gonal-F following in vitro fertilization (IVF) - embryo transfer (ET).
No full textPURPOSE: To evaluate whether the equal mixture of human menopausal gonadotropin (hMG) to recombinant (r) follicle stimulating hormone (FSH) for controlled ovarian hyperstimulation (COH) adversely affects outcome following in vitro fertilization (IVF). Furthermore, to determine if the specific rFSH preparation used has any differing effects on outcome.
METHODS: Retrospective study of women using the luteal phase leuprolide acetate-gonadotropin COH regimen. Outcome measures included clinical and viable pregnancy rates (PRs) and implantation rates.
RESULTS: The clinical and viable PRs and implantation rates were significantly lower in the group receiving exclusively Gonal-F. Addition of hMG to the treatment protocol not only did not lower the PRs further, but in fact seemed to obviate the adverse effect of Gonal-F.
CONCLUSION: Since exclusive use of Gonal-F did not adversely affect fertilization rates or quality of embryos we suspect its exclusive use in some way makes the uterine environment less receptive
Fermat's polygonal number theorem for repeated generalized polygonal numbers
No full textIn this paper, we consider sums of generalized polygonal numbers with repeats, generalizing Fermat's polygonal number theorem which was proven by Cauchy. In particular, we obtain the minimal number of generalized m-gonal numbers required to represent every positive integer and we furthermore generalize this result to obtain optimal bounds when many of the generalized m-gonal numbers are repeated r times, where r is a fixed positive integer
Binary positive semidefinite matrices and associated integer polytopes
No full textWe consider the positive semidefinite (psd) matrices with binary entries, along with the corresponding integer polytopes.We begin by establishing some basic properties of these matrices and polytopes. Then, we show that several families of integer polytopes in the literature—the cut, boolean quadric, multicut and clique partitioning polytopes—are faces of binary psd polytopes. Finally,we present some implications of these polyhedral relationships. In particular, we answer an open question in the literature on the max-cut problem, by showing that the rounded psd inequalities define a polytope
Complexity results for the gap inequalities for the max-cut problem
No full textWe prove several complexity results about the gap inequalities for the max-cut problem, including (i) the gap-1 inequalities do not imply the other gap inequalities, unless NP=Co NP; (ii) there must exist non-redundant gap inequalities with exponentially large coefficients, unless NP=Co NP; (iii) the associated separation problem can be solved in finite (doubly exponential) time
Comparative assessment of the structural features of human follicle-stimulating hormone in products from multiple markets
No full textStudy question
The aim of the study is to explore the structural differences occurring in recombinant human follicle-stimulating hormone alfa (r-hFSH- α), originator and its biosimilars, from various countries.
Summary answer
When compared with r-hFSH-α originator (Gonal-f), its biosimilars presented structural differences, namely Primapur showed a significant different glycosylation profile.
What is known already
FSH is part of cystine knot growth factor superfamily and plays a central role in reproduction, as FSH stimulates follicular development and estrogen synthesis. R-hFSH- α is commonly used in assisted reproductive technologies to achieve multifollicular development. At the present r-hFSH- α biosimilars are available in Europe and other regions. R-hFSH-α is a complex glycoprotein, that possesses several structural features critical for its efficacy and safety1–2. Glycosylation profile is one of the most impactful attributes of the molecule defining a moiety of FSH isoforms with impact on its biological net effect3. Efficacy and safety of r-hFSH- α are strictly correlated with glycoforms’ composition3–8.
Study design, size, duration
At least two different batches of each r-hFSH- α originator and its biosimilars have been included in the study.
Participants/materials, setting, methods
The structural features of products from six different marketed r-hFSH α (Gonal-f, Primapur, Folisurge Intas, Corneumon, Jin Sai Heng, Follitrope LG) have been investigated with a variety of analytical techniques in order to evaluate the presence of molecular differences, which could have a severe impact on the efficacy and safety of the product. The attributes which have been investigated in-depth include primary, secondary and tertiary structure as well as post-translational modifications (PTMs), including glycosylation and contaminants.
Main results and the role of chance
All r-hFSH- α biosimilars analyzed presented differences compared to the originator. We firstly investigated Primapur and found significant differences regarding multiple structural attributes, particularly in the glycosylation profile. Gonal-f exhibited lower glycan branching, expressed by an A-index* of 2.5, while Primapur showed an A-index of 2.4. Furthermore, Primapur showed a lower level of sialylation in comparison with Gonal-f, as measured by their respective S-index* of 1.8 and 2.1. FSH glycosylation exhibits both macroheterogeneity and microheterogeneity, impacting both FSH protein’s half-life and affinity with the follicle-stimulating hormone receptor (FSHR). Antennarity, representing FSH microheterogeneity, influence r-hFSH-α activity since it has been shown that bulky and extended glycans may take longer to fit into the FSHR cavity compared to less sterically hindering glycans, resulting in a delayed response 7,8.Additionaly, sialylation has been shown in-vivo to correlate with plasma half-life and effect on granulosa cells proliferation 1,2,3. The slower clearance of highly sialylated r-hFSH has been shown to lead to a higher in-vivo activity, despite the lower in-vitro bioactivity 1,2,3.
*A-index and S-index express respectively a measure of the number of antennae and sialic acid per glycan. Final values are generated from many relative abundances normalized to 100, highlighting the significance of small numerical differences.
Limitations, reasons for caution
More batches should be tested for each product. The authors are presenting full characterization of only one of the biosimilars since the rest of the products are under characterization.
Wider implications of the findings: r-hFSH-α originator and its biosimilar showed differences in terms of glycosylation profile that is well known as the major protein characteristic impacting FSH activity as extensively demonstrated in in-vivo and in-vitro models. This structural difference could have impact also on product efficacy and safety.
Trial registration number
‘not applicable
Major results of a phase III comparative multicenter study on the follitropin alfa biosimilar (Primapur®) and the original follitropin alfa (Gonal-f®)
No full textA clinical study on the efficacy and safety of follitropin alfa has been conducted. The aim of the study was to confirm the therapeutic equivalence between the follitropin alfa biosimilar (Primapur®) and the reference medication (Gonal-f®) in controlled induction of superovulation within the assisted reproductive technologies (ART) programs. Materials and methods. This multicenter, randomized, blind at the embryological stage, in parallel groups, comparative study of phase III (RCT 754 from 26.10.16/NCT03088137) involved 110 women aged 20-35 years with established causes of infertility (tubal factor, male factor). The patients were randomized into 2 equal groups of 55 participants each. The primary end-point for assessing the therapeutic equivalence was the number of aspirated oocytes. The secondary end-points included the number of fertilized oocytes, the number of days of stimulation, the total dose of the injected drug, the occurrence rate of biochemical and clinical pregnancies. Results. In this study, the follitropin alfa biosimilar was shown to be equivalent to the original follitropin in terms of the number of aspirated oocytes. Also, no statistically significant differences were found in the number of mature and fertilized oocytes, the days of stimulation, the dose of the drug administered during the treatment, and the rate of the onset of biochemical or clinical pregnancy. Conclusion. The therapeutic equivalence between the follitropin alfa containing Primapur® and Gonal-f® has been demonstrated
Study of microstructure and electrical properties of Y123 cylinders prepared by melt textured growth technique
No full text
Clinical experience with recombinant human FSH (Gonal F): a collaborative study in IVF/ET
No full textGlycosylation Pattern and in vitro Bioactivity of Reference Follitropin alfa and Biosimilars
No full textRecombinant follicle-stimulating hormone (FSH) (follitropin alfa) and biosimilar preparations are available for clinical use. They have specific FSH activity and a unique glycosylation profile dependent on source cells. The aim of the study is to compare the originator (reference) follitropin alfa (Gonal-f (R))- with biosimilar preparations (Bemfola (R) and Ovaleap (R))-induced cellular responses in vitro. Gonadotropin N-glycosylation profiles were analyzed by ELISA lectin assay, revealing preparation specific-patterns of glycan species (Kruskal-Wallis test; p < 0.05, n = 6) and by glycotope mapping. Increasing concentrations of Gonal-f (R) or biosimilar (1 x 10(-3) -1 x 10(3) ng/ml) were used for treating human primary granulosa lutein cells (hGLC) and FSH receptor (FSHR)-transfected HEK293 cells in vitro. Intracellular cAMP production, Ca2+ increase and beta-arrestin 2 recruitment were evaluated by BRET, CREB, and ERK1/2 phosphorylation by Western blotting. 12-h gene expression, and 8- and 24-h progesterone and estradiol synthesis were measured by real-time PCR and immunoassay, respectively. We found preparation-specific glycosylation patterns by lectin assay (Kruskal-Wallis test; p < 0.001; n = 6), and similar cAMP production and beta-arrestin 2 recruitment in FSHR-transfected HEK293 cells (cAMP EC50 range = 12 +/- 0.9-24 +/- 1.7 ng/ml; beta-arrestin 2 EC50 range = 140 +/- 14.1-313 +/- 18.7 ng/ml; Kruskal-Wallis test; p >= 0.05; n = 4). Kinetics analysis revealed that intracellular Ca2+ increased upon cell treatment by 4 mu g/ml Gonal-f (R), while equal concentrations of biosimilars failed to induced a response (Kruskal-Wallis test; p < 0.05; n = 3). All preparations induced both 8 and 24 h-progesterone and estradiol synthesis in hGLC, while no different EC(50)s were demonstrated (Kruskal -Wallis test; p > 0.05; n = 5). Apart from preparation-specific intracellular Ca2+ increases achieved at supra-physiological hormone doses, all compounds induced similar intracellular responses and steroidogenesis, reflecting similar bioactivity, and overall structural homogeneity
