title: The combination of Everolimus with Verapamil reduces ovarian weight and vascular permeability on ovarian hyperstimulation syndrome: a preclinical experimental randomized controlled study.
abstract: The efficacy of pathways inhibition and the combined effect of Everolimus (mTOR inhibitor) and Verapamil (CYP3A inhibitor) in ovarian hyperstimulation syndrome (OHSS) need to be tested. Therefore, the impact of a leucotriene receptor antagonist, an anticoagulant, a GnRH antagonist as well as Everolimus plus Verapamil (at various doses and days of administration) on an OHSS rat model was tested. Sixty three female Wistar rats were randomly divided into seven groups. The control group received saline, while the OHSS group received rec-FSH for four consecutive days. The other five groups received rec-FSH for four days and Montelukast daily, Heparin daily, GnRH antagonist daily, Everolimus plus Verapamil in the last two days (half days group) and Everolimus plus Verapamil (half dose group) daily, respectively. All groups received also hCG at the fifth day. Significantly reduced ovarian weight was observed in the Everolimus plus Verapamil groups (half days and half-dose groups) and the Montelukast group compared to the OHSS group (p = 0.001 and p = 0.001, respectively). The vascular permeability was significantly reduced in the Everolimus plus Verapamil group (half dose group) and the GnRH antagonist group compared to the OHSS group (p < 0.001 and p = 0.011, respectively). However, estradiol and progesterone levels did not differ significantly between the groups. Studying the inhibition of different pathways, we concluded that the co-administration of Everolimus and Verapamil (at half dose) is beneficial for reducing ovarian weight and vascular permeability in an OHSS animal model.
authors.affiliation: a Department of Obstetrics and Gynecology , Genetics and IVF Unit, Medical School, Ioannina University , Ioannina , Greece.
authors.forename: Chrysoula
authors.initials: C
authors.lastname: Kitsou
authors.affiliation: b Department of Obstetrics and Gynecology , Ioannina State General Hospital G. Chatzikosta , Ioannina , Greece.|c The International Translational Medicine and Biomodeling Research Team, Laboratory of Molecular and Cellular Technologies, MIPT Center for Human Physiology Studies, Moscow Institute of Physics and Technology , Dolgoprudny , Russia.
authors.forename: Ioannis
authors.initials: I
authors.lastname: Kosmas
authors.affiliation: a Department of Obstetrics and Gynecology , Genetics and IVF Unit, Medical School, Ioannina University , Ioannina , Greece.
authors.forename: Leandros
authors.initials: L
authors.lastname: Lazaros
authors.affiliation: d Laboratory of Biochemistry , Ioannina University Hospital , Ioannina , Greece.
authors.forename: Christos
authors.initials: C
authors.lastname: Tzallas
authors.affiliation: c The International Translational Medicine and Biomodeling Research Team, Laboratory of Molecular and Cellular Technologies, MIPT Center for Human Physiology Studies, Moscow Institute of Physics and Technology , Dolgoprudny , Russia.|e Department of Obstetrics and Gynecology , Division of Experimental Endoscopic Surgery, Imaging, Minimally Invasive Therapy and Technology, Vito Fazzi Hospital , Lecce , Italy , and.
authors.forename: Andrea
authors.initials: A
authors.lastname: Tinelli
authors.affiliation: c The International Translational Medicine and Biomodeling Research Team, Laboratory of Molecular and Cellular Technologies, MIPT Center for Human Physiology Studies, Moscow Institute of Physics and Technology , Dolgoprudny , Russia.
authors.forename: Ospan
authors.initials: O
authors.lastname: Mynbaev
authors.affiliation: f Iakentro IVF Center , Thessaloniki , Greece.
authors.forename: Nikolaos
authors.initials: N
authors.lastname: Prapas
authors.affiliation: f Iakentro IVF Center , Thessaloniki , Greece.
authors.forename: Ioannis
authors.initials: I
authors.lastname: Prapas
authors.affiliation: a Department of Obstetrics and Gynecology , Genetics and IVF Unit, Medical School, Ioannina University , Ioannina , Greece.
authors.forename: Alexandros
authors.initials: A
authors.lastname: Dalkalitsis
authors.affiliation: a Department of Obstetrics and Gynecology , Genetics and IVF Unit, Medical School, Ioannina University , Ioannina , Greece.
authors.forename: Ioannis
authors.initials: I
authors.lastname: Georgiou
mesh_terms: D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects*; D065692:Cytochrome P-450 CYP3A Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D004195:Disease Models, Animal; D000068338:Everolimus / Q000008:administration & dosage / Q000494:pharmacology*; D005260:Female; D009929:Organ Size / Q000187:drug effects*; D016471:Ovarian Hyperstimulation Syndrome / Q000188:drug therapy*; D010053:Ovary / Q000187:drug effects*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D014700:Verapamil / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D065692:Cytochrome P-450 CYP3A Inhibitors; D047428:Protein Kinase Inhibitors; D000068338:Everolimus; D014700:Verapamil; D058570:TOR Serine-Threonine Kinases
keywords: Everolimus; ovarian hyperstimulation; ovarian weight; vascular permeability; verapamil