Evaluation of Pharmacokinetics of a BCS Class III Drug with Two Different Study Designs: Tenofovir Alafenamide Monofumarate Film-coated Tablet.

Tenofovir alafenamide (TAF) is a BCS Class III compound and an oral pro-drug of Tenofovir (TFV) with limited oral bioavailability. The bioavailability of the oral intake increases with food as a result of the low stability of the active substance in the stomach. The reference drug is "Vemlidy® 25 mg Film Tablet", which contains 25 mg of TAF in "hemifumarate" form, is under patent protection until 15.08.2032 by Gilead, and so the "monofumarate" form was used in the present study. At first, a pilot study was conducted involving 12 subjects under fed conditions. The results of the pilot study revealed the test and reference products were not bioequivalent, as a result of insufficient statistical power and high inter-subject variability. Secondly, a physiologically based pharmacokinetic (PBPK) simulation was performed based on the pilot study results and literature data. Finally, the power of the design was increased and the pivotal study design was optimized into a four-period, full-replicated, cross-over study with 34 subjects under fed conditions and it was concluded that the test and reference products were bioequivalent. In conclusion, the present study proved the importance of a correct study design with higher statistical power for a BCS Class III compound with high variability, to present the pharmacokinetics.

A Study to Compare Bioequivalence Approach Between FDA and EMA in a Highly Variable Drug: Pinaverium Bromide Film Tablets.

The aim of this study is to investigate pharmacokinetic parameters of test and reference film tablet formulations of a highly variable drug, pinaverium bromide, under fasting conditions and to assess their bioequivalence in accordance with the FDA and EMA criteria. A randomised open-label, single oral dose, three-sequence, three-period, semi-replicated, cross-over trial was conducted with 36 healthy subjects. The intrasubject variability of reference products for Cmax and AUC0-tlast was found to be more than 50%. While bioequivalence was proven according to the FDA reference scaled average bioequivalence approach with only 36 subjects, more than 200 subjects are required to demonstrate bioequivalence in accordance with the EMA bioequivalence guideline. It is believed that the EMA bioequivalence criteria are too stringent for highly variable drugs whose intrasubject variability are more than 30% for both Cmax and AUC0-tlast and that in consequence the EMA ought to revise their bioequivalence guidelines for such drugs in the future.

Bioequivalence study of two favipiravir tablet formulations in healthy male subjects.

OBJECTIVE: The global pandemic called COVID-19 has dragged the world into a healthcare crisis, and favipiravir is one of the most prescribed agents against the virus so far. Favipiravir is a repurposed antiviral agent in treatment of SARS-CoV-2 infection, and to meet the current need, pharmaceutical companies are working for manufacturing licensed generic favipiravir. For getting the marketing authorization, the bioequivalence of the generic product must be proven first. The aim of this study is to demonstrate the bioequivalence of a new favipiravir tablet formulation as compared to the reference tablet formulation in healthy male subjects under fasting conditions. MATERIALS AND METHODS: To prove the bioequivalence, a randomized, single oral dose, cross-over, two-period study was carried out in 30 healthy subjects under fasting conditions. Plasma favipiravir levels were quantified by using an in-house-developed high performance liquid chromatography with mass spectrometry detector (LC-MSD) method. RESULTS: The 90% CIs for the test/reference geometric mean ratios of the Cmax and AUC0-tlast were 88.02 - 103.11% and 98.19 - 102.06%, respectively. CONCLUSION: This single-dose study has shown that the test and reference favipiravir products met the required bioequivalence criteria. Besides, both products were well tolerated and safe.

Genetic Burden and Outcome of Cystic Hygromas Detected Antenatally: Results of 93 Pregnancies from a Single Center in the Northern Region of Turkey.

OBJECTIVE: Genetic burden, fetal malformations, and fetal outcomes of 93 fetuses with cystic hygroma (CH) are reported from a single center in Turkey. PATIENTS AND METHODS: Pregnancies, having a diagnosis of fetal CH, detected between January 2010 and October 2016, were included in the study except fetuses having increased nuchal translucency. Fetal age/gender, maternal age, the age of pregnancy, types of fetal malformations, karyotype, and outcomes were evaluated. RESULTS: The average gestational age was 16.2 weeks. Nearly 47% of the pregnancies had multiple congenital anomalies, of which 58% had a chromosomal anomaly. Chromosomal anomaly rate was 68.2% in patients with hydrops fetalis. Aneuploidies were major chromosomal defects. All trisomies were of regular type except one with Robertsonian translocation (46, XY, +13, rob[13;14][q10;q10]). Seventy-four percentage pregnancies were terminated due to either fetal/karyotype anomaly. CONCLUSION: Characteristics of fetal CH were similar in different ethnical backgrounds. Aneuploidy is the dominant chromosomal constitution of fetal CH. Little information was known about the genes involved. Gene dosage effect implies that fetal CH is a complex genetic situation involving multiple genes interactions. For proper genetic counseling, each fetus with CH should be karyotyped, and fetal ultrasound examination should be performed. In the case of normal chromosome set, application of aCGH should be considered.

Leiomyoma With Bizarre Nuclei: Clinical and Pathologic Features of 30 Patients.

Leiomyoma with bizarre nuclei (LBN) have significant cytologic atypia, but high mitotic rate and tumor cell necrosis are absent. Although it is a benign leiomyoma variant, recurrent cases have been described. In this study, we investigated the clinical and pathologic features of LBN and compared them with related studies. A total of 30 patients diagnosed with LBN in our department were included in this study. In all cases, clinical data (age, complaint, surgery type), macroscopic features (size, location, number of leiomyomas, necrosis, and hemorrhage), microscopic features (bizarre cell distribution, bizarre cell density, cellularity, mitotic rate, tumor margin, necrosis, nuclear pseudoinclusions, karyorrhectic nuclei, prominent eosinophilic nucleoli with perinucleolar clearing, cytoplasmic eosinophilic inclusions, staghorn vessels, and alveolar-type edema), and follow-up data (recurrence and survival period) were evaluated. The mean age of the patients was 49.76 yr (range: 38-89 yr). Twenty-two patients (73%) had undergone hysterectomy and 8 patients (27%) had undergone myomectomy. The mean tumor diameter was 6.12 cm (range: 0.5-25 cm). The tumor was intramural in 11 patients (37%), subserosal in 7 patients (23%), and submucosal in 4 patients (13%). Microscopically, the bizarre cell distribution was focal in 8 patients (27%), multifocal in 12 patients (40%), and diffuse in 10 patients (33%). Bizarre cell density was low in 15 patients (50%), intermediate in 8 patients (27%), and high in 7 patients (23%). The mean mitotic count was 1.4 (0-4) in 10 high-power fields, and the tumor margin was regular in all cases. We observed pseudoinclusions in 24 of 30 (80%) tumors, karyorrhectic nuclei in 21 of 30 tumors (70%), prominent eosinophilic nucleoli with perinucleolar clearing in 12 tumors (40%), cytoplasmic eosinophilic inclusions in 11 tumors (37%), staghorn vessels in 9 tumors (30%), and alveolar-type edema in 9 tumors (30%). In addition, we examined the follow-up records of 26 patients (average duration: 58.1 mo). One patient had a smooth muscle tumor in the L3-L4 paravertebral region at 67 mo after hysterectomy. This tumor did not share similar microscopic and immunohistochemical findings to the patient's earlier uterine tumor. The definitive diagnosis of uterine smooth muscle tumors is important for the determination of the prognosis of the patient and the most appropriate therapeutic approach. As in several recent studies, our series has shown that LBN has a benign clinical course. However, other malignant morphologic criteria such as high mitotic rate and tumor cell necrosis should be excluded in the diagnosis of LBN.

Serum VEGF and PGF may be significant markers in prediction of severity of preeclampsia.

OBJECTIVE: The aim of this study evaluate the value of vascular endothelial growth factor (VEGF) and placental growth factor (PGF) serum levels in prediction of preeclampsia, severity and onset time of the disease. METHODS: Twenty five placentas of pregnant women diagnosed with preeclampsia (15 severe preeclampsia, 10 mild preeclampsia) and peripheral venous blood samples were collected. The placental and serum levels of VEGF and PGF were measured. RESULTS: VEGF level was significantly higher in cases and the optimal cut-off point was calculated as 600.5 to differentiate the cases and the controls, with 64% sensitivity and 100% specificity. There was a significant increase in median serum level of VEGF in severe cases compared to the mild cases and the controls. The optimal cut-off point for VEGF was calculated as 673.5 to differentiate mild and severe cases, with 93.3% sensitivity and 90% specificity. Whereas, PGF was significantly lower in severe cases than that in the mild cases and controls. The optimal cut-off point for PGF was calculated as 16.1 to differentiate mild and severe cases, with 66.7% sensitivity and 100% specificity. CONCLUSION: VEGF and PGF may be significant markers in prediction of severity of preeclampsia, and VEGF may also be valuable in prediction of preeclampsia.

Role of vascular endothelial growth factor and placental growth factor expression on placenta structure in pre-eclamptic pregnancy.

AIM: Pre-eclampsia is a hypertensive disease that is characterized by high blood pressure and proteinuria after 20 gestational weeks and complicates 3-8% of all pregnancies. It is classified as either mild or severe pre-eclampsia according to severity, and the aim of this study was to investigate the structural differences between these two classifications. METHODS: Placenta samples were collected from 68 women who underwent cesarean delivery. Total volume of villi and numerical density of vascular endothelial growth factor (VEGF)- and placental growth factor (PIGF)-positive cells were estimated on stereology and evaluated using one-way ANOVA. RESULTS: There was no significantly difference in total villi volumes between the groups (P > 0.05). In contrast, on immunohistochemistry, the numerical density of VEGF-positive cells in severe pre-eclampsia was significantly different to the control and mild pre-eclampsia groups (P<0.05). Additionally, the numerical density of PIGF-positive cells in the mild and severe pre-eclampsia group was significantly higher than in the control group (P<0.01). CONCLUSION: There is no relationship between villi volume and pre-eclampsia, although growth factors play a role in placental changes. The present results were supported by histopathology and several studies in the literature.

Do Leukocyte and Platelet Counts Have Benefit for \Preoperative Evaluation of Endometrial Cancer?

PURPOSE: The aim of this study was to investigate the association between preoperative leukocyte and platelet counts and the stage of the disease in patients with endometrial cancer. MATERIALS AND METHODS: Data for 100 patients undergoing total abdominal hysterectomy and bilateral salpingoophorectomy for benign uterine diseases and 177 patients surgically staged for endometrial cancer at Ondokuz Mayis University, Department of Gynecology and Obstetrics between 2005 and 2013, with preoperative complete blood count in the week prior to surgery including WBC, platelet count, pathologic evaluation for both benign and malign endometrium lesions, tumor stage and presence of lymphovascular space invasion (LVI), were retrospectively analyzed. RESULTS: The preoperative leukocyte count was significantly higher in patients with endometrial cancer when compared to the patients with benign diseases. However, there were no significant differences in platelet counts between the groups. Patients with advanced stage endometrial cancer had higher preoperative leukocyte counts when compared to the early stage disease whereas there was no difference in platelet count. Multivariate regression analysis identified preoperative leukocytosis as an independent prognostic factor for endometrial cancer. The optimal cut-off point for WBC was calculated as 10,500 to differentiate stage 1-2-3 and 4 with 88.9% sensitivity and 86.3% specificity (AUC: 0.901, 95% CI: 0.829-0.973, p<0.001, PPV: 25.8%, NPV: 99.3%). CONCLUSIONS: Preoperative leukocytosis is independently associated with advanced endometrial cancer.

Is Surgical Staging Necessary for Patients with Low-risk Endometrial Cancer? A Retrospective Clinical Analysis.

PURPOSE: The aim of this study was to compare the tumor-free and overall survival rates between patients with low-risk endometrial cancer who underwent surgical staging and those who did not undergo surgical staging. MATERIALS AND METHODS: Data, including demographic characteristics, grade of the tumor, myometrial invasion, cervical involvement, peritoneal washing, lymph node involvement, lymphovascular space invasion, postoperative complication, adjuvant treatment, cancer recurrence, and tumor-free and overall survival rates, for patients with low-risk endometrioid endometrial cancer who were treated surgically with and without pelvic and paraaortic lymph node dissection (LND) were analyzed retrospectively. The patients diagnosed with endometrioid endometrial cancer including the following criteria were considered low-risk: 1) a grade 1 (G1) or grade 2 (G2) endometrioid histology; 2) myometrial invasion of <50% upon magnetic resonance imaging (MRI); 3) no stromal glandular or stromal invasion upon MRI; and 4) no evidence of intra-abdominal metastasis. Then the patients at low-risk were divided into two groups; group 1 (n=117): patients treated surgically with pelvic and paraaortic LND and group 2 (n=170): patients treated surgically without pelvic and paraaortic LND. RESULTS: There was no statistical significance when the groups were compared in terms of lymphovascular space invasion, cervical involvement, positive cytology, and recurrence, whereas the administration of an adjuvant therapy was higher in group 2 (p<0.005). The number of patients with positive pelvic nodes and the number of metastatic pelvic nodes were significantly higher in the group with positive LVI than in the group without LVI (p<0.005). No statistically significant differences were detected between the groups in terms of tumor-free survival (p=0.981) and overall survival (p=0.166). CONCLUSIONS: Total hysterectomy with bilateral salpingo-oophorectomy and stage-adapted postoperative adjuvant therapy without pelvic and/or paraaortic lymphadenectomy may be safe and efficient treatments for low-risk endometrial cancer.

Platelet Indices May be Useful in Discrimination of Benign and Malign Endometrial Lesions, and Early and Advanced Stage Endometrial Cancer.

BACKGROUND: The aim of this study was to investigate the predictive value of white blood cells (WBC), the neutrophil to lymphocyte ratio (NLR), platelet indices including mean platelet volume (MPV), platelet distribution width (PDW), platelet crit (PCT) and platelet to lymphocyte ratio (PLR) in discrimination between benign and malign endometrial lesions, and early and advanced stage endometrial adenocarcinomas. MATERIALS AND METHODS: Data for 105 patients undergoing total abdominal or vaginal hysterectomy for benign uterine diseases and 114 patients surgically staged for endometrium adenocarcinoma at Ondokuz Mayis University, Department of Gynecology and Obstetrics, between 2008 and 2014, were collected. Parameters were preoperative and postoperative complete blood counts in the week prior to surgery with differentials including WBC, platelet count, platelet indices (MPV, PCT, PDW), NLR and PLR. Pathologic evaluations for both benign and malign endometrium lesions, grade of endometrium adenocarcinoma, tumor stage, presence of lymphovascular space invasion (LVI) were retrospectively analyzed. RESULTS: Regarding definitive factors in discriminating patients with endometrium cancer from those with benign diseases, MPV was significantly increased in the malign group whereas there was a significant decrease in the PDW value compared to the benign group. The best cut-off value in differentiation of the benign and malign groups, malign cases were found to increase over the value of 7.54 for MPV, and under 37.8 for PDW. When definitive factors in discrimination of early stage endometrium cancer from advanced stage disease and LVI in the malign group were evaluated according to the ROC analysis, no significant relation was detected between blood parameters and the stage and the LVI of the disease. CONCLUSIONS: MPV and PDW may have predictive value in the discrimination of benign and malign endometrium diseases. Nevertheless, since there have been few reports on this topic, further large-scale prospective studies are necessary.

Does surgical menopause affect sexual performance differently from natural menopause?

INTRODUCTION: Hysterectomy is the most common major gynecologic operation, together with bilateral salpingo-oophorectomy in the majority of women over the age of 45. AIM: To investigate whether surgical menopause affects female sexual performance differently from natural menopause. METHODS: The study included 121 women who had undergone surgical menopause and 122 women who had undergone natural menopause. All the women had similar economic, sociocultural, and personal demographic profiles, had been postmenopausal for at least 1 year, and were between the ages of 45 and 65. The women were asked to complete a six-question survey of sexual performance parameters (sexual desire, coital frequency, arousal, orgasm frequency, dyspareunia, and vaginal lubrication). These sexual performance parameters were compared between the surgical and natural menopause groups. RESULTS: With the exception of vaginal lubrication, sexual performance parameters were not statistically different between the two groups (P > 0.05). Vaginal lubrication in the surgically menopausal group was lower than in the naturally menopausal group (P < 0.05). Serum dehydroepiandrosterone sulphate, prolactin, and thyrotropin levels were not statistically different between the groups (P > 0.05), whereas serum estradiol and total testosterone levels in the surgically menopausal group were lower than those of the naturally menopausal group (P < 0.05). CONCLUSION: The results of this study showed that surgical menopause did not affect female sexual performance differently from natural menopause, with the exception of vaginal lubrication.

May ratio of neutrophil to lymphocyte be useful in predicting the risk of developing preeclampsia? A pilot study.

OBJECTIVE: The aim of the study was to evaluate the relationship between neutrophil to lymphocyte ratio (NLR) and preeclampsia. METHODS: Demographic data and laboratory tests for NLR of 203 pregnant women (73 normotensive pregnants, 23 pregnants with mild preeclampsia and 107 pregnants with severe preeclampsia) were retrospectively analyzed. Neutrophil to lymphocyte ratios were compared between the study groups. RESULTS: Preeclamptic pregnant women had smaller gestation weeks, lower hemoglobin level and fetal birth weight than that of normal pregnant women. NLR in preeclamptic group was significantly higher than that of normal group (p=0.023) and area under ROC curve was found statistically significant (p=0.023). However, there was no statistically significant relationship between NLR and severity, proteinuria level, subjective symptoms and onset time of the disease. CONCLUSION: The findings showed that the measurement of NLR periodically may be useful to predict high-risk pregnancies in terms of preeclampsia, but further studies are needed to determine its contribution.

May the platelet to lymphocyte ratio be a prognostic factor for epithelial ovarian cancer?

BACKGROUND: The study aimed to evaluate changes in hematologic parameters, including white blood cell, platelet count, platelet indices, the platelet to lymphocyte and neutrophil to lymphocyte ratios in patients with early and advanced stages of epithelial ovarian cancers. MATERIALS AND METHODS: The study included 100 patients with epithelial ovarian cancer who underwent primary staging exploratory laparotomy. Preoperative hematologic parameters, tumor histopathologic type, grade, stage and serum CA-125 levels were retrospectively analyzed. These parameters were compared between the patients with early (stage I-II) and advanced (stage III-IV) ovarian cancer. RESULTS: White blood cell count and platelet indices, including mean platelet volume, platelet distribution width and platelet crit did not show a statistically significant difference between groups with early and advanced ovarian cancer. However, the neutrophil to lymphocyte ratio, platelet count, the platelet to lymphocyte ratio and CA-125 level showed a statistically significant difference between the two groups (p<0.05, p<0.01, p<0.001, p<0.01 respectively). CONCLUSIONS: It was found that the neutrophil to lymphocyte ratio, platelet count and the platelet to lymphocyte ratio increased with the increasing stage of ovarian cancer. Furthermore, it was seen that the platelet to lymphocyte ratio is an independent prognostic factor related to the stage of epithelial ovarian cancer.

Asynchronous bilateral ovarian torsion. A case report and mini review.

BACKGROUND: Adnexal torsion is a serious condition and delay in surgical intervention may result in loss of ovary. Children and adolescents who have suffered from uterine adnexal torsion may be at risk for asynchronous torsion of the contralateral adnexa. CASE: We report the case of asynchronous bilateral ovarian torsion in a 9-year-old girl, resulting in right and subsequently left salpingo-oophorectomy. CONCLUSION: The diagnosis of ovarian torsion often is delayed. When ovarian torsion is suspected, laparoscopy should be performed without delay, and conservative management should be strongly considered to prevent surgical castration. Oophoropexy of the ipsilateral and contralateral ovary should be considered to prevent a recurrent torsion.

Comparison of perinatal outcome between adolescent and adult pregnancies.

OBJECTIVE: The aim of this study was to compare perinatal outcomes between adolescent and adult pregnancies. MATERIAL AND METHODS: In 527 adolescent and 1334 adult pregnant women who delivered at Ondokuz Mayis University Obstetrics and Gynecology Department between 2006 and 2013, perinatal outcomes were retrospectively compared in terms of including spontaneous abortion, induced abortion rate, dilatation and curettage (D&C), pregnancy-induced hypertension, premature prelabor and prelabor rupture of membranes, polihydramnios, oligohydramnios, maternal anemia, delivery modes and also neonatal outcomes including 5th minute Apgar score and fetal birth weight. RESULTS: The ratio of pregnancy induced hypertension and postpartum hemorrhage was higher in adults, but, anemia was more common in adolescents. There was statistically significant difference in the mode of delivery; the ratio of cesarean section was higher in adults whereas the rate of induced abortions and D&C significantly increased in adolescents. Low birth weight (LBW) and extremely LBW rates were significantly higher in adolescents, however, 5th minute Apgar scores were found to be higher than adult group. CONCLUSION: These results show that the perinatal care is fairly improved in Turkey.