Valerio Gaetano Vellone

Advances in pharmacotherapy for treating endometriosis

Introduction: Endometriosis is an estrogen-dependent chronic disease requiring long-term therapy. Therefore, the choice of medical treatment should be based on efficacy, preference of patients, incidence and severity of adverse effects and cost. Areas covered: This review briefly summarizes the currently available medical treatment for endometriosis. The treatments most recently proposed for endometriosis will be described in detail, including gonadotropin-releasing hormone (GnRH) antagonists, aromatase inhibitors (AIs) and the flexible extended combined oral contraceptive. Expert opinion: The oral contraceptive pill and progestogens allow for the treatment of the majority of patients with endometriosis. The flexible extended dosing regimen, containing drospirenone and ethinylestradiol, may be particularly useful in patients suffering severe dysmenorrhea and improving the adherence and compliance with treatment. GnRH agonists may be used in patients resistant to first-line therapy; up to now, limited data are available on the use of GnRH antagonist (such as elagolix) in patients with endometriosis. AIs should be regarded as experimental therapies and used only in patients with symptoms resistant to other therapies; however, the use of these drugs is limited by the possibility to administer the treatment for short-term periods only (6 months) and, similarly to GnRH antagonists, by the high incidence of adverse effects, requiring the use of add-back therapy.

Three-month treatment with ulipristal acetate prior to laparoscopic myomectomy of large uterine myomas: a retrospective study.

OBJECTIVE To assess the usefulness of 3-month treatment with ulipristal acetate (UPA) before laparoscopic myomectomy of large uterine myomas. STUDY DESIGN This retrospective analysis of a prospectively collected database included women of reproductive age requiring laparoscopic myomectomy with the following characteristics: FIGO type 3, 4 or 5 myomas; largest diameter of the main myoma ≥10cm; number of myomas ≤3; largest diameters of the other myomas ≤5cm (second myoma) and ≤3cm (third myoma). Patients either underwent direct surgery (group S) or were treated before surgery with UPA for 3 months (group UPA). RESULTS The mean (±SD) intraoperative blood loss was lower in group UPA (507.1±214.9ml) than in group S (684.2±316.8; p=0.012). The total operative time was lower in group UPA (137.6±26.8min) than in group S (159.7±26.8min; p<0.001); there was no significant difference in the suturing time between the two study groups (p=0.076). Hemoglobin drop was lower in group UPA (1.1±0.5g/dl) than in group S (1.3±0.7g/dl; p=0.034). Six patients in group S and no patient in group UPA required postoperative blood transfusions (p=0.031). Complications were not different between the two groups (p=0.726). Moreover, preoperative treatment with UPA caused a significant increase in hemoglobin levels (11.9±1.6g/dl) compared with baseline (9.1±1.1g/dl; p<0.001). CONCLUSION A 3-month treatment with UPA before laparoscopy for large uterine myomas decreases intraoperative blood loss, hemoglobin drop, postoperative blood transfusion and length of surgery.

Pharmacological Sirt6 inhibition improves glucose tolerance in a type 2 diabetes mouse model

Sirtuin 6 (SIRT6) is a sirtuin family member involved in a wide range of physiologic and disease processes, including cancer and glucose homeostasis. Based on the roles played by SIRT6 in different organs, including its ability to repress the expression of glucose transporters and glycolytic enzymes, inhibiting SIRT6 has been proposed as an approach for treating type 2 diabetes mellitus (T2DM). However, so far, the lack of small‐molecule Sirt6 inhibitors has hampered the conduct of in vivo studies to assess the viability of this strategy. We took advantage of a recently identified SIRT6 inhibitor, compound 1, to study the effect of pharmacological Sirt6 inhibition in a mouse model of T2DM (i.e., in high‐fat‐diet–fed animals). The administration of the Sirt6 inhibitor for 10 d was well tolerated and improved oral glucose tolerance, it increased the expression of the glucose transporters GLUT1 and ‐4 in the muscle and enhanced the activity of the glycolytic pathway. Sirt6 inhibition also resulted in reduced insulin, triglycerides, and cholesterol levels in plasma. This study represents the first in vivo study of a SIRT6 inhibitor and provides the proof‐of‐concept that targeting SIRT6 may be a viable strategy for improving glycemic control in T2DM.—Sociali, G., Magnone, M., Ravera, S., Damonte, P., Vigliarolo, T., Von Holtey, M., Vellone, V. G., Millo, E., Caffa, I., Cea, M., Parenti, M. D., Del Rio, A., Murone, M., Mostoslavsky, R., Grozio, A., Nencioni, A., Bruzzone S. Pharmacological Sirt6 inhibition improves glucose tolerance in a type 2 diabetes mouse model. FASEB J. 31, 3138–3149 (2017). www.fasebj.org

Efficacy and acceptability of long-term norethindrone acetate for the treatment of rectovaginal endometriosis

OBJECTIVE To study the efficacy of long-term treatment with norethindrone acetate (NETA) in patients with rectovaginal endometriosis. STUDY DESIGN This retrospective cohort study included 103 women with pain symptoms caused by rectovaginal endometriosis. Patients received NETA alone (2.5mg/day up to 5mg/day) for 5 years. Primary outcome was the degree of satisfaction with treatment after 5 years of progestin therapy. Secondary outcomes were the assessment of any variation in pain symptoms and the volumetric assessment of the disease by magnetic resonance imaging (MRI). RESULTS Sixty-one women completed the 5-year follow-up (61/103, 59.2%) with 16 women withdrawing because of adverse effects (38.1%). Overall, 68.8% (42/61) of the women who completed the study were satisfied or very satisfied of this long term NETA treatment. This represents a 40.8% (42/103) of the patients enrolled. Intensity of chronic pelvic pain and deep dyspareunia significantly decreased during treatment (p<0.001 versus baseline at 1 and 5year). Dyschezia improved after 1-year respect to baseline (p=0.008) but remained stable between first and second year (p=0.409). At the end of 5 years treatment, a radiological partial response was observed in 33 patients (55.9%, n 33/59); a stable disease in 19 patients (32.2%, n 19/59). Seven women (7/59, 11.9%) displayed a volumetric increase of rectovaginal endometriosis under NETA treatment. CONCLUSION Five-year therapy with NETA is safe and well tolerated by women with rectovaginal endometriosis. Due to its low cost and good pharmacological profile, it represents a good candidate for long-term treatment in this setting.

Nicotinic acid phosphoribosyltransferase regulates cancer cell metabolism, susceptibility to NAMPT inhibitors and DNA repair

In the last decade, substantial efforts have been made to identify NAD+ biosynthesis inhibitors, specifically against nicotinamide phosphoribosyltransferase (NAMPT), as preclinical studies indicate their potential efficacy as cancer drugs. However, the clinical activity of NAMPT inhibitors has proven limited, suggesting that alternative NAD+ production routes exploited by tumors confer resistance. Here, we show the gene encoding nicotinic acid phosphoribosyltransferase (NAPRT), a second NAD+-producing enzyme, is amplified and overexpressed in a subset of common types of cancer, including ovarian cancer, where NAPRT expression correlates with a BRCAness gene expression signature. Both NAPRT and NAMPT increased intracellular NAD+ levels. NAPRT silencing reduced energy status, protein synthesis, and cell size in ovarian and pancreatic cancer cells. NAPRT silencing sensitized cells to NAMPT inhibitors both in vitro and in vivo; similar results were obtained with the NAPRT inhibitor 2-hydroxynicotinic acid. Reducing NAPRT levels in a BRCA2-deficient cancer cell line exacerbated DNA damage in response to chemotherapeutics. In conclusion, NAPRT-dependent NAD+ biosynthesis contributes to cell metabolism and to the DNA repair process in a subset of tumors. This knowledge could be used to increase the efficacy of NAMPT inhibitors and chemotherapy. Cancer Res; 77(14); 3857-69. ©2017 AACR.

Computed tomographic colonography versus rectal-water contrast transvaginal ultrasonography in the diagnosis of rectosigmoid endometriosis: a pilot study.

To compare the performance of computed tomographic colonography (CTC) and rectal water‐contrast transvaginal sonography (RWC‐TVS) in the diagnosis of rectosigmoid endometriosis, and compare precision in estimating the length of the rectosigmoid nodules and the distance between the nodules and the anal verge.

Intestinal Endometriosis: Mimicker of Inflammatory Bowel Disease?

Background/Aims: Endometriosis of the intestinal tract (IE) is thought to mimic inflammatory bowel disease (IBD) both clinically and pathologically but robust data on a large unselected series are missing. Diagnostic problems arise both at colonoscopy as well as on resection specimens for IE when IBD-like features are encountered. The aim was to establish the frequency of IBD-like histology in IE and which type of histological lesions are shared by these two entities. Methods: One hundred consecutive, unselected cases of surgically resected IE were collected and clinical features and histopathology reviewed and reevaluated. Results: Seventy-five surgical specimens showed no histological alterations except for endometriosis foci. Twenty-two cases showed focal architectural alterations in the absence of significant inflammation. Three cases showed marked inflammatory and architectural mucosal changes making a differential diagnosis with IBD particularly challenging. On follow-up, however, these patients remained symptom-free and with no need for anti-inflammatory therapy after surgical resection of IE. Conclusions: Diagnostic problems may arise in women who have IBD-like symptoms and histology at colonoscopy but who lack a known diagnosis of endometriosis. Clinicians must be aware that the diagnosis of IBD in patients with IE should be reevaluated over time.

Magnetic resonance enema vs rectal water‐contrast transvaginal sonography in diagnosis of rectosigmoid endometriosis

To compare the accuracy of magnetic resonance enema (MR‐e) and rectal water‐contrast transvaginal sonography (RWC‐TVS) in the diagnosis of rectosigmoid endometriosis.

Folate receptor alpha antagonists in preclinical and early stage clinical development for the treatment of epithelial ovarian cancer

ABSTRACT Introduction: The prognosis of patients affected by ovarian cancer has not substantially changed in the last decades and improving survival still remains a challenge. In the promising era of ‘personalized therapy’ several new biologic therapies are currently being investigated: in this setting, targeting the folate receptor (FR) has been considered a new potential strategy for biologic therapy. Areas covered: The aim of the current review is to summarize, giving a critical overview,promising folate receptor alpha antagonists under preclinical or early clinical development for ovarian cancer. Expert opinion: Two categories of therapeutics are included in this class: FRα targeted mAbs and FRα-binding-ADC (Antibody drug conjugates); both share the interesting possibility of selecting patients via a biomarker which is already available. In the first class, farletuzumab has reached the most advanced stage in clinical evaluation and results of a Phase II randomized trial are awaited to assess its efficacy in a specific patients’ setting. MOv18 IgE represents a novel strategy to target FRα expressing cells, which has shown encouraging results in preclinical studies: further evaluation is needed in the clinical setting. IMGN 853 is an innovative FRα-binding ADC under development, with only preliminary results of a Phase I trial available.

Pharmacokinetic drug evaluation of ulipristal acetate for the treatment of uterine fibroids

ABSTRACT Introduction: Uterine fibroids are the most common form of benign gynecological tumors in women of reproductive ages. Although surgery is the main option to treat them, alternative pharmacological approaches are being investigated to control their symptoms. Among them, ulipristal acetate (UPA) has been the first selective progesterone-receptor modulator (SPRM) approved for the pre-operative and long-term treatment of uterine fibroids. Areas covered: The aim of this article is to review the literature on the pharmacodynamics, pharmacokinetics (PK), clinical efficacy and safety of UPA for the treatment of uterine fibroids. Expert opinion: UPA has both agonistic and antagonistic activity on progesterone receptor. Results from PK studies have shown that it has good oral bioavailability, and that it is extensively metabolized in the liver by cytochrome (CYP) 3A4. The PEARL I-II showed that the preoperative treatment with UPA decreases uterine bleeding, uterine volume and fibroid size in women with symptomatic uterine leiomyomas. The PEARL III and IV trials demonstrated the efficacy and safety of long-term intermittent treatment with UPA for the control of fibroid-related symptoms.