Iron Protein Succinylate in the Management of Iron Deficiency Anemia: A Comparative Study with Ferrous Sulphate at Low and High Therapeutic Doses.

Oral iron supplementation constitutes the first line treatment for iron deficiency anemia (IDA), with daily doses between 80 mg and 200 mg of elemental iron. Ferrous salts, such as ferrous sulphate (FeSO4), while efficacious, frequently give rise to gastrointestinal side effects. In the present paper we attempted to directly compare the efficacy of an alternative to the FeSO4 formulation, which presents a better tolerability profile, iron protein succinylate (Ferplex®). In a diet-induced anemia model, rats were treated by oral gavage with vehicle, FeSO4, or Ferplex® at a human-dose equivalent of 80 mg and 200 mg of elemental iron. We evaluated the change in anemia-related hematological and biochemical parameters, conducting a histological examination of the intestine at sacrifice. Results indicate that both types of iron supplementation are equally effective in the treatment of IDA, restoring hemoglobin, hematocrit, erythrocytes, free iron and transferrin levels in 15 days, with no statistical differences between treated groups and control. The impact of anemia on body weight was also attenuated following treatment with both iron supplements. Thrombocyte and reticulocyte levels, altered by the anemic condition, returned to homeostasis after 15 days of either FeSO4 or Ferplex® treatment. Importantly, the lower and higher doses of iron were equally effective, thus supporting the current school of thought which states that lower therapeutic doses are sufficient for management of IDA. In addition, the study shows for the first time that oral treatment with Ferplex® does not increase serum hepcidin. Finally, Ferplex® induced minimal iron depositions in the intestinal tissue compared to FeSO4.

In Vitro-In Vivo Correlation (IVIVC) Population Modeling for the In Silico Bioequivalence of a Long-Acting Release Formulation of Progesterone.

Health authorities carefully evaluate any change in the batch manufacturing process of a drug before and after regulatory approval. In the absence of an adequate in vitro-in vivo correlation (Level A IVIVC), an in vivo bioequivalence (BE) study is frequently required, increasing the cost and time of drug development. This study focused on developing a Level A IVIVC for progesterone vaginal rings (PVRs), a dosage form designed for the continuous delivery in vivo. The pharmacokinetics (PK) of four batches of rings charged with 125, 375, 750 and 1500 mg of progesterone and characterized by different in vitro release rates were evaluated in two clinical studies. In vivo serum concentrations and in vitro release profiles were used to develop a population IVIVC progesterone ring (P-ring) model through a direct differential-equation-based method and a nonlinear-mixed-effect approach. The in vivo release, Rvivo(t), was predicted from the in vitro profile through a nonlinear relationship. Rvivo(t) was used as the input of a compartmental PK model describing the in vivo serum concentration dynamics of progesterone. The proposed IVIVC P-ring model was able to correctly predict the in vivo concentration-time profiles of progesterone starting from the in vitro PVR release profiles. Its internal and external predictability was carefully evaluated considering the FDA acceptance criteria for IVIVC assessment of extended-release oral drugs. Obtained results justified the use of the in vitro release testing in lieu of clinical studies for the BE assessment of any new PVRs batches. Finally, the possible use of the developed population IVIVC model as a simulator of virtual BE trials was explored through a case study.

Multidisciplinary laparoscopic management of deep infiltrating endometriosis from 2010 to 2017: A retrospective cohort study. / Manejo laparoscópico multidisciplinario de la endometriosis profunda del 2010 al 2017: estudio de cohorte retrospectivo.

BACKGROUND: Laparoscopy has become the standard of care in the surgical management of deep infiltrating endometriosis (DIE). However, it is a challenging procedure with a high complication rate. Despite the benefits of the minimally invasive approach, DIE resection is often performed by surgeons without adequate training, especially in developing countries like Chile. OBJECTIVE: To asses our experience in the diagnosis and laparoscopic management of DIE during seven years. METHODS: A retrospective cohort study of data including 137 patients with pathology-proven DIE. Surgical and fertility outcomes were evaluated. RESULTS: All procedures were performed laparoscopically without conversion. Dysmenorrhea and dyspareunia were the most common symptoms in 85.4% and 56.9%, respectively. Uterosacral ligaments were the most common DIE location. Endometrioma was present in 48.9% of cases. Median operative time was 140 minutes; however, it was longer in cases requiring bowel surgery (p < 0.0001). The complication rate was 10.9%. Median follow-up was 24.5 months. The pregnancy rate was 58.1% and 90% of patients reported significant symptom relief after surgery. CONCLUSION: Laparoscopic surgical management of DIE is effective and safe but it must be performed in tertiary centers with the availability of multidisciplinary teams.

INTRODUCCIÓN: La laparoscopía es actualmente el estándar en el manejo de la endometriosis profunda. Sin embargo, requiere de un entrenamiento específico e involucra la realización de procedimientos complejos y asociados a una alta tasa de complicaciones. Por lo anterior en Chile y Latinoamérica, la endometriosis profunda es frecuentemente manejada de manera inadecuada. OBJETIVO: Describir nuestra experiencia en el enfrentamiento clínico y manejo quirúrgico laparoscópico de la endometriosis profunda, durante los últimos siete años. MÉTODOS: Estudio de cohorte retrospectivo de 137 pacientes consecutivas operadas y con confirmación histológica de endometriosis profunda. Se recolectaron los datos demográficos, datos quirúrgicos, complicaciones, resultados reproductivos y seguimiento. RESULTADOS: Todas las cirugías fueron completadas por laparoscopía, sin conversión. La dismenorrea y la dispareunia fueron los síntomas más frecuentes en 85,4 y 56,9%, respectivamente. La localización más frecuente de endometriosis profunda fueron los ligamentos úterosacros, coexistiendo un endometrioma en 48,9% de los casos. La mediana de tiempo operatorio fue de 140 minutos, siendo significativamente más prolongado en casos con compromiso intestinal (p < 0,0001). Quince pacientes (10,9%) presentaron complicaciones. El seguimiento medio fue de 24,5 meses. La tasa de embarazo fue de 58,1% y 90% de las pacientes reportó una mejoría significativa de su sintomatología. CONCLUSIONES: El manejo laparoscópico de la endometriosis profunda es efectivo y seguro, pero debe reservarse a centros especializados y con disponibilidad de equipo multidisciplinario.

New inhibitors of angiogenesis with antitumor activity in vivo.

Angiogenesis is a requirement for the sustained growth and proliferation of solid tumors, and the development of new compounds that induce a sustained inhibition of the proangiogenic signaling generated by tumor hypoxia still remains as an important unmet need. In this work, we describe a new antiangiogenic compound (22) that inhibits proangiogenic signaling under hypoxic conditions in breast cancer cells. Compound 22 blocks the MAPK pathway, impairs cellular migration under hypoxic conditions, and regulates a set of genes related to angiogenesis. These responses are mediated by HIF-1α, since the effects of compound 22 mostly disappear when its expression is knocked-down. Furthermore, administration of compound 22 in a xenograft model of breast cancer produced tumor growth reductions ranging from 46 to 55% in 38% of the treated animals without causing any toxic side effects. Importantly, in the responding tumors, a significant reduction in the number of blood vessels was observed, further supporting the mechanism of action of the compound. These findings provide a rationale for the development of new antiangiogenic compounds that could eventually lead to new drugs suitable for the treatment of some types of tumors either alone or in combination with other agents.

The therapeutic effect of a new ultra low concentration estriol gel formulation (0.005% estriol vaginal gel) on symptoms and signs of postmenopausal vaginal atrophy: results from a pivotal phase III study.

OBJECTIVE: The aim of this study was to evaluate the efficacy and safety of a new low-concentration estriol formulation (0.005% estriol vaginal gel), providing an ultra low dose of estriol per application (50 µg), for the local treatment of postmenopausal vaginal atrophy. METHODS: Postmenopausal women with symptoms and signs of vaginal atrophy were enrolled in a prospective, double-blind, placebo-controlled study. Women received either 1 g of vaginal gel containing 50 µg of estriol or placebo gel, daily for 3 weeks and then twice weekly up to 12 weeks. A cytological vaginal study, evaluation of vaginal pH, and assessment of symptoms and signs of vaginal atrophy were performed, and changes between baseline and weeks 3 and 12 were assessed. Adverse events were recorded. RESULTS: A total of 167 women were included (114 received estriol and 53 received placebo). After 12 weeks of therapy, a superiority of estriol compared with placebo gel was shown in the change in maturation value and vaginal pH (P < 0.001 and P < 0.001, respectively). The superiority of estriol was well demonstrated in improvement of vaginal dryness (P = 0.001) and the Global Symptom Score (P = 0.018). Estriol gel proved also superior in the improvement of several of the most outstanding vaginal signs of vaginal atrophy evaluated. After 3 weeks, estriol gel also showed a superiority over the placebo gel in most symptoms and signs evaluated. Treatment-related adverse events were similar among groups. CONCLUSIONS: 0.005% Estriol vaginal gel, a new formulation providing an ultra low dose of estriol per application, was shown to be safe and effective in the treatment of postmenopausal vaginal atrophy.

Comparative uterine effects on ovariectomized rats after repeated treatment with different vaginal estrogen formulations.

OBJECTIVE: Topical estrogen therapy is recommended for the treatment of vaginal atrophy. This study was designed to compare the uterotrophic effects of a new estrogen vaginal formulation (0.005% estriol vaginal gel) and other existing topical treatments (Ovestinon(®) and Colpotrofin(®)). METHODS: Each one of the studied formulations was administered intravaginally to groups of ovariectomized rats with cytologically confirmed vaginal atrophy. The doses were adjusted by animal weight according to human dosage. After daily treatment for 14days, the animals were sacrificed and their vaginas and uteri removed. All uteri were weighted. Uteri and vaginas were fixed for histological evaluation. RESULTS: All three active formulations proved to be very effective in the cytological reversal of vaginal atrophy. However, they differ in their effects in the uteri. Ovestinon(®) and Colpotrofin(®) produced a significant increase in uterine weight, myometrial and endometrial thickness as well as histological modifications in the endometrium suggestive of estrogenic activity. Conversely, animals treated with 0.005% estriol vaginal gel, did not show significant weight increase or any other macroscopical or microcospical modifications of the uteri, an effect comparable to placebo. CONCLUSIONS: There are significant differences in the uterotrophic effect of three different topical estrogen formulations as tested in a rat model of vaginal postmenopausal atrophy. While the three formulations were equally effective in reversing vaginal atrophy, only the newly developed ultra-low dose 0.005% estriol vaginal gel has proved to lack any significant estrogenic effect on the uterus.

Intravitreal injection of the heparin analog 5-amino-2-naphthalenesulfonate reduces retinal neovascularization in mice.

The effect of the heparin analog 5-amino-2-naphthalenesulfonate (5-amino-2-NMS) on retinal neovascularization was investigated in the mouse model for oxygen-induced retinopathy (OIR). From postnatal day 7 (P7) until P12, mice were kept in a 75% oxygen environment. On P12, they received an intravitreal injection of 10mM 5-amino-2-NMS in one eye and PBS as control substance in the fellow eye. The animals were intracardially perfused with fluorescein-dextran solution on P17. Retinal whole mounts were prepared and ischemic retinopathy was evaluated in 30 animals using a standardized retinopathy score. A single intravitreal injection of 5-amino-2-NMS reduces significantly angioproliferative changes (blood vessel tufts, extra-retinal neovascularization, and blood vessel tortuosity) compared to the contralateral control eye (p=0.025). The median retinopathy score (maximal 13) for the 5-amino-2-NMS treated eyes was 6 versus 8 for the control eyes. 5-Amino-2-NMS binds to the heparin-binding site of FGF1 and FGF2 and thus may be a promising substance for the local treatment of retinal neovascularization.

A comparative pharmacokinetic study of micronized estradiol valerate administered alone and in combination with medroxyprogesterone acetate in postmenopausal women.

The objective of this study was to evaluate a possible pharmacokinetic interaction between 17beta-estradiol (E2) and medroxyprogesterone (MP) when administered together in a combined tablet because both hormones have common metabolic routes of biotransformation. The study assessed the mean pharmacokinetics parameters of E2 found after 1-dose administration of 2 different tablets containing E2, 1 containing 2 mg of micronized 17beta-estradiol valerate (E2V) and the other, administered after 2 weeks, 2 mg of E2V in combination with 5 mg of medroxyprogesterone acetate (MPA). The subjects were 15 healthy postmenopausal women with normal laboratory and clinic tests. The study was randomized, double blind, crossover, with 2 periods and 2 sequences. The blood samples were obtained at 0, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours after each administration. The E2 serum concentrations were determined by electrochemoluminiscence assay. From these data, the following pharmacokinetic parameters were calculated for E2 alone and E2 in combination with MPA (E2V/MPA): Cmax = 104.89 +/- 26.96, 103.27 +/- 44.40; AUC0-24 =1900.30 +/- 392.23, 1783.70 +/- 756.39; AUC0-infinity = 5576.06 +/- 4065.87, 5317.89 +/- 3702.54; ka = 1.06 +/- 0.31, 1.09 +/- 0.13; t1/2 = 35.65 +/- 20.62, 36.12 +/- 18.04; MRT = 16.29 +/- 8.77, 16.27 +/- 4.88; V/F = 16.29 +/- 8.76, 16.27 +/- 4.88. No significant differences between the pharmacokinetic parameters of E2 and E2/MPA were found, which led us to conclude that there is no pharmacokinetic interaction.

Allergen vaccination with a liposome-encapsulated extract of Dermatophagoides pteronyssinus: a randomized, double-blind, placebo-controlled trial in asthmatic patients.

BACKGROUND: Liposomes are potent immunologic adjuvants and have been proposed as allergen carriers in allergy vaccination. OBJECTIVE: We sought to investigate the efficacy and safety of vaccination with Dermatophagoides pteronyssinus encapsulated in liposomes. METHODS: We conducted a double-blind, placebo-controlled study. Fifty-five asthmatic patients sensitized to mites were randomly assigned vaccination with D pteronyssinus extract encapsulated in liposomes or empty liposomes for a period of 12 months. The principal parameters were symptom and medication-consumption scores. The percentage of healthy days (ie, days without medication and with absent or mild symptoms) was calculated. Immediate and late skin test results, allergen bronchial challenge test results, and allergen-specific serum immunoglobulin levels were evaluated before and after treatment. RESULTS: All clinical scores were markedly lower in the active group than in the placebo group after vaccination. Nearly half (45.8%) of the patients actively treated reduced their symptom and medication scores by at least 60% versus only 12% of patients receiving placebo treatment (P =.0388). The percentage of healthy days in the active group rose from 10.5% before treatment to 64.5% afterward (P =.0008). Reduction in organ sensitivity was demonstrated by skin prick test responses (P <.01), late-phase response after intradermal testing (P =.009), and bronchial challenge test results (P =.026) in the active group. Serum levels of specific IgG increased throughout the treatment, whereas specific IgE levels showed only an initial transient increase. No change in these parameters was observed in the placebo group. Vaccination was well tolerated, and no subcutaneous nodules appeared. CONCLUSION: Vaccination with D pteronyssinus encapsulated in liposomes is an effective and safe treatment for allergy-induced asthma.

Vigilancia endometrial y terapia de reemplazo hormonal / Endometrial surveillance and hormonal replacement therapy

Se revisa la literatura en el tema de vigilancia endometrial respecto de la ecografía transvaginal, histerosonografía, biopsia aspirativa e histeroscopia. Se propone un flujograma de manejo ante alteración de flujo rojo y terapia de reemplazo hormonal