Phase 1b investigation of the MEK inhibitor binimetinib in patients with advanced or metastatic biliary tract cancer.

Background The MAPK pathway plays a central role in regulation of several cellular processes, and its dysregulation is a hallmark of biliary tract cancer (BTC). Binimetinib (MEK162), a potent, selective oral MEK1/2 inhibitor, was assessed in patients with advanced BTC. Patients and Methods An expansion cohort study in patients who received ≤1 line of therapy for advanced BTC was conducted after determination of the maximum tolerated dose in this Phase 1 trial. Patients received binimetinib 60 mg twice daily. The primary objectives were to characterize the safety profile and pharmacokinetics of binimetinib in advanced BTC. Secondary objectives included assessment of clinical efficacy, changes in weight and lean body mass, and pharmacodynamic effects. Tumor samples were assessed for mutations in relevant genes. Results Twenty-eight patients received binimetinib. Common adverse events (AEs) were mild, with rash (82%) and nausea (54%) being most common. Two patients experienced grade 4 AEs, one generalized edema and the other pulmonary embolism. The pharmacokinetics in this patient population were consistent with those previously reported (Bendell JC et al., Br J Cancer 2017;116:575-583). Twelve patients (43%) experienced stable disease and two had objective responses (1 complete response, 1 partial response) per Response Evaluation Criteria in Solid Tumors and stable metabolic disease by positron emission tomography/computed tomography. Most patients (18/25; 72%) did not have KRAS, BRAF, NRAS, PI3KCA, or PTEN mutations, nor was there correlation between mutation status and response. The average non-fluid weight gain was 1.3% for lean muscle and 4.7% for adipose tissue. Conclusion Binimetinib was well tolerated and showed promising evidence of activity in patients with BTC. Correlative studies suggested the potential for binimetinib to promote muscle gain in patients with BTC.

Ovulation requires the activation on proestrus of M1 muscarinic receptors in the left ovary.

We analyzed the effects of chemically blocking type 1 muscarinic receptors (M1R) on either the left or right ovary on ovulation rate, number of ova shed and steroid hormones levels. M1R were unilaterally blocked in ovary with the M1R selective antagonist pirenzepine (PZP). PZP was delivered into the bursa ovarica of the left or right ovary of adult rats at 13:00 h on proestrus day. PZP treatment in the left but not in the right ovary blocked ovulation. PZP did not modify the number of ova shed, nor progesterone or 17ß-estradiol serum levels. The surge of luteinizing hormone levels was diminished while that of follicle-stimulating hormone did not change in animals treated with PZP in the left ovary. Interestingly, treatment with either synthetic luteinizing hormone-releasing hormone or human chorionic gonadotropin 1 h after PZP administration in the left ovary restored ovulation in both ovaries. The presence of M1R protein in the theca cells of the ovarian follicles as well as in cells of the corpus luteum was detected on proestrus day. These results suggest that M1R activation in the left ovary is required for pre-ovulatory gonadotropin-releasing hormone (GnRH) secretion and ovulation. Furthermore, these results also suggest that M1R in the left ovary might be regulating ovulation asymmetrically through a stimulatory neural signal relayed to the hypothalamus via the vagus nerve to induce the GnRH secretion which then triggers ovulation.

Effects of systemic administration or intrabursal injection of serotonin on puberty, first ovulation and follicular development in rats.

To elucidate the role of serotonin in the onset of puberty, the effects of both systemic and in-ovarian bursa administration of serotonin on the neuroendocrine mechanism that modulates the onset of puberty, follicular development and first ovulation were evaluated. Two experiments were carried out. For the first, 25 or 37.5 mg kg⁻¹ of bodyweight of serotonin creatinine sulfate was administered by a subcutaneous route to 30-day-old female rats. In the second experiment, serotonin creatinine sulfate was administered directly into the ovarian bursa of 34-day-old female rats. Systemic administration of 25 or 37.5 mg kg⁻¹ of serotonin creatinine sulfate induced a delay in the ages of vaginal opening and first vaginal oestrus, a decrease in the number of ovulating animals, and serum concentrations of FSH, LH, oestradiol and progesterone. An increase in the number of Class 3 (>500 µm) and atretic follicles was observed in the ovaries of these animals. The administration of serotonin creatinine sulfate in the ovarian bursa did not modify the onset of puberty and ovulation, but a reduced serum concentration of oestradiol was observed. Our results suggest that serotonin acts on the components of the hypothalamus-hypophysis-ovary axis by modulating follicular development, ovarian functions and the onset of puberty.

Changes in progesterone receptor isoforms content in the rat brain during the oestrous cycle and after oestradiol and progesterone treatments.

We studied the effects of oestradiol and progesterone on progesterone receptor (PR) isoform content in the brain of ovariectomized rats and in intact rats during the oestrous cycle by Western blot analysis. In the hypothalamus and the preoptic area of ovariectomized rats, PR-A and PR-B content was increased by oestradiol, whereas progesterone significantly diminished the content of both PR isoforms after 3 h of treatment in the hypothalamus, but not in the preoptic area. In the hippocampus, only PR-A content was significantly increased by oestradiol while progesterone significantly diminished it after 12 h of treatment. In the frontal cortex, no treatment significantly modified PR isoform content. During the oestrous cycle, the lowest content of PR isoforms in the hypothalamus was observed on diestrus day and, by contrast, in the preoptic area, the highest content of both PR isoforms was observed on diestrus day. We observed no changes in PR isoform content in the hippocampus during the oestrous cycle. These results indicate that the expression of PR isoforms is differentially regulated by sex steroid hormones in a regionally specific manner.

Changes in monoaminergic activity in the anterior, medium and posterior hypothalamus, gonadotropins levels and ovarian hormones during puberty of the female rat.

The aim of present study is the analysis of monoamines concentrations changes in the anterior, medium and posterior hypothalamus, as well as changes in serum gonadotropins levels, ovarian steroids and follicular growth during the prepubertal development of the female rat. Noradrenergic activity in the anterior, medium and posterior hypothalamus reached highest level at day 13 after birth, followed by a subsequent decrease from day 15 to 19 and an increase on days 22 and 27 postnatal. At day 1, neural activity in the medium hypothalamus was higher than the activity in the anterior and posterior hypothalamus. Serotoninergic activity in three portions of the hypothalamus was higher throughout the prepubertal development. Follicle-stimulating hormone and luteinizing hormone serum levels increased between days 11 and 17 and decreased from day 19 to 36. The concentration of 17beta-estradiol was consistently low throughout the prepubertal development and increased at day 39 after birth. These results indicate that during the prepubertal development of the rat, the three regions of the hypothalamus show significant changes in the monoaminergic neural activity. There is an inverse relationship between the noradrenergic activity on the anterior and medium hypothalamus and serotoninergic activity in the posterior hypothalamus with ovarian steroids during sexual maturation. These changes may be linked to the development of the neuroendocrine processes that modulate gonadotropin secretion and ovarian function.

Ovulation delay induced by blockade of the cholinergic system on dioestrus-1, is related to changes in dopaminergic activity of the preoptic anterior-hypothalamic area of the rat.

One hour after the injection of 100 mg/kg of atropine-sulphate at 1300 h of dioestrus-1, there was an abrupt increase of 17beta-oestradiol plasma level and a significant increase in dopaminergic neural activity in preoptic anterior-hypothalamic area, without changes in luteinizing hormone serum level, in comparison with the saline injected group. Animals injected with atropine-sulphate showed a second increase in dopaminergic neural activity in the preoptic anterior-hypothalamic at 1100 of dioestrus-2 (atropine-sulphate 0.471 +/- 0.7 vs. saline 0.241 +/- 0.03, p < 0.01). In this group of animals, the preovulatory surges of 17beta-oestradiol and luteinizing hormone occurred simultaneously at 1700 h of the expected day of oestrus; spontaneous ovulation was delayed until the expected day of dioestrus-1. Present results suggest that during dioestrus-1 there is a functional relationship between the cholinergic and dopaminergic systems in preoptic anterior-hypothalamic area, regulating the release of luteinizing hormone resulting in ovulation.

Biochemical evidence of the functional recovery and regeneration of adrenal autotransplants in the rat spleen.

Adrenal transplantation may restore adrenal function after bilateral adrenalectomy or when adrenal function is lost. Thus, animal experiments could provide useful information before clinical application of adrenal transplantation. Using an experimental model of autotransplantion of a complete adrenal gland in the spleen of adrenalectomized rats, several biochemical and hormonal parameters were studied to evaluate the function of transplanted adrenal tissue compared to control and adrenalectomized animals. Three weeks after surgery, the animals were sacrificed and plasma and tissue samples were obtained for biochemical studies. In the autotransplanted rats, plasma glucose, hepatic glycogen, plasma, and hepatic proteins, which were decreased in adrenalectomized rats, increased to values close to those of the control group; whereas muscle and thymus proteins, which were increased in adrenalectomized animals, decreased and reached normal levels. Corticosterone plasma levels in autotransplanted rats showed a 50% recovery compared to control animals, whereas plasma aldosterone concentrations were low, with similar values to those of the adrenalectomized group. These results provide evidence that the adrenal grafts secrete corticosterone in quantities enough to overcome hepatic inactivation. On the other hand, aldosterone plasma concentrations remain very low, plasma potassium levels are increased, and plasma sodium levels are decreased in animals with intrasplenic adrenal grafts, indicating that aldosterone production is insufficient to avoid hypoaldosteronism.

Effects of infantile thymectomy on ovarian functions and gonadotrophin-induced ovulation in prepubertal mice: role of thymulin.

The effects of thymectomy performed on 10-day-old (Tx-10) mice on spontaneous puberty and the ovulatory response induced by gonadotrophin treatment were analysed, together with the effects of thymulin replacement from 10 days of age. Infantile thymectomy induced a delay of puberty, a decrease in serum 17beta-oestradiol concentration and a reduced total number of follicles. Injection of thymulin (12 ng/g body weight) to Tx-10 mice resulted in an earlier onset of puberty, a decrease in the weights of ovaries and uterus, and an increase in serum 17beta-oestradiol concentrations. In control and Tx-10 mice, treatment with pregnant mare serum gonadotrophin (PMSG) (5 IU) at 25 days of age resulted in ovulation and the numbers of ova shed by ovulating animals were similar. When the animals were injected with 1 IU PMSG ovulation did not occur. In Tx-10 mice, both 1 and 5 IU PMSG increased the number of follicles to values similar to those observed in the controls. In Tx-10 mice the sequential injection of PMSG (1 IU) and human chorionic gonadotrophin (hCG) (3 IU) resulted in ovulation, but the number of ova shed was lower than in controls. When these animals were injected daily with thymulin, an increase in the number of ova shed and serum 17beta-oestradiol concentrations was observed. The uterine weight of Tx-10 mice was always significantly reduced in response to gonadotrophin treatment. Thymulin injection in PMSG-hCG-treated Tx-10 mice provoked a significant increase in uterine weight. The results suggest that the presence of the thymus after the neonatal period is necessary to normal ovarian development and function. The increase in gonadotrophin-induced ovarian response produced by thymulin replacement indicates that this peptide has a role in this process as one of the connecting signals between thymus and ovaries.

[Gastroesophageal reflux in asthmatic patients: an incidence study and clinical correlation]. / El reflujo gastroesofágico en pacientes asmáticos: estudio de frecuencia y correlación clínica.

The prevalence of gastroesophageal reflux (GER) in asthmatic patients is elevated, but the exact frequency remains unknown. The relationship between GER and asthma has not been investigated in Mexico. The objective of this study is to know the frequency of GER in Mexican asthmatic patients and the possible relationship with the severity of asthma. Fifty patients with adult-onset asthma were studied. AII of them fulfill the diagnostic criteria of the National Institutes of Health, U.S. The evaluation included a symptoms questionnaire, spirometry, esophageal manometry, 24-h esophageal pH-recording, and an upper gastrointestinal endoscopy. Twenty-three patients had mild asthma (46%), 16 moderate (32%) and 11 had severe asthma (22%). Twenty-seven (54%) reported heartburn and regurgitation at least twice a week. The esophageal pH-recording showed pathologic GER in 37 subjects (74%) and endoscopic esophagitis was found in 7 cases (14%). The pH-recording showed pathologic GER in 13 patients with mild asthma (57%), in 13 with moderate asthma (81%) and in all patients with severe asthma (100%). The frequency of GER in Mexican asthmatic patients is high and increases proportionately with the severity of asthma. This factor must be considered in the integral evaluation of these patients.

[Hiatal hernia in asthmatic patients: prevalence and its association with gastroesophageal reflux]. / La hernia hiatal en pacientes asmáticos: prevalencia y su asociación con reflujo gastroesofágico.

INTRODUCTION: Evidence of a high prevalence of hiatal hernia (HH) and gastroesophageal reflux (GER) in asthmatic patients has been found. However, the relationship between these entities has not been studied in our country. OBJECTIVES: 1) To inform the prevalence of hiatal hernia in asthmatic patients, 2) To compare the prevalence of hiatal hernia in asthmatic vs. non-asthmatic patients, 3) To establish a possible association between hiatal hernia and GER in asthmatic patients. MATERIALS AND METHODS: In order to detect and to compare the prevalence of hiatal hernia in asthmatic and non-asthmatic patients, upper gastrointestinal endoscopy was performed. To establish the association between asthma and GER, data obtained from a gastrointestinal symptoms questionnaire, an esophageal manometry and an ambulatory pH recording in asthmatics with or without hiatal hernia were compared. RESULTS: Hiatal hernia was more frequently observed in asthmatics than in non-asthmatics (62% vs. 34%, p = 0.02). The frequency of typical symptoms of GER was similar in both asthmatics with or without hiatal hernia (54 vs. 43%, p = 0.3). Lower esophageal sphincter incompetence was similar in asthmatics with hiatal hernia (35%) vs. asthmatics without hiatal hernia (22%), as detected by manometry. Pathological GER was diagnosed by pH recording in 81% of the asthmatics with hiatal hernia and in 65% of asthmatics without hiatal hernia (p = 0.1). CONCLUSIONS: There is a high prevalence of hiatal hernia in asthmatics, which in turn results to be greater than in non-asthmatic patients. The presence of hiatal hernia does not correlate with the detection of pathological GER as determined by pH recording in this group of patients.

Effects of thymulin on spontaneous puberty and gonadotrophin-induced ovulation in prepubertal normal and hypothymic mice.

The effects of thymulin administration beginning on days 19 or 24 of age on spontaneous puberty and gonadotrophin-induced ovulation were analysed in female normal and hypothymic mice. In normal and hypothymic mice, the daily administration of thymulin at 24 days of age resulted in a delay in the age of vaginal opening, with an increase in serum progesterone levels. Normal mice treated with 200 ng thymulin beginning on day 19 of age and injected with pregnant mare serum gonadotrophin (PMSG) 24 h later had an increase in ovulation rate, number of ova shed and weight of the ovaries. None of the hypothymic mice treated with thymulin on day 19 and PMSG on day 20 ovulated. PMSG treatment on day 25 induced ovulation in hypothymic mice. When these animals were injected previously with 200 ng thymulin, the number of ova shed by ovulating animals was lower than in PMSG-treated animals. Administration of thymulin and sequential injection of PMSG and human chorionic gonadotrophin 54 h later resulted in an increase in ovulatory response in comparison with those receiving only PMSG. The results suggest that thymulin plays a role in the regulation of spontaneous puberty through its effects on adrenal and ovarian endocrine functions. The increase in the ovarian PMSG response-treated animals, previously given thymulin, showed that this thymic hormone participates in the regulation of gonadotrophin secretion mechanisms and seems to be dose- and age-dependent. In hypothymic mice, neuroendocrine mechanisms regulating puberty are different from those of normal mice.

Colchicine, D-penicillamine, and prednisone in the treatment of idiopathic pulmonary fibrosis: a controlled clinical trial.

STUDY OBJECTIVE: We compared the long-term efficacy of the combination of colchicine and/or D-penicillamine with prednisone, in comparison to prednisone alone in patients with idiopathic pulmonary fibrosis (IPF). DESIGN: Nonrandomized prospective study in patients with IPF confirmed by biopsy specimen. SETTING: National Institute of Respiratory Diseases, Mexico. PATIENTS: Fifty-six IPF patients were included in this study. Patients received either colchicine/ prednisone (n=19), D-penicillamine/prednisone (n=11), D-penicillamine/colchicine/prednisone (n=11), or prednisone alone (n=15). Prednisone therapy was started at 1.0 mg/kg/d for 1 month followed by a biweekly taper to a maintenance dose of 15 mg/d. Colchicine was administered at a daily dose of 1.0 mg, and D-penicillamine was given at a daily dose of 600 mg. MEASUREMENTS AND RESULTS: Response to therapy was assessed by changes in lung function test results as measured by total and vital lung capacities, arterial blood gas analysis at rest breathing room air, and survival. No significant differences either in lung mechanics or in arterial gases were found in any group relative to the baseline measurement. Thirteen of the 56 patients died during the first 2 years, and 29 were dead at 5 years follow-up. Comparison of survival curves by Cox regression model showed no statistically significant difference among the four groups. Known side effects attributable to prednisone were more common and severe than those attributable to the other drugs. CONCLUSIONS: Our results suggest that neither colchicine nor D-penicillamine modified the progressive course of prednisone-treated IPF, and that the search for new drugs is imperative.