D-cycloserine in the treatment of posttraumatic stress disorder.

INTRODUCTION: Posttraumatic stress disorder (PTSD) is a common and serious psychiatric illness. Exposure therapy is a type of cognitive behavioral therapy that is considered a first-line treatment option for PTSD. D-cycloserine (DCS) enhances fear extinction/exposure therapy in patients with various anxiety disorders, presumably via its N-methyl-D-aspartate receptor partial agonist effects. The aim of this paper is to review the published literature regarding the efficacy of DCS in the treatment of PTSD. METHODS: A literature search for placebo-controlled trials assessing the use of DCS as the primary study drug in PTSD was conducted for trials published before June 2015 using PubMed, Ovid International Pharmaceutical Abstracts, and www.clinicaltrials.gov. The search terms were variations of "cycloserine" and "posttraumatic stress disorder." RESULTS: Seven clinical trials were analyzed, including 2 trials comparing DCS with placebo as add-on treatment to ongoing stable pharmacotherapy and 5 trials that compared DCS with placebo given prior to exposure therapy. D-cycloserine as adjunctive therapy showed no benefit in 1 trial and limited benefit in the other. As an enhancement of exposure therapy, DCS showed beneficial effects in 1 trial, detrimental effects in 1 trial, and inconclusive effects in 3 trials. DISCUSSION: Current literature does not adequately support the use of DCS as adjunctive therapy without psychotherapy, but limitations of the 2 studies that exist make firm conclusions unfeasible. D-cycloserine might have a role in augmentation of exposure therapy. Future studies should consider receptor selectivity, administration time with respect to peak cerebrospinal fluid concentrations, number of exposure therapy sessions, and dose.

Current and emerging treatments for irritable bowel syndrome with constipation and chronic idiopathic constipation: focus on prosecretory agents.

Irritable bowel syndrome with constipation (IBS-C) and chronic idiopathic constipation (CIC) are two common functional gastrointestinal disorders that impair quality of life and pose a significant economic burden to the health care system. Current therapeutic options include lifestyle modifications, over-the-counter (OTC) agents, antispasmodics, serotonin agonists, and lubiprostone and linaclotide, two prosecretory prescription drugs approved for the treatment of IBS-C and CIC. This review discusses the efficacy and safety of current treatments and emerging therapies for the treatment of IBS-C and CIC, with a focus on the prosecretory agents. A search of the PubMed database (1966-November 2014) was performed to identify relevant articles; clinical trials on emerging agents were also identified by searching the ClinicalTrials.gov registry. OTC laxatives may relieve constipation but do not treat abdominal pain and discomfort. Antispasmodics may provide short-term relief in patients with IBS-C, but their utility is limited by anticholinergic adverse effects. Tricyclic antidepressants, selective serotonin reuptake inhibitors, and serotonin-norepinephrine reuptake inhibitors have shown benefit in providing global symptom relief and in improving abdominal discomfort, but further research is needed. Phase III clinical trials have demonstrated the efficacy of lubiprostone and linaclotide relative to placebo for the short-term treatment of IBS-C and CIC, with improvements reported in stool frequency, perceived constipation severity, and abdominal pain and discomfort. Relatively small response rates, higher costs, and adverse effects associated with lubiprostone and linaclotide will likely render these agents suitable as second-line therapies in the treatment of IBS-C and CIC. Emerging potential treatment options include prucalopride, plecanatide, elobixibat, and tenapanor. Several of these emerging therapies have novel mechanisms of action and may show promise in patients with IBS-C and CIC who have not responded to other therapies.

Parental perspectives of diabetes management in Alabama public schools.

OBJECTIVES: The purpose of this study was to assess parental perceptions of the current state of care for children with diabetes in the Alabama public school system, identify existing disparities, and determine what resources would most improve diabetes management in this setting. There is a significant need for such information because of the paucity of published data on the current state of diabetes care in Alabama public schools. METHODS: We based our survey on the American Diabetes Association guidelines and collected responses on the Internet via SurveyMonkey and by paper surveys. We distributed surveys to parents of children with diabetes through the Children's Hospital endocrinology clinic, a diabetes camp, and through the Alabama Association of School Nurses e-mail listserv. RESULTS: A majority of children had type 1 diabetes mellitus. Students who could conveniently check their blood glucose levels (BGLs) at school were significantly more likely to participate in all school activities and their parents were significantly more likely to be satisfied with their child's diabetes care at school. Compared with minority students (defined as all races other than white), white students were more likely to be able to conveniently check their BGLs at school. CONCLUSIONS: The accommodation and care for children with diabetes is highly variable within much of the Alabama public school system. The ability to conveniently check BGLs at school is key for participation in all school activities and for parental satisfaction with diabetes care at school. Institution of a uniform, statewide diabetes training protocol for school personnel could improve care and parental satisfaction.

Linaclotide: a novel approach to the treatment of irritable bowel syndrome.

OBJECTIVE: To review the pharmacology, pharmacokinetics, efficacy, and safety of linaclotide for irritable bowel syndrome (IBS). DATA SOURCES: A literature search using PubMed (1966-August 2011) and International Pharmaceutical Abstracts (1970-July 2011) was conducted using the terms linaclotide and MD-1100. Additional publications were identified by reviewing bibliographies. Abstracts were included in the absence of published full studies. Product information was requested from the manufacturer. STUDY SELECTION AND DATA EXTRACTION: The search was limited to English-language publications. All available clinical trials of linaclotide pertinent to the pharmacology, pharmacokinetics, efficacy, and safety of linaclotide as a treatment for IBS were included. Animal studies were included in the absence of data in humans. DATA SYNTHESIS: Linaclotide is a guanylate cyclase-C agonist currently being studied in Phase 3 trials for the treatment of IBS with constipation. Controlled clinical trials have found that linaclotide significantly improves the number of complete spontaneous bowel movements per week, in addition to symptoms such as abdominal pain/discomfort, bloating, and straining. The most common adverse event associated with linaclotide is diarrhea. CONCLUSIONS: Linaclotide appears to be a safe and effective treatment for IBS. Additional clinical trials will more fully elucidate the safety profile of linaclotide and better define its place in therapy.

Wheel access does not attenuate weight gain in mice fed high-fat or high-CHO diets.

PURPOSE: To determine the effect of a high-fat or high-carbohydrate diet and running wheel activity on body composition, body mass, and caloric intake in C57Bl/6 mice. METHODS: At 4 wk of age, five groups of C57Bl/6 mice were housed individually. Two groups had running wheels, whereas the other three groups did not. Within the running wheel groups, FAT-W consumed a high-fat diet (60.3% fat) and CHO-W consumed a high-carbohydrate diet (70.4% carbohydrate). Within the nonrunning groups, FAT consumed the high-fat diet, CHO consumed the high-carbohydrate diet, and the fifth group consumed standard chow. All groups consumed food ad libitum and were exposed to their respective conditions for 12 wk. Wheel activity, food consumption, body mass (BM), and percentage of body fat (%BF) were recorded. RESULTS: There was no significant difference in %BF or BM at the end of 12 wk between FAT-W and FAT or between CHO-W and CHO (P > 0.05). %BF was significantly higher in both FAT-W (42.9% +/- 0.6%) and FAT (45.9% +/- 0.8%) compared with CHO-W (30.8% +/- 1.4%) or CHO (33.4% +/- 1.0%; P < 0.001). BM was significantly higher in both FAT-W (42.8 +/- 0.7 g) and FAT (44.7 +/- 1.2 g) compared with either CHO-W (32.8 +/- 1.6 g) or CHO (37.1 +/- 0.8; P < 0.01). There was no difference in wheel activity between FAT-W and CHO-W (P > 0.05). Daily caloric intake was higher in both FAT-W (17.0 +/- 0.8 kcal) and FAT (15.9 +/- 0.9 kcal) compared with that in CHO-W (13.9 +/- 0.7 kcal) and CHO (13.6 +/- 0.5 kcal; P < 0.01). CONCLUSIONS: Access to a running wheel had no protective effect on BM or %BF in C57Bl/6 mice that consumed either a high-fat or a high-carbohydrate diet during a 12-wk period. Access to a running wheel did not affect caloric intake; however, average daily caloric intake was higher in mice on high-fat diets compared with that in mice on a high-carbohydrate diet.

Anti-obesity effects of small molecule melanin-concentrating hormone receptor 1 (MCHR1) antagonists.

Over the past ten years, tremendous advances in our understanding of the role of the hypothalamic neurohormone, melanin-concentrating hormone (MCH), and its involvement in the regulation of food intake and body weight have been achieved. The MCHR1 receptor has been actively targeted as a much-needed, novel treatment for obesity, a disease of epidemic proportion in the United States. Numerous companies have joined the competition to be the first to produce a small molecule antagonist targeting MCHR1 receptors in the race for therapeutics for this disease. This review details the rising need for new treatments for obesity; the rationale and target validation of MCHR1 receptor antagonists as potential treatments for this disease; and the current status of the numerous small molecule MCHR1 antagonists in development by different companies. MCHR1 antagonists might find an additional usage in the treatment of anxiety and depression disorders. The rationale and current status of this effort by several companies is also reviewed.

Discovery of a novel, orally active, small molecule gonadotropin-releasing hormone (GnRH) receptor antagonist.

Gonadotropin releasing hormone (GnRH) plays an important role in the biology of reproduction. The use of GnRH receptor antagonists has been reported in the literature for the treatment of breast, ovarian, and prostate cancers. In this article, we report the synthesis, in vitro characterization, pharmacokinetics, and pharmacodynamics of an orally bioavailable, potent, small molecule GnRH receptor antagonist N-{4,6-dimethoxy-2-[(3-morpholin-4-ylpropyl)amino]pyrimidin-5-yl}-5-[3,3,6-trimthyl-2,3-dihydro-1H-inden-5-yl)oxy]-2-furamide (compound 1).

Biological characterization of a novel, orally active small molecule gonadotropin-releasing hormone (GnRH) antagonist using castrated and intact rats.

Gonadotropin-releasing hormone (GnRH) receptor antagonists have potential in treating numerous hormone-dependent pathologies including cancers of the prostate, breast, and ovary, endometriosis, and fertility disorders. An unmet clinical need exists for an orally available GnRH receptor antagonist. Guided by structure-activity relationships, ligand-based targeted library designs, and biomarker measurements, our discovery efforts have yielded a novel, small molecule GnRH receptor antagonist, 5-[(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthalenyl)methyl]-N-(2,4,6-trimethoxyphenyl)-2-furamide (CMPD1). CMPD1 bound with low nanomolar affinities to human, rat, and mouse GnRH receptors (6.0, 3.8, and 2.2 nM, respectively). CMPD1 was more than 100-fold selective for GnRH receptors versus various G-protein-coupled receptors and other enzymes and ion channels. In cells expressing recombinant rat GnRH receptors, CMPD1 was a competitive antagonist of GnRH-stimulated increases in extracellular acidification rates in Cytosensor microphysiometer assays. In cells expressing recombinant human GnRH receptors, CMPD1 was a potent inhibitor of GnRH-stimulated total inositol phosphate accumulation. The effects of CMPD1 on circulating levels of luteinizing hormone (LH) and testosterone were studied in castrated and intact male rats, respectively. Intravenous and oral administration of CMPD1 dose dependently suppressed GnRH-mediated elevations of LH in castrated male rats and testosterone in gonad-intact male rats. Moreover, CMPD1, when given at 20 mg/kg i.v. to intact male rats, inhibited the elevations of LH and testosterone stimulated by the superagonist of GnRH, [d-Ala(6), des-Gly(10)]GnRH (GnRH-A). These data suggest that CMPD1 is a potent, selective, orally active GnRH receptor antagonist that may have potential application as a therapeutic agent for treating hormone-dependent cancers and diseases.

The discovery of novel small molecule non-peptide gonadotropin releasing hormone (GnRH) receptor antagonists.

A novel series of non-peptide derivatives 1, 14, and 15 that bind with high affinity to the human GnRH receptors is discussed. The discovery was made from screening our in-house libraries that contained the active structure 2 along with a trace amount of a second active structure 1 that was derived from an acid-induced rearrangement. From this structure type 1, a series of guanidine and non-guanidine containing analogues were prepared and tested as GnRH receptor antagonists. Compounds derived from this series bind to both human and rat GnRH receptors and antagonize GnRH-mediated increases in inositol phosphate production in cells containing recombinant human receptors. These compounds or their analogues may be useful as therapeutic agents for the treatment of hormone-dependent pathologies including prostate, breast and ovarian cancers.

Characterization of mono- and diaminopyrimidine derivatives as novel, nonpeptide gonadotropin releasing hormone (GnRH) receptor antagonists.

A novel series of derivatives of mono- and diaminopyrimidines 1 potently displaced binding of a radiolabeled GnRH analogue to human and rat GnRH receptors. Analogues from these series competitively antagonized GnRH-stimulated increases in extracellular acidification in vitro and suppressed GnRH-mediated increases in circulating luteinizing hormone (LH) in castrated rats and testosterone in intact rats. These compounds or their analogues may be useful in treating sex hormone-dependent disease.

Effect of testosterone suppression on the pharmacokinetics of a potent gnRH receptor antagonist.

PURPOSE: The expression of cytochrome P450 enzymes (CYPs) in animals and humans is under complex hormonal regulation. Chronic treatment with drugs that alter sex hormone levels such as GnRH receptor agonists or antagonists may affect the expression of hormone-dependent CYPs, and as a result the pharmacokinetics of drugs metabolized by them. METHODS: Enzyme kinetic parameters were obtained by incubating AG-045572 (0.1-30 microM) with human or rat liver microsomes, or expressed CYP3A4 and CYP3A5. The pharmacokinetics of AG-045572 (10 mg/kg i.v. or 20 mg/kg p.o.) were studied in intact male, female, castrated male and male rats pretreated with AG-045572 for 4 days. RESULTS: AG-045572 is metabolized by CYP3A in both rats and humans. The Km values were similar in male and female human, female rat liver microsomes, and expressed CYP3A4 and CYP3A5 (0.39, 0.27, 0.28, 0.25, and 0.26 microM, respectively). The Km in male rat liver microsomes was 1.5 microM, suggesting that in male and female rats AG-045572 is metabolized by different CYP3A isozymes. The oral bioavailability of AG-045572 in intact male rats was 8%, while in female or castrated male rats it was 24%. Pretreatment of intact male rats with AG-045572 i.m. for 4 days resulted in suppression of testosterone to castrate levels, accompanied by an increase in oral bioavailability of AG-045572 to 27%. In the same experiment, the male-specific pulsatile pattern of growth hormone remained unchanged with slightly elevated baseline levels. CONCLUSIONS: The potent GnRH receptor antagonist AG-045572 is metabolized by hormone-dependent CYP3A. As a result, suppression of testosterone by pretreatment with AG-045572 "feminized" its own pharmacokinetics.