Discovery of potent small-molecule inhibitors of lipoprotein(a) formation.

Lipoprotein(a) (Lp(a)), an independent, causal cardiovascular risk factor, is a lipoprotein particle that is formed by the interaction of a low-density lipoprotein (LDL) particle and apolipoprotein(a) (apo(a))1,2. Apo(a) first binds to lysine residues of apolipoprotein B-100 (apoB-100) on LDL through the Kringle IV (KIV) 7 and 8 domains, before a disulfide bond forms between apo(a) and apoB-100 to create Lp(a) (refs. 3-7). Here we show that the first step of Lp(a) formation can be inhibited through small-molecule interactions with apo(a) KIV7-8. We identify compounds that bind to apo(a) KIV7-8, and, through chemical optimization and further application of multivalency, we create compounds with subnanomolar potency that inhibit the formation of Lp(a). Oral doses of prototype compounds and a potent, multivalent disruptor, LY3473329 (muvalaplin), reduced the levels of Lp(a) in transgenic mice and in cynomolgus monkeys. Although multivalent molecules bind to the Kringle domains of rat plasminogen and reduce plasmin activity, species-selective differences in plasminogen sequences suggest that inhibitor molecules will reduce the levels of Lp(a), but not those of plasminogen, in humans. These data support the clinical development of LY3473329-which is already in phase 2 studies-as a potent and specific orally administered agent for reducing the levels of Lp(a).

A Novel Nociceptin Receptor Antagonist LY2940094 Inhibits Excessive Feeding Behavior in Rodents: A Possible Mechanism for the Treatment of Binge Eating Disorder.

Nociceptin/orphanin FQ (N/OFQ), a 17 amino acid peptide, is the endogenous ligand of the ORL1/nociceptin-opioid-peptide (NOP) receptor. N/OFQ appears to regulate a variety of physiologic functions including stimulating feeding behavior. Recently, a new class of thienospiro-piperidine-based NOP antagonists was described. One of these molecules, LY2940094 has been identified as a potent and selective NOP antagonist that exhibited activity in the central nervous system. Herein, we examined the effects of LY2940094 on feeding in a variety of behavioral models. Fasting-induced feeding was inhibited by LY2940094 in mice, an effect that was absent in NOP receptor knockout mice. Moreover, NOP receptor knockout mice exhibited a baseline phenotype of reduced fasting-induced feeding, relative to wild-type littermate controls. In lean rats, LY2940094 inhibited the overconsumption of a palatable high-energy diet, reducing caloric intake to control chow levels. In dietary-induced obese rats, LY2940094 inhibited feeding and body weight regain induced by a 30% daily caloric restriction. Last, in dietary-induced obese mice, LY2940094 decreased 24-hour intake of a high-energy diet made freely available. These are the first data demonstrating that a systemically administered NOP receptor antagonist can reduce feeding behavior and body weight in rodents. Moreover, the hypophagic effect of LY2940094 is NOP receptor dependent and not due to off-target or aversive effects. Thus, LY2940094 may be useful in treating disorders of appetitive behavior such as binge eating disorder, food choice, and overeating, which lead to obesity and its associated medical complications and morbidity.

A Novel, Orally Bioavailable Nociceptin Receptor Antagonist, LY2940094, Reduces Ethanol Self-Administration and Ethanol Seeking in Animal Models.

BACKGROUND: The nociceptin/orphanin-FQ (or opioid receptor-like [ORL1]) receptor (NOP) is localized in the mesolimbic reward pathway and has been suggested to play a role in feeding, mood, stress, and addiction. Since its deorphanization in 1995, there has been a clear dichotomy in the literature regarding whether an agonist or antagonist would provide therapeutic benefit. Specifically, the literature reports indicate that NOP receptor antagonists produce efficacy in animal models of hyperphagia and antidepressant-like activity, whereas NOP agonists produce anxiolytic-like effects and dampen reward/addiction behaviors including ethanol consumption. METHODS: We characterize here the potent, orally bioavailable NOP antagonist, LY2940094, in rodent models of ethanol consumption, including ethanol self-administration, progressive ratio operant self-administration, stress-induced reinstatement of ethanol seeking, and in vivo microdialysis in the nucleus accumbens. RESULTS: LY2940094 dose dependently reduced homecage ethanol self-administration in Indiana alcohol-preferring (P) and Marchigian Sardinian alcohol-preferring (msP) rats, without affecting food/water intake or locomotor activity. Reduced ethanol intake in P rats did not show significant tolerance over 4 days of subchronic dosing. LY2940094 attenuated progressive ratio operant responding and break points for ethanol in P rats. Moreover, stress-induced reinstatement of ethanol seeking in msP rats was completely blocked by LY2940094. Furthermore, LY2940094 blocked ethanol-stimulated dopamine release in response to ethanol challenge (1.1 g/kg, intraperitoneally). CONCLUSIONS: Our findings demonstrate for the first time that blockade of NOP receptors attenuates ethanol self-administration and ethanol-motivated behaviors, stress-induced ethanol seeking, and ethanol-induced stimulation of brain reward pathways in lines of rats that exhibit excessive ethanol consumption. Results suggest that LY2940094 may have potential therapeutic utility in treating alcohol addiction.

Checklist of the temporal bone and lateral skull base CT-scan.

Computed tomography scan of the temporal bone is a fundamental imaging modality for both the diagnosis and treatment of a wide range of pathologies affecting this complex structure. Temporal bone computed tomography scan provides a more detailed depiction of bone structures, compared with magnetic resonance imaging and, for this reason computed tomography scan is the imaging modality of choice in the planning of otological surgery. The aim of this article is to present a checklist to allow the otolaryngologist to assess systematically and in an organized manner the main anatomical landmarks, anatomical variants, as well as the most common postoperative surgical changes, which can be identified before any safe otological surgery. This revision was promoted by the Spanish Society of Otolaryngology and elaborated in a checklist template divided into the different areas of the temporal bone and the lateral skull base.

The Angiopoietin-Like Protein 3 and 8 Complex Interacts with Lipoprotein Lipase and Induces LPL Cleavage.

Lipoprotein lipase (LPL) is the key enzyme that hydrolyzes triglycerides from triglyceride-rich lipoproteins. Angiopoietin-like proteins (ANGPTL) 3, 4, and 8 are well-characterized protein inhibitors of LPL. ANGPTL8 forms a complex with ANGPTL3, and the complex is a potent endogenous inhibitor of LPL. However, the nature of the structural interaction between ANGPTL3/8 and LPL is unknown. To probe the conformational changes in LPL induced by ANGPTL3/8, we found that HDX-MS detected significantly altered deuteration in the lid region, ApoC2 binding site, and furin cleavage region of LPL in the presence of ANGPTL3/8. Supporting this HDX structural evidence, we found that ANGPTL3/8 inhibits LPL enzymatic activities and increases LPL cleavage. ANGPTL3/8-induced effects on LPL activity and LPL cleavage are much stronger than those of ANGPTL3 or ANGPTL8 alone. ANGPTL3/8-mediated LPL cleavage is blocked by both an ANGPTL3 antibody and a furin inhibitor. Knock-down of furin expression by siRNA significantly reduced ANGPT3/8-induced cleavage of LPL. Our data suggest ANGPTL3/8 promotes furin-mediated LPL cleavage.

Fournier's gangrene in a 44-year-old woman: CT scan findings.

OBJECTIVES: To show standard CT findings and their diagnostic usefulness in female patients suffering from Fournier's gangrene. METHOD/RESULT: A woman who had undergone a previous lateral internal sphincterotomy presented to the emergency department with severe pain in the hypogastrium and perianal region; physical examination revealed an induration in the left buttock. CT images showed an abscessed collection in the rectovaginal space and gas in the levator ani muscle, left ischiorectal fossa and the root of the left thigh. CONCLUSIONS: CT scan is considered an excellent diagnostic tool in the management of patients with Fournier's gangrene, as it shows both the origin of the infection and its extent.

Lista de verificación de tomografía computarizada de hueso temporal y base de cráneo lateral / Checklist of the temporal bone and lateral skull base CT- scan

La tomografía computarizada del hueso temporal es una prueba de imagen fundamental para el diagnóstico y tratamiento de diversas entidades que afectan a esta compleja estructura. La tomografía computarizada permite una representación más detallada de las estructuras óseas que la resonancia magnética, lo que determina que sea la prueba de elección para la planificación de la cirugía otológica.El objetivo de este trabajo es el de elaborar una lista de verificación o checklist que permita al otorrinolaringólogo estudiar y valorar de forma sistemática y organizada las principales estructuras de referencia, variantes anatómicas y cambios posquirúrgicos más frecuentes antes de una cirugía segura.Esta revisión ha sido promovida por la Sociedad Española de Otorrinolaringología y redactada en un formato de lista de verificación dividida en las diferentes regiones del hueso temporal y base de cráneo lateral. (AU)

Computed tomography scan of the temporal bone is a fundamental imaging modality for both the diagnosis and treatment of a wide range of pathologies affecting this complex structure. Temporal bone computed tomography scan provides a more detailed depiction of bone structures, compared with magnetic resonance imaging and, for this reason computed tomography scan is the imaging modality of choice in the planning of otological surgery.The aim of this article is to present a checklist to allow the otolaryngologist to assess systematically and in an organized manner the main anatomical landmarks, anatomical variants, as well as the most common postoperative surgical changes, which can be identified before any safe otological surgery.This revision was promoted by the Spanish Society of Otolaryngology and elaborated in a checklist template divided into the different areas of the temporal bone and the lateral skull base. (AU)

Preclinical findings predicting efficacy and side-effect profile of LY2940094, an antagonist of nociceptin receptors.

Nociceptin/Orphanin FQ (N/OFQ) is a 17 amino acid peptide whose receptor is designated ORL1 or nociceptin receptor (NOP). We utilized a potent, selective, and orally bioavailable antagonist with documented engagement with NOP receptors in vivo to assess antidepressant- and anxiolytic-related pharmacological effects of NOP receptor blockade along with measures of cognitive and motor impingement. LY2940094 ([2-[4-[(2-chloro-4,4-difluoro-spiro[5H-thieno[2,3-c]pyran-7,4'-piperidine]-1'-yl)methyl]-3-methyl-pyrazol-1-yl]-3-pyridyl]methanol) displayed antidepressant-like behavioral effects in the forced-swim test in mice, an effect absent in NOP -/- mice. LY2940094 also augmented the behavioral effect of fluoxetine without changing target occupancies (NOP and serotonin reuptake transporter [SERT]). LY2940094 did not have effects under a differential-reinforcement of low rate schedule. Although anxiolytic-like effects were not observed in some animal models (conditioned suppression, 4-plate test, novelty-suppressed feeding), LY2940094 had effects like that of anxiolytic drugs in three assays: fear-conditioned freezing in mice, stress-induced increases in cerebellar cGMP in mice, and stress-induced hyperthermia in rats. These are the first reports of anxiolytic-like activity with a systemically viable NOP receptor antagonist. LY2940094 did not disrupt performance in either a 5-choice serial reaction time or delayed matching-to-position assay. LY2940094 was also not an activator or suppressor of locomotion in rodents nor did it induce failures of rotarod performance. These data suggest that LY2940094 has unique antidepressant- and anxiolytic-related pharmacological effects in rodents. Clinical proof of concept data on this molecule in depressed patients have been reported elsewhere.

Discovery of a novel series of orally active nociceptin/orphanin FQ (NOP) receptor antagonists based on a dihydrospiro(piperidine-4,7'-thieno[2,3-c]pyran) scaffold.

Nociceptin/OFQ (N/OFQ) is a 17 amino acid peptide that is the endogenous ligand for the ORL1/NOP receptor. Nociceptin appears to regulate a host of physiological functions such as biological reactions to stress, anxiety, mood, and drug abuse, in addition to feeding behaviors. To develop tools to study the function of nociceptin and NOP receptor, our research effort sought to identify orally available NOP antagonists. Our effort led to the discovery of a novel chemical series based on the dihydrospiro(piperidine-4,7'-thieno[2,3-c]pyran) scaffold. Herein we show that dihydrospiro(piperidine-4,7'-thieno[2,3-c]pyran)-derived compounds are potent NOP antagonists with high selectivity versus classical opioid receptors (µ, δ, and κ). Moreover, these compounds exhibit sufficient bioavailability to produce a high level of NOP receptor occupancy in the brain following oral administration in rats.

Development of LC-MS/MS-based receptor occupancy tracers and positron emission tomography radioligands for the nociceptin/orphanin FQ (NOP) receptor.

Currently, a lack of sufficient tools has limited the understanding of the relationship between neuropsychiatric disorders and the nociceptin/orphanin FQ (N/OFQ) peptide (NOP) receptor. Herein, we describe the discovery and development of an antagonist NOP receptor occupancy (RO) tracer and a novel positron emission tomography (PET) radioligand suitable to probe the NOP receptor in human clinical studies. A thorough structure-activity relationship (SAR) around the high-affinity 3-(2'-fluoro-4',5'-dihydrospiro[piperidine-4,7'-thieno[2,3-c]pyran]-1-yl)-2-(2-halobenzyl)-N-alkylpropanamide scaffold identified a series of subnanomolar, highly selective NOP antagonists. Subsequently, these unlabeled NOP ligands were evaluated in vivo by liquid chromatography-tandem mass spectrometry (LC-MS/MS) in rat to determine brain uptake, kinetics and specific binding. (S)-27 was identified as a suitable unlabeled preclinical RO tracer to accurately quantify NOP receptor engagement in rat brain. Three compounds were selected for evaluation in nonhuman primates as PET tracers: (-)-26, (-)-30, and (-)-33. Carbon-11 labeling of (+)-31 yielded [(11)C]-(S)-30, which exhibited minimal generation of central nervous system (CNS) penetrant radiometabolites, improved brain uptake, and was an excellent PET radioligand in both rat and monkey. Currently [(11)C]-(S)-30 is being evaluated as a PET radiotracer for the NOP receptor in human subjects.

Gangrena perineal en mujer de 44 años. Hallazgos en Tomografía Axial Computarizada (TAC) / Fournier´s gangrene in a 44-year-old woman: CT scan findings

OBJETIVOS: Mostrar los hallazgos característicos en TAC y su utilidad diagnóstica en la gangrena de Fournier en mujeres.METODO/RESULTADO: Mujer con antecedentes de esfinterotomía lateral interna que acude a urgencias por intenso dolor en hipogastrio y en región perineal con endurecimiento del glúteo izquierdo. En la TAC se observa una colección abscesificada en el espacio rectovaginal y gas en músculos elevadores del ano, fosa isquiorrectal izquierda y en raíz del muslo izquierdo(AU)

OBJECTIVES: To show standard CT findings and their diagnostic usefulness in female patients suffering from Fournier’s gangrene.METHOD/RESULT: A woman who had undergone a previous lateral internal sphincterotomy presented to the emergency department with severe pain in the hypogastrium and perianal region; physical examination revealed an induration in the left buttock. CT images showed an abscessed collection in the rectovaginal space and gas in the levator ani muscle, left ischiorectal fossa and the root of the left thigh.CONCLUSIONS: CT scan is considered an excellent diagnostic tool in the management of patients with Fournier’s gangrene, as it shows both the origin of the infection and its extent(AU)

Synthesis of 3a,4-dihydro-3H-[1]benzopyrano[4,3-c]isoxazoles, displaying combined 5-HT uptake inhibiting and alpha2-adrenoceptor antagonistic activities. Part 2: Further exploration on the cinnamyl moiety.

In our previous paper we have described the synthesis of a series of 3-piperazinylmethyl-3a,4-dihydro-3H-[1]benzopyrano[4,3-c]isoxazoles, as novel dual 5-HT reuptake inhibitors and alpha2-adrenoceptor antagonists. That investigation led to the identification of the cinnamyl fragment as the most suitable moiety for combined activity. This paper outlines a further optimisation programme, focused on the exploration of the aromatic ring present on the cinnamyl moiety of compounds 1, 2 and 3.

Leiomiomatosis intravascular / Intravascular leiomyomatosis

Los leiomiomas son las neoplasias uterinas más frecuentes en las mujeres, están presentes en el 20 - 30% de las pacientes mayores de 30 años y se encuentran en el 75% de las histerectomías. Estos tumores poseen receptores de estrógenos y progesterona y su crecimiento está influenciado por niveles hormonales. En raras ocasiones, estos tumores pueden tener una extensión intravascular a partir de las venas uterinas. A pesar de que histológicamente se trata de un tumor benigno, se puede considerar agresivo, ya que tiene altos índices de recurrencia y puede tener consecuencias fatales, ya sea por su capacidad de metastatizar o por la invasión vascular, que aunque es muy poco frecuente, puede extenderse a través de las venas gonadales e ilíacas hasta la vena cava inferior y llegar hasta las cavidades cardiacas, donde produce obstrucción al flujo sanguíneo, altera la dinámica valvular de manera severa y favorece el desarrollo de embolismo pulmonar. Cuando esto ocurre la presentación clínica puede ser muy variable e inconstante; desde muerte súbita, extrasístoles, taquicardia, síncope, disnea e insuficiencia cardiaca derecha En otras ocasiones puede ser asintomático y diagnosticarse únicamente mediante la necropsia (AU)

Uterine leiomyomas are the most common tumors in women and are found in 20-30% of patients older than 30 years and in 75% of hysterectomies. These tumors have estrogen and progesterone receptors and their growth is influenced by hormone levels. Although histologically benign, uterine leiomyomas can be considered aggressive due to their high recurrence index and life-threatening consequences, whether due to metastases or vascular invasion. Although vascular invasion is extremely rare, these tumors can spread through the gonadal veins to the iliac and inferior vena cava and reach the heart cavities. At this site, the infiltration causes blood flow obstruction and severe alterations in vascular dynamics and favors the development of pulmonary embolism. When this occurs, the clinical presentation can be highly variable and inconsistent, ranging from sudden death, extrasystoles, tachycardia, syncope, dyspnea and right heart failure. On other occasions, these tumors can be asymptomatic and diagnosed only by autopsy (AU)