ABSTRACT
BACKGROUND: Information exchange between hospitals and primary care physicians is suboptimal. Most physicians are dissatisfied with the current referral process, and poor communication leads to negative care transition outcomes. METHOD: To identify the key information needed for a successful transition of care, we conducted a qualitative study using consecutive, semistructured in-person interviews and focus group sessions. We recruited five participants engaged in clinical work for individual interviews and 16 participants for focus groups. We analyzed all data using qualitative thematic analysis. All results were returned to the participants and modified based on their feedback. RESULTS: The five individual interviews provided a general picture of the current referral process and an interview guide for the following focus group sessions. The focus group discussions were used to identify the essential information needed at admission and discharge from the hospital. Essential information on hospital admission was as follows: (1) basic medical and care information, (2) care resources available at home, (3) the purpose of admission and the goals of care during hospitalization, and (4) status of advance care planning (ACP) and patient's will in an emergency. Essential information on hospital discharge was as follows: (1) clinical course, (2) explanation of medical condition during hospitalization, (3) status of ACP and patient's will in an emergency, and (4) medical procedures to be continued at home. CONCLUSIONS: We identified the essential information needed for a successful transition of care in Japan. The clinical effectiveness of a template that contains the information identified in our study warrants further investigation.
ABSTRACT
Peptide YY (PYY)(3-36), a neuropeptide Y (NPY) Y2 receptor agonist, is a powerful inhibitor of intestinal secretion. Based on this anti-secretory effect, NPY Y2 receptor agonists may be useful as novel anti-diarrheal agents, but anti-diarrheal efficacy has yet to be determined. We therefore examined the anti-diarrheal efficacy of PYY(3-36) and a selective Y2 receptor agonist, N-acetyl-[Leu28, Leu31]-NPY(24-36), in experimental mouse models of diarrhea. Intraperitoneal administration of PYY(3-36) (0.01-1mg/kg) and N-acetyl-[Leu28, Leu31]-NPY(24-36) (10mg/kg) significantly inhibited diarrhea (increase in wet fecal weight and diarrhea score) induced by dimethyl-prostaglandin E2, 5-hydroxytryptamine, and castor oil. Anti-diarrheal activities of PYY(3-36) and N-acetyl-[Leu28, Leu31]-NPY(24-36) were comparable to the effects of loperamide (1mg/kg), a widely used anti-diarrheal drug. To clarify the anti-diarrheal mechanisms of NPY Y2 receptor agonists, we investigated the effects of PYY(3-36) and N-acetyl-[Leu28, Leu31]-NPY(24-36) on intestinal fluid secretion and colonic transit. PYY(3-36) (1mg/kg) and N-acetyl-[Leu28, Leu31]-NPY(24-36) (10mg/kg) significantly reduced dimethyl-prostaglandin E2-induced intestinal fluid accumulation in conscious mice, suggesting that NPY Y2 receptor agonists inhibit diarrhea, at least in part, by reducing intestinal secretion. In addition, PYY(3-36) (0.01-1mg/kg) and N-acetyl-[Leu28, Leu31]-NPY(24-36) (10mg/kg) potently inhibited normal fecal output, suggesting that NPY Y2 receptor activation inhibits colonic motor function and NPY Y2 receptor agonists inhibit diarrhea partly by slowing colonic transit. These results indicate that NPY Y2 receptor agonists inhibit diarrhea in mice by not only reducing intestinal fluid secretion, but also slowing colonic transit, and illustrate the therapeutic potential of NPY Y2 receptor agonists as effective treatments for diarrhea.
Subject(s)
Diarrhea , Gastrointestinal Transit/drug effects , Intestinal Secretions/metabolism , Peptide YY , Receptors, Neuropeptide Y/agonists , Animals , Antidiarrheals/pharmacology , Antidiarrheals/therapeutic use , Diarrhea/drug therapy , Diarrhea/physiopathology , Disease Models, Animal , Humans , Loperamide/pharmacology , Loperamide/therapeutic use , Male , Mice , Mice, Inbred C57BL , Peptide Fragments , Peptide YY/pharmacology , Peptide YY/therapeutic useABSTRACT
The synthesis and evaluation of a series of 2,4-diaminopyridine-based neuropeptide Y Y1 (NPY Y1) receptor antagonists are described. Compound 1 was previously reported by our laboratory to be a potent and selective Y1 antagonist; however, 1 was also found to have potent hERG inhibitory activity. The main focus of this communication is structure-activity relationship development aimed at eliminating the hERG activity of 1. This resulted in the identification of compound 3d as a potent and selective NPY Y1 antagonist with reduced hERG liability.
Subject(s)
4-Aminopyridine/analogs & derivatives , Ether-A-Go-Go Potassium Channels/antagonists & inhibitors , Receptors, Neuropeptide Y/antagonists & inhibitors , 4-Aminopyridine/chemistry , Animals , CHO Cells , Cell Line , Chemistry, Pharmaceutical/methods , Cricetinae , Cricetulus , Drug Design , ERG1 Potassium Channel , Ether-A-Go-Go Potassium Channels/chemistry , Humans , Hydrogen-Ion Concentration , Inhibitory Concentration 50 , Models, Chemical , Receptors, Neuropeptide Y/chemistry , Recombinant Proteins/chemistry , Structure-Activity RelationshipABSTRACT
Spiroindoline urea derivatives, designed to act as NPY Y5 receptor antagonists, were synthesized and their structure-activity relationships were investigated. Of these derivatives, compound 3a showed good Y5 binding affinity with favorable pharmacokinetic properties. Compound 3a significantly inhibited bPP Y5 agonist-induced food intake in rats, and suppressed body weight gain in DIO mice.
Subject(s)
Anti-Obesity Agents/chemistry , Anti-Obesity Agents/pharmacology , Indoles/chemistry , Indoles/pharmacology , Receptors, Neuropeptide Y/antagonists & inhibitors , Receptors, Neuropeptide Y/metabolism , Animals , Anti-Obesity Agents/chemical synthesis , Anti-Obesity Agents/pharmacokinetics , Biological Availability , Body Weight/drug effects , Eating/drug effects , Indoles/chemical synthesis , Indoles/pharmacokinetics , Mice , Mice, Inbred C57BL , Molecular Structure , Protein Binding , Rats , Rats, Sprague-Dawley , Receptors, Neuropeptide Y/agonists , Spiro Compounds/chemical synthesis , Spiro Compounds/chemistry , Spiro Compounds/pharmacokinetics , Spiro Compounds/pharmacology , Structure-Activity RelationshipABSTRACT
Nociceptin/orphanin FQ (N/OFQ), an endogenous ligand for opioid receptor-like 1 (ORL1), is involved in various central functions, such as pain, psychological stress, locomotor activity, learning and memory, and feeding regulation. Of these functions, the role of N/OFQ in the regulation of feeding has been suggested by the fact that the central administration of N/OFQ leads to feeding behavior. However, the manner in which N/OFQ influences body weight control and subsequent obesity is unclear. To clarify the involvement of N/OFQ in the development of obesity, we evaluated the effects of intracerebroventricular infusion of N/OFQ on food intake and body weight in C57BL/6J mice that were fed a regular chow diet or moderately high-fat (MHF) diet (32.6% kcal fat). N/OFQ significantly increased food intake and body weight both in the regular diet- and MHF diet-fed mice, and these changes were more apparent in the MHF diet-fed mice. When we performed a pair-feeding study in N/OFQ intracerebroventricularly infused mice, N/OFQ did not cause body weight gain but increased white adipose tissue weight and plasma leptin, insulin, and cholesterol levels. N/OFQ reduced rectal temperature in pair-fed mice, in keeping with decreased UCP1 mRNA expression in brown adipose tissue. These results suggest that N/OFQ contributes to the development of obesity not only by inducing hyperphagia but also by decreasing energy expenditure.
Subject(s)
Appetite Regulation/drug effects , Cerebral Ventricles/drug effects , Energy Metabolism/drug effects , Opioid Peptides/pharmacology , Vasodilator Agents/pharmacology , Weight Gain/drug effects , Adipose Tissue, Brown/metabolism , Animals , Appetite Regulation/physiology , Body Weight/drug effects , Body Weight/physiology , Cerebral Ventricles/physiology , Disease Models, Animal , Dose-Response Relationship, Drug , Eating/drug effects , Eating/physiology , Energy Metabolism/physiology , Hyperphagia/physiopathology , Infusion Pumps, Implantable , Male , Mice , Mice, Inbred C57BL , Models, Animal , Opioid Peptides/administration & dosage , Opioid Peptides/physiology , Vasodilator Agents/administration & dosage , NociceptinABSTRACT
Syntheses and structure-activity relationships of a novel class of 2-[3-oxospiro[isobenzofuran-1(3H),1'-cyclohexan]-4'-yl]benzimidazole NPY Y5 receptor antagonists are described. Optimization of the lead compound 2a by incorporating substituents into the 5-position or into both the 5- and 6-positions of the benzimidazole core part led to the identification of 5-(5-methyl-1,2,4-oxadiazol-2-yl)benzimidazole (2r: IC(50)=3.3 nM) and 5-(2-methyltetrazol-5-yl)benzimidazole (2u: IC(50)=5.9 nM), both of which are potent, selective, and orally bioavailable Y5 receptor antagonists.
Subject(s)
Benzimidazoles/chemical synthesis , Benzimidazoles/pharmacology , Receptors, Neuropeptide Y/antagonists & inhibitors , Administration, Oral , Benzimidazoles/chemistry , Brain/drug effects , Combinatorial Chemistry Techniques , Drug Design , Humans , Inhibitory Concentration 50 , Molecular Structure , Structure-Activity RelationshipABSTRACT
Design, syntheses, and structure-activity relationships of a novel class of 2-{3-oxospiro[isobenzofuran-1(3H),4'-piperidin]-1'-yl}benzimidazole NPY Y5 receptor antagonists are described. The benzimidazole structures were newly designed based on the urea linkage of our prototype Y5 receptor antagonists (2 and 3). By optimizing substituents on the benzimidazole core part of the lead compound 5a, we were able to develop a potent, orally available, and brain-penetrable Y5 selective antagonist (5k).
Subject(s)
Benzimidazoles/chemical synthesis , Benzimidazoles/pharmacology , Receptors, Neuropeptide Y/antagonists & inhibitors , Administration, Oral , Animals , Benzimidazoles/chemistry , Brain/drug effects , Combinatorial Chemistry Techniques , Drug Design , Molecular Structure , Rats , Structure-Activity RelationshipABSTRACT
A series of phenylpiperazine derivatives were synthesized and evaluated for their neuropeptide Y (NPY) Y5 receptor antagonistic activities. The benzindane portion of 2 was replaced by 1-phenylpiperazine, resulting in novel urea derivative 3f. Subsequent optimization of the phenylpiperazine template by substitution of the phenyl moiety resulted in a series of (2-methanesulfonamidephenyl)piperazine derivatives that showed potent binding affinity and antagonistic activity for the Y5 receptor.
Subject(s)
Piperazines/chemistry , Receptors, Neuropeptide Y/antagonists & inhibitors , Humans , Molecular Structure , Piperazines/chemical synthesis , Receptors, Neuropeptide Y/metabolism , Structure-Activity RelationshipABSTRACT
A series of substituted 4-alkoxy-2-aminopyridines 2, which were formally derived from neuropeptide Y1 antagonist 1 by replacing the morpholino portion with alkoxy groups, were synthesized and evaluated as neuropeptide Y Y1 receptor antagonists. Primary structure-activity relationships and identification of potent 4-alkoxy derivatives are described.
Subject(s)
Aminopyridines/chemistry , Receptors, Neuropeptide Y/antagonists & inhibitors , Aminopyridines/metabolism , Aminopyridines/pharmacology , Animals , CHO Cells , Cricetinae , Drug Evaluation, Preclinical/methods , Humans , Receptors, Neuropeptide Y/metabolismABSTRACT
We previously generated a strain of transgenic mice carrying the human renin gene, hRN8-12, in the background of C57BL/6j. In this study, we discovered that hRN8-12 male mice, but not females, developed obesity starting at 15 weeks of age. The body weight of 60-week-old male transgenic mice was 2 times higher than that of age-matched wild-type mice. Interestingly, male mice heterozygous for the human renin gene showed moderate weight gain compared with transgenic and wild-type mice. Obese hRN8-12 mice exhibited hyperglycemia, hyperinsulinemia, hyperleptinemia, and hyperlipidemia, and increase in weight in the adipose tissue, liver, heart, and kidneys. Histological analysis demonstrated that fatty hRN8-12 mice developed hypertrophy of pancreatic islets and fatty liver. These results suggested that hRN8-12 mice are associated with obesity dependent on the transgene dosage and should be a genetic model for late-onset obesity.
Subject(s)
Obesity/genetics , Renin/genetics , Renin/physiology , Age of Onset , Animals , Body Weight/genetics , Disease Models, Animal , Eating/genetics , Female , Gene Dosage , Heterozygote , Humans , Liver/pathology , Male , Mice , Mice, Inbred C57BL , Mice, Transgenic , Obesity/etiology , Obesity/pathology , Obesity/physiopathology , Organ Size/genetics , Pancreas/pathology , Sex CharacteristicsABSTRACT
1. An experiment was conducted to examine whether a potent, orally active and highly selective neuropeptide Y Y1 receptor antagonist attenuates hyperphagia and obesity in genetically obese Zucker fatty rats. 2. Oral administration of the Y1 antagonist (30 and 100 mg x kg(-1), once daily for 2 weeks) significantly suppressed the daily food intake and body weight gain in Zucker fatty rats accompanied with a reduction of fat cell size and plasma corticosterone levels. 3. Despite the fact that food intake was gradually returned to near the control level, the body weight of the treated animals remained significantly less when compared to that of the controls for the duration of the treatment. 4. These results suggest that the Y1 receptor, at least in part, participate in pathophysiological feeding and/or fat accumulation observed in Zucker fatty rats. Y1 antagonists might be useful for the treatment of obesity.