Factors affecting the effect of naldemedine for opioid-induced constipation: a single-institution, retrospective analysis.

Naldemedine is the newest orally available, peripherally selective µ-opioid receptor antagonist blocker approved for opioid-induced constipation (OIC) treatment in adult patients. On the other hand, some patients have insufficient OIC control even with naldemedine. Thus, this retrospective study was conducted to identify factors affecting the effect of naldemedine. The participants were 210 patients who had received naldemedine at our institute between June 2017 and August 2019. Variables associated with alleviation of OIC were extracted from clinical records and used for regression analysis. The effect of naldemedine was determined according to the degree of constipation. The degree of constipation was categorized as grade 0 - 2 with reference to the CTCAE version 5.0. Multivariate ordered logistic regression analysis was conducted to identify factors affecting the effect of naldemedine. Use of naldemedine within 2 days of opioid initiation [odds ratio (OR) =0.346, 95% confidence interval (CI) =0.173-0.693; P = 0.003], concomitant use of anticholinergics (OR = 2.033, 95% CI = 1.150-3.594; P = 0.015), tramadol (OR = 0.488, 95% CI = 0.250-0.953; P =0.036), and chronic non-cancer pain (OR = 0.429, 95% CI = 0.197-0.937; P = 0.034) were identified as significant factors related to the effect of naldemedine.

Predictors of the usefulness of mirogabalin for neuropathic pain: a single-institution retrospective study.

Mirogabalin is a novel, preferentially selective α2δ-1 ligand to treat neuropathic pain. However, this agent is not always effective for patients with neuropathic pain. We therefore attempted to identify factors that could predict the efficacy of mirogabalin. The study comprised 133 patients given mirogabalin for alleviation of neuropathic pain between April and November 2019 at our hospital. Variables were extracted from medical records for regression analysis of factors associated to alleviation of neuropathic pain. We evaluated the effect of mirogabalin at two weeks after administration. Groups were categorized according to degree of improvement: poor, effective, or very effective. Multivariate ordered logistic regression analysis was conducted to identify predictors for the usefulness of mirogabalin. Threshold measures were analysed using receiver operating characteristic (ROC) curves. Maintenance dose [odds ratio (OR) = 0.90; 95% confidence interval (CI) = 0.84-0.98; P = 0.01], concomitant use of opioids (OR = 0.26, 95% CI = 0.08-0.83; P = 0.023) and Neurotropin® (NTP) (OR = 4.78, 95% CI =1.04-21.93; P = 0.044) were factors significantly correlated to the effect of mirogabalin. ROC curve analysis of the effective group indicated a threshold maintenance dose of≤ 20 mg/day (area under the curve [AUC] = 0.53). In conclusion, maintenance dose (≤ 20 mg), concomitant use of opioids and NTP were identified as predictors for the utility of mirogabalin.

4ß-Hydroxywithanolide E isolated from Physalis pruinosa calyx decreases inflammatory responses by inhibiting the NF-κB signaling in diabetic mouse adipose tissue.

BACKGROUND: Chronic inflammation in adipose tissue together with obesity induces insulin resistance. Inhibitors of chronic inflammation in adipose tissue can be a potent candidate for the treatment of diabetes; however, only a few compounds have been discovered so far. The objective of this study was to find a novel inhibitor that can suppress the inflammatory response in adipose tissue and to elucidate the intracellular signaling mechanisms of the compound. METHODS: To find the active compounds, we established an assay system to evaluate the inhibition of induced MCP-1 production in adipocyte/macrophage coculture in a plant extract library. The active compound was isolated by performing high-performance liquid chromatography (HPLC) and was determined as 4ß-hydroxywithanolide E (4ßHWE) by nuclear magnetic resonance (NMR) and mass spectroscopy (MS) spectral analyses. The effect of 4ßHWE on inflammation in adipose tissue was assessed with adipocyte culture and db/db mice. RESULTS: During the screening process, Physalis pruinosa calyx extract was found to inhibit production of MCP-1 in coculture strongly. 4ßHWE belongs to the withanolide family of compounds, and it has the strongest MCP-1 production inhibitory effect and lowest toxicity than any other withanolides in coculture. Its anti-inflammatory effect was partially dependent on the attenuation of NF-κB signaling in adipocyte. Moreover, in vivo experiments showed that the oral administration of 4ßHWE to db/db mice resulted in the inhibition of macrophage invasion and cytokine expression in adipose tissue after 2 weeks of treatment; improved the plasma adiponectin, non-esterified fatty acids and MCP-1 concentrations; and increased glucose tolerance after 3 to 4 weeks of treatment. CONCLUSIONS: These results suggest that 4ßHWE has anti-inflammatory effect via inhibition of NF-κB activation in adipocyte. Moreover, the attenuation of inflammation in adipocyte has an effect on the inhibition of macrophage accumulation in obese adipose tissue. Consequently, 4ßHWE improves impaired glucose tolerance. Thus, 4ßHWE is a useful natural anti-inflammatory compound to attenuate progression of diabetes and obesity.

Pharmacokinetic-pharmacodynamic analysis of voriconazole in Japanese patients with hematological malignancies.

Voriconazole has been shown to be safe and effective for fungal infection. However, its population pharmacokinetics for patients with hematological malignancies remains unknown. We performed a population pharmacokinetics study of nine hematological patients with 36 points samples. We approximated the drug concentration curve using a linear one-compartment model. The distribution of volume (Vd), elimination rate constant, and clearance (CL) were 68.7 L, 0.163 h(-1), and 11.2 L/h, respectively. By coincidence, our study has verified that the current administration is enough to treat fungus infections by using Monte Carlo simulation. Our data demonstrated that the current administration method is appropriate and effective. Our results may prove to be useful as a basic reference for the clinical usage of voriconazole.

Formation of biologically active protein from the subunits of islets-activating protein (IAP), a new protein isolated from Bordetella pertussis.

Based on the finding reported in the preceding paper (Kanbayashi, et al.: J. Biochem) that subunits of islets-activating protein (IAP), a new protein purified from the culture media of Bordetella pertussis, were inactive as such, but regained the original biological activities when recombined, the conditions required for recovery of the biological activities were studied. Essentially the same biological activities as the native IAP were recovered when the smallest subunit, F-3, was incubated with one of the other subunits, F-1 and F-2, at a pH of around 7, at temperatures below 30 degrees C and for longer than 12 h. During the incubation, association products were formed which were isolated by gel filtration as homogenous proteins that consisted of two subunits probably in a molar ratio of 1 : 1. The native IAP (consisting of two IAP subunits including F-3) were equipotent in enhancing insulin secretory responses, in inhibiting epinephrine-induced hyperglycemia, in inducing leukocytosis and in increasing histamine sensitivity in experimental animals.

Biological properties of islets-activating protein (IAP) purified from the culture medium of Bordetella pertussis.

The biological activities were studied of a new protein, islets-activating protein (IAP), purified from the culture medium of Bordetella pertussis. Rats injected intravenously with 1 microgram of purified IAP exhibited markedly enhanced insulin secretory responses to glucose, glucagon, epinephrine, and sulfonylureas over a period from 3 to 10 days after the injection. The degree and duration of the enhancement were proportional to the dose of IAP; the maximal effect induced by 1-2 microgram of IAP persisted for as long as 2 months. There was a highly significant correlation between the enhancement of insulin secretion and suppression of epinephrine hyperglycemia over a wide range of doses of IAP, indicating that suppression of epinephrine hyperglycemia resulted from hypoglycemic action of insulin secreted in response to epinephrine challenge. Additional actions of IAP were observed in mice; mice treated with higher doses of IAP showed symptoms were observed when lower doses of IAP were injected into mice. Thus, it is concluded that IAP is a protein primarily possessing a unique action to potentiate insulin secretory responses of experimental animals to nutritional and hormonal stimuli.

Subunit structure of islets-activating protein (IAP), a new protein isolated from the culture media of Bordetella pertussis.

The subunit structure was studied of islets-activating protein (IAP), a new protein recently isolated from the culture media of Bordetella pertussis and possessing a unique action, i.e., potentiating insulin secretory responses of animals, IAP dissociated into three subunits, F-1, F-2, and F-3, when incubated in 8M urea. Three subunits isolated by chromatography on CM-Sepharose and DEAE-Sepharose columns showed different molecular weights (F-1: 44,000, F-2: 20,000, F-3: 11,000) and different isoelectric points, but similar amino acid compositions. The F-1 subunit consisted of two polypeptide chains linked by S-S bonding(s), while the F-2 and F-3 subunits were single-chain peptides. These subunits, none of which was biologically active alone, associated upon incubation for 2 h at 37 degrees C and regained biological activities after association only when the F-3 subunit was present in the association product. Thus, the F-3 subunit was essential, and the F-1 and F-2 subunits were permissive, for the development of IAP activity in animals.

[Research and development of beraprost sodium, a new stable PGI2 analogue].

A novel prostaglandin I2 (PGI2) analogue, beraprost sodium, is the first launched drug as an orally active PGI2. PGI2 was discovered in 1976, and has attracted much attention as a medicine for cardiovascular diseases such as strokes and heart attacks because of its potent antiplatelet and vasodilating effect. However, PGI2 is extremely unstable for the use as practical medicines. Thus, stable PGI2 analogues have been explored by a large number of researchers in the world. Just after the discovery of PGI2, we started a research on chemically and metabolically stable PGI2 derivatives with longer duration of action and less adverse reaction. We invented a novel class of stable PGI2, 5,6,7-trinor-4,8-inter-m-phenylenePGI2 analogues that have the phenol moiety instead of the enolether moiety of PGI2. Further efforts were devoted to enhance the efficacy of the PGI2 analogues and to eliminate their side effects, and an orally active analogue, beraprost sodium, was obtained. In order to establish the synthetic route of beraprost sodium, various novel processes were invented, including ortho-selective metalation of bromoanisoles by means of Grignard reagents, copper-catalyzed SN2' cyclization to prepare cyclopenta[b]benzofuran, and stereo-selective elongation of the omega-side chain by Prins reaction. Beraprost sodium inhibit platelet aggregation induced by adenosine 5'-diphosphate (ADP), collagen and arachidonic acid. It was shown that the drug has a potent antiplatelet effect both in vitro and ex vivo in human and several animal species. In clinical studies, beraprost sodium exerted a marked effect to improve arteriosclerosis obliterans. No serious adverse effects related with the drug have been reported. It was highly evaluated as an orally active PGI2 by pharmaceutical companies overseas as well, and now clinical trials are under way in U.S.A. and Europe.

[Midazolam-atropine lollipop for pediatric premedication].

Strawberry flavored sweet lollipop containing midazolam (5 mg) and atropine (0.25 mg) was evaluated for the premedication of pediatric patients as judged by sedative and anti-anxious effects and gastric fluid volume and acidity. The subjects of this prospective, double blind, random and controlled study were 175 children aged between 6 months and 10 years. They were divided into three groups: group A patients receiving the lollipop containing only 5 mg midazolam (n = 78), group B patients receiving the lollipop containing only 0.25 mg atropine (n = 21), and group C patients receiving the lollipop containing 5 mg midazolam and 0.25 mg atropine (n = 76). The plasma midazolam concentration was measured in ten children in group A. The sedative and anti-anxious effects were scaled with four levels. The children receiving the lollipop containing midazolam (group A and C) showed a better level of the sedative and anti-anxious state. The volume of gastric fluid of group A was more than those of group B and C. The pH of group A gastric fluid was also higher than those of other groups. The correlation equation of the plasma midazolam concentration (y ng.ml-1) against time (t min) was y = 149 x e(-t/64), (r = 0.775). These results suggest that midazolam-atropine lollipop is one of the favorable choices as the premedication for pediatric patients.

Yielding ability of erect- and narrow-leaved rice mutant in heavy manuring and dense planting culture.

A dwarf rice mutant was induced through the chronic exposure of 60Co gamma-rays. This mutant was crossed with a heavy-panicle type variety, and semi-dwarf plants permitting a more efficient distribution of light within the canopy were obtained. They along with current commercial varieties and the parent mutant were assessed for yield components, the yielding ability at three levels of nitrogen fertilizer by varying plant density and several other agronomic traits. The ssmidwarf rice possessed significantly higher rates of net photosynthetic CO2 uptake compared with that of current commercial varieties, and it was improved in yield return by increasing nitrogen application. Manner of display of leaves could be manipulated by induced mutations.

ADHD-related behavior among non-referred children: parents' ratings of DSM-III-R symptoms.

To identify the prevalence of ADHD symptoms among non-referred children, parents' ratings based on DSM-III-R criteria for ADHD were obtained for 1022 metropolitan children of ages 4 to 12. The prevalence rates of fourteen behavior items were markedly lower for boys of ages 10-12 than of ages 7-9, and for girls of ages 7-9 than of ages 4-6. 41.5% of the 7.7% subjects meeting ADHD criteria had been identified by their teachers as having problems symptomatic of ADHD, and one third had been reported by their parents as having conduct problems and emotional difficulties. A factor analysis revealed three factors: inattention; hyperactivity; and excessive verbal activities.

Clinical evaluation of attention-deficit hyperactivity disorder by objective quantitative measures.

This study assessed the diagnostic potential of the actigraph, the Continuous Performance Test, and the Matching Familiar Figures Test in diagnosing attention-deficit hyperactivity disorder (ADHD). Twenty boys previously diagnosed with ADHD and 52 controls were examined. By these measures the boys with ADHD were differentiated from the controls with sensitivity and specificity above 75%. We were able to classify ADHD into eight subtypes by combining the scores of the actigraph and the CPT: "hyperactive-impulsive", "hyperactive-inattentive", "impulsive-inattentive", "hyperactive", "impulsive", "inattentive", "mixed", and "unspecified" type. These classifications may be useful in diagnosing ADHD.