八巻 史子

INTRODUCTION: The National Database of Health Insurance Claims and Specific Health Checkups (NDB) Open Data Japan provides a nationwide health-related dataset based on region. This study aimed to identify lifestyle habits that correlated with the prevalence of hypertension, diabetes, and dyslipidemia by analyzing a dataset. METHODS: Data from 28.9 million respondents regarding lifestyle habits were collected in the fiscal year 2020 and provided in the 8th NDB Open Data Japan. Medication status for hypertension, diabetes, and dyslipidemia was used to determine the prevalence of each disorder. Responses to lifestyle habit questions were used as lifestyle variables. Pearson's correlation coefficient (r) was calculated to determine the relationships between variables. RESULTS: Lifestyle habits that had a moderate or larger correlation with the prevalence of each disorder were identified by setting the criterion |r| > 0.5. Smoking, weight gain, chewing condition, eating speed, snacking, and alcohol consumption were associated with the prevalence of hypertension. Smoking, weight gain, and chewing conditions correlated with the prevalence of diabetes. No single lifestyle habit showed correlations above the set criterion for dyslipidemia prevalence. CONCLUSION: Due to the diversity of lifestyle habits of residents within each of the 47 Japanese prefectures, the prefecture-based dataset in NDB Open Data Japan is pragmatic and useful for epidemiologically investigating the association between lifestyle habits and the prevalence of disorders of interest. It would be important to raise the alarm about the lifestyle habits identified in the present study to reduce the risk of developing the corresponding disorders.

Docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) are n-3 polyunsaturated fatty acids (PUFAs), and are abundant in fish oil. These n-3 PUFAs have been reported to improve the lower gastrointestinal (LGI) disorders such as ulcerative colitis and Crohn's disease through their anti-inflammatory effects. However, there are few studies on the effect of n-3 PUFAs on motility of the LGI tract, such as the ileum and colon, the parts frequently affected by these inflammatory disorders. To elucidate the effects of DHA and EPA on the LGI tract motility, we performed comparative evaluation of their effects and linoleic acid (LA), an n-6 PUFA, on contractions in the ileal and colonic longitudinal smooth muscles (LSMs) isolated from guinea pigs. In the ileal and colonic LSMs, DHA and EPA (3 × 10-5 M each) significantly inhibited contractions induced by acetylcholine (ACh), histamine, and prostaglandin (PG) F2α (vs. control), and these effects are stronger than that of LA (3 × 10-5 M). In the colonic LSMs, DHA and EPA also significantly inhibited contractions induced by PGD2 (vs. control). In addition, DHA and EPA significantly inhibited CaCl2-induced ileal and colonic LSM contractions in Ca2+-free 80 mM-KCl solution (vs. control). Any ileal and colonic LSM contractions induced by ACh, histamine, PGF2α, and CaCl2 were completely suppressed by verapamil (10-5 M), a voltage-gated/dependent Ca2+ channel (VGCC/VDCC) inhibitor. These findings suggest that DHA and EPA could improve the abnormal contractile functions of the LGI tract associated with inflammatory diseases, partly through inhibition of VGCC/VDCC-dependent ileal and colonic LSM contractions.

The clinical applications of antipsychotics for symptoms unrelated to schizophrenia, such as behavioral and psychological symptoms, in patients with Alzheimer's disease, and the likelihood of doctors prescribing antipsychotics for elderly people are increasing. In elderly people, drug-induced and aging-associated urinary disorders are likely to occur. The most significant factor causing drug-induced urinary disorders is a decrease in urinary bladder smooth muscle (UBSM) contraction induced by the anticholinergic action of therapeutics. However, the anticholinergic action-associated inhibitory effects of antipsychotics on UBSM contraction have not been sufficiently assessed. In this study, we examined 26 clinically available antipsychotics to determine the extent to which they inhibit acetylcholine (ACh)-induced contraction in rat UBSM to predict the drugs that should not be used by elderly people to avoid urinary disorders. Of the 26 antipsychotics, six (chlorpromazine, levomepromazine (phenothiazines), zotepine (a thiepine), olanzapine, quetiapine, clozapine (multi-acting receptor targeted antipsychotics (MARTAs))) competitively inhibited ACh-induced contractions at concentrations corresponding to clinically significant doses. Further, 11 antipsychotics (perphenazine, fluphenazine, prochlorperazine (phenothiazines), haloperidol, bromperidol, timiperone, spiperone (butyrophenones), pimozide (a diphenylbutylpiperidine), perospirone, blonanserin (serotonin-dopamine antagonists; SDAs), and asenapine (a MARTA)) significantly suppressed ACh-induced contraction; however, suppression occurred at concentrations substantially exceeding clinically achievable blood levels. The remaining nine antipsychotics (pipamperone (a butyrophenone), sulpiride, sultopride, tiapride, nemonapride (benzamides), risperidone, paliperidone (SDAs), aripiprazole, and brexpiprazole (dopamine partial agonists)) did not inhibit ACh-induced contractions at concentrations up to 10-5 M. These findings suggest that chlorpromazine, levomepromazine, zotepine, olanzapine, quetiapine, and clozapine should be avoided by elderly people with urinary disorders.

The β-adrenoceptor (β-AR)-mediated pharmacological effects of catecholamine (CA) metabolites are not well known. We examined the effects of seven CA metabolites on smooth muscle relaxation in mouse and guinea pig (GP) tracheas and rat thoracic aorta. Among them, metadrenaline (MA) significantly relaxed GP trachea (β2-AR dominant), even in the presence of clorgiline, a monoamine oxidase-A inhibitor. In mouse trachea (β1-AR dominant), normetadrenaline (NMA) and MA (10-4 M each) apparently did not affect isoprenaline (ISO)-induced relaxation, but significantly inhibited it in the presence of clorgiline. ISO-induced relaxation was also unaffected by 3,4-dihydroxyphenylglycol (DHPG) (10-4 M), but significant suppression was observed with the addition of 3,5-dinitrocatechol, a catechol-O-methyltransferase inhibitor. In GP trachea, NMA, MA, 3,4-dihydroxymandelic acid (DOMA), and DHPG (10-4 M each) significantly augmented ISO-induced relaxation. However, in the presence of clorgiline plus 3,5-dinitrocatechol, both NMA and MA (10-4 M) significantly suppressed ISO-induced relaxation. DHPG (10-4 M) also significantly suppressed ISO-induced relaxation in the presence of 3,5-dinitrocatechol. In rat thoracic aorta, DHPG (10-4 M) significantly suppressed relaxation induced by CGP-12177 A (a β3-AR partial agonist) in the presence of 3,5-dinitrocatechol plus propranolol. Our findings indicate that 1) MA may possess β2-AR agonistic action; 2) NMA and MA augment β2-AR-mediated tracheal relaxation in the absence of CA metabolic inhibitors, though themselves possessing β1-, β2-AR antagonistic action (β2 > β1); 3) DHPG exhibits β1-, β2-, β3-AR antagonistic action, and this is particularly marked for β3-AR. Our observations may help explain some of the pathologies associated with pheochromocytoma, which is characterized by increased CA metabolite levels.

INTRODUCTION: Benzodiazepine anxiolytics are believed to cause urination disorders due to their anticholinergic effects. OBJECTIVE: This study was carried out to investigate the potential inhibitory effects of 15 clinically available anxiolytics in Japan on acetylcholine (ACh)-induced contractions in rat detrusor smooth muscle (DSM) to predict whether these anxiolytics could induce urination disorders. METHODS: -Effects of anxiolytics on contractions induced by ACh and 80 mmol/L KCl solution in rat DSM and effects of anxiolytics on specific binding of [N-methyl-3H]scopolamine ([3H]NMS) in mouse cerebral cortex were investigated. RESULTS AND CONCLUSIONS: ACh-induced contractions in rat DSM were inhibited by clotiazepam and diazepam (benzodiazepine anxiolytics) at concentrations that were clinically relevant. These contractions were also significantly inhibited by paroxetine, escitalopram (selective serotonin reuptake inhibitors -[SSRIs]), and hydroxyzine (a histamine H1 receptor antagonist), albeit at concentrations that substantially exceeded clinically achievable blood levels. At a concentration of 10-5 mol/L, paroxetine, escitalopram, and hydroxyzine inhibited 80 mmol/L high-KCl solution-induced rat DSM contractions but not clotiazepam and diazepam. Paroxetine, escitalopram, and hydroxyzine also inhibited specific binding of [3H]NMS in mouse cerebral cortex but clotiazepam and diazepam did not. In contrast to the effects of the abovementioned anxiolytics, ACh-induced contractions were not significantly affected by tofisopam, alprazolam, lorazepam, bromazepam, oxazolam, chlordiazepoxide, clonazepam, ethyl loflazepate (benzodiazepine anxiolytics), fluvoxamine (an SSRI), or tandospirone (a serotonin 5-HT1A receptor agonist). These findings suggest that most clinically used anxiolytics are not likely to result in anticholinergic-induced urination disorders within their clinically achievable blood concentration ranges. However, clotiazepam and diazepam may induce urination disorders within their clinical dose ranges via nonanticholinergic inhibition of DSM contractility.

<jats:p>&lt;b&gt;&lt;i&gt;Background/Aims:&lt;/i&gt;&lt;/b&gt; Extrapyramidal symptoms (EPS) are representative side effects of antipsychotics, caused by their inhibitory action on dopaminergic nerves in nigrostriatal pathways. EPS could be also caused by direct augmentation of cholinergic effects, for example, by acetylcholinesterase (AChE) inhibition. We investigated the potential inhibitory effects of 26 clinically available antipsychotics on the activity of recombinant human AChE (rhAChE) to predict the role of antipsychotic-induced AChE inhibition in EPS onset. &lt;b&gt;&lt;i&gt;Method:&lt;/i&gt;&lt;/b&gt; The degree of rhAChE activity inhibition was calculated using the 5,5′-dithio-bis-(2-nitrobenzoic acid) method. &lt;b&gt;&lt;i&gt;Results:&lt;/i&gt;&lt;/b&gt; At a concentration of 10&lt;sup&gt;–5&lt;/sup&gt; mol/L, haloperidol, bromperidol, timiperone, nemonapride, pimozide, risperidone, blonanserin, aripiprazole, and brexpiprazole inhibited rhAChE activity by &amp;#x3e;20%. Risperidone, aripiprazole, and brexpiprazole inhibited rhAChE activity in a concentration-dependent manner, and their effects were more potent than those of other antipsychotics. The inhibitory effects of these 3 drugs were evident from 10&lt;sup&gt;–6&lt;/sup&gt; mol/L, and their pIC&lt;sub&gt;50&lt;/sub&gt; values were 4.74 ± 0.04, 4.80 ± 0.04, and 4.93 ± 0.06, respectively. Notably, the concentration range in which aripiprazole inhibited rhAChE activity (≥10&lt;sup&gt;–6&lt;/sup&gt; mol/L) overlapped with its clinically achievable blood levels. &lt;b&gt;&lt;i&gt;Conclusion:&lt;/i&gt;&lt;/b&gt; Aripiprazole may cause EPS at clinical dosages by augmenting cholinergic effects via AChE inhibition, in addition to its suppressive effect on dopaminergic neurons.</jats:p>

<jats:title>Summary</jats:title><jats:p>We investigated the potential augmenting effects of 19 clinically available antidepressants on noradrenaline (<jats:styled-content style="fixed-case">NA</jats:styled-content>)‐induced contractions in guinea pig urethra smooth muscle (<jats:styled-content style="fixed-case">USM</jats:styled-content>). Concentration‐response curves for <jats:styled-content style="fixed-case">NA</jats:styled-content>‐induced contractions in guinea pig <jats:styled-content style="fixed-case">USM</jats:styled-content> strips were obtained in the absence or presence of selected antidepressants. Desipramine, an active metabolite of imipramine, produced a contraction and potentiated <jats:styled-content style="fixed-case">NA</jats:styled-content>‐induced contraction at the distal urethra without affecting the proximal urethra. Further, nortriptyline and amoxapine, tricyclic antidepressants, produced a contraction and potentiated <jats:styled-content style="fixed-case">NA</jats:styled-content>‐induced contraction at the distal urethra. <jats:styled-content style="fixed-case">NA</jats:styled-content>‐induced contraction was unaffected or reduced by imipramine, clomipramine, trimipramine, and amitriptyline at the proximal and distal urethra. Maprotiline, a tetracyclic antidepressant, potentiated <jats:styled-content style="fixed-case">NA</jats:styled-content>‐induced contraction at the distal urethra. <jats:styled-content style="fixed-case">NA</jats:styled-content>‐induced contraction was unaffected by mianserin at the proximal and distal urethra. Paroxetine, a selective serotonin reuptake inhibitor (<jats:styled-content style="fixed-case">SSRI</jats:styled-content>), potentiated <jats:styled-content style="fixed-case">NA</jats:styled-content>‐induced contraction at the distal urethra, while <jats:styled-content style="fixed-case">NA</jats:styled-content>‐induced contraction was unaffected by fluvoxamine, sertraline, and escitalopram at the proximal and distal urethra. Milnacipran, a serotonin‐noradrenaline reuptake inhibitor (<jats:styled-content style="fixed-case">SNRI</jats:styled-content>), potentiated <jats:styled-content style="fixed-case">NA</jats:styled-content>‐induced contraction at the proximal and distal urethra, whereas duloxetine potentiated it at the distal urethra. Mirtazapine slightly inhibited <jats:styled-content style="fixed-case">NA</jats:styled-content>‐induced contraction at the distal urethra. Aripiprazole and sulpiride did not affect <jats:styled-content style="fixed-case">NA</jats:styled-content>‐induced contractions at the proximal nor distal urethra. Trazodone inhibited <jats:styled-content style="fixed-case">NA</jats:styled-content>‐induced contraction at both urethras. Desipramine, nortriptyline, amoxapine, maprotiline, paroxetine, milnacipran, and duloxetine likely induce urinary disturbance by increasing urethral resistance and augmenting <jats:styled-content style="fixed-case">NA</jats:styled-content>‐induced contraction, which should be carefully considered when delivering guidance for drug administration to patients.</jats:p>

<jats:p>&lt;b&gt;&lt;i&gt;Background:&lt;/i&gt;&lt;/b&gt; A report examining whether clinically available antidepressants increase urethral smooth muscle contraction via antagonistic effects on the α&lt;sub&gt;2&lt;/sub&gt;-adrenoceptor (α&lt;sub&gt;2&lt;/sub&gt;-AR) is lacking. &lt;b&gt;&lt;i&gt;Objectives:&lt;/i&gt;&lt;/b&gt; The present study was performed to evaluate the potential of clinically available antidepressants to reverse α&lt;sub&gt;2&lt;/sub&gt;-AR-mediated contractile inhibition in rat vas deferens, in order to predict whether they can induce voiding impairment. &lt;b&gt;&lt;i&gt;Method:&lt;/i&gt;&lt;/b&gt; The effects of 18 antidepressants of different classes on electrical field stimulation (EFS)-induced contractions suppressed by 10&lt;sup&gt;–8&lt;/sup&gt; mol/L clonidine (a selective α&lt;sub&gt;2&lt;/sub&gt;-AR agonist) in isolated rat vas deferens were investigated and related to their respective clinical blood concentrations. &lt;b&gt;&lt;i&gt;Results:&lt;/i&gt;&lt;/b&gt; The EFS-induced contractions suppressed by clonidine were recovered by amitriptyline (a tricyclic antidepressant), mirtazapine (a noradrenergic and specific serotonergic antidepressant), and trazodone (a serotonin 5-HT&lt;sub&gt;2A&lt;/sub&gt; receptor antagonist) at concentrations close to the clinical blood levels. EFS-induced contractions were also recovered by trimipramine, clomipramine (tricyclic antidepressants), mianserin (a tetracyclic antidepressant), sertraline (a selective serotonin reuptake inhibitor [SSRI]), and sulpiride (a dopamine D&lt;sub&gt;2&lt;/sub&gt;-receptor antagonist), albeit at concentrations that substantially exceeded their clinically-achievable blood levels. EFS-induced contractions were not significantly affected by imipramine, nortriptyline, amoxapine (tricyclic antidepressants), maprotiline (a tetracyclic antidepressant), fluvoxamine, paroxetine, escitalopram (SSRIs), milnacipran, duloxetine (serotonin and noradrenaline reuptake inhibitors), and aripiprazole (a dopamine partial agonist). Conclusions: These findings suggest that amitriptyline, mirtazapine, and trazodone induce voiding impairment caused by increased urethral resistance by enhancing sympathetic nerve activities attributed to α&lt;sub&gt;2&lt;/sub&gt;-AR antagonism.</jats:p>