Hange-shashin-to raises levels of somatostatin, motilin, and gastrin in the plasma of healthy subjects

Hange-shashin-to has been used for chronic hypofunction of the gastrointestinal tract and to improve functional abnormalities of the upper and lower gastrointestinal system. To determine whether the pharmacological effects of Hange-shashin-to are due to gut-regulatory peptide levels, we developed a sensitive and specific double-antibody enzyme immunoassay (EIA) for detecting motilin and also examined the levels of somatostatin-, motilin-, gastrin-, and vasoactive intestinal peptide (VIP)-immunoreactive substances (IS) in plasma from healthy subjects. We developed a sensitive (3.5 pg, 1.4 pg/well) and specific (carboxy-terminal region) EIA for motilin. A single oral administration of Hange-shashin-to 6.0 g caused significant increases somatostatin-IS (20-60 min), motilin-IS (40 min), and gastrin-IS (40-90 min) levels in plasma compared with levels in a placebo group. Hange-shashin-to had no significant effect on VIP-IS levels after single administration. These changes in hormone levels (somatostatin, motilin, and gastrin) might relate to normalization of the upper and lower gastrointestinal system by Hange-shashin-to.     

Effects of mosapride citrate on human plasma levels of motilin, gastrin, somatostatin, and secretin

The effect of mosapride citrate (mosapride) on plasma levels of gastrointestinal peptides (motilin, gastrin, somatostatin, and secretin) was studied in five healthy volunteers. After a single oral administration of mosapride (15 mg), the plasma mosapride level (85.0+/-13.7 ng/ml) was highest in the 60-min sample after the administration and then the plasma level fell. Peak plasma motilin levels (18.6+/-1.7 pg/ml) were achieved 60 min after administration of mosapride (p<0.01 vs. placebo), and returned to baseline levels within a further 120 min. Plasma gastrin levels (42.4+/-3.6 pg/ml) increased 60 min after administration of mosapride (p<0.01 vs. placebo). Plasma somatostatin and secretin levels did not change significantly. These results suggest that the pharmacological effects of mosapride on gastrointestinal functions are closely related to changes in motilin-immunoreactive substance levels in human plasma.     

Effects of domperidone on human plasma levels of motilin, somatostatin, gastrin, adrenocorticotropic hormone and cortisol

Domperidone, an upper gastrointestinal function regulatory medicine, has recently been evaluated for its clinical usefulness in the treatment of stress and depression. We examined the effects of domperidone on the plasma levels of motilin-immunoreactive substance (IS), somatostatin-IS, gastrin-IS, adrenocorticotropic hormone (ACTH)-IS, and cortisol under stress conditions by repetitive blood sampling. After a single oral administration of domperidone (30 mg), the plasma domperidone level was highest (58.6+/-6.4 ng/ml) in the sample taken 40 min after administration, after which the plasma level fell. Peak plasma motilin-IS levels (23.1+/-1.4 pg/ml) were achieved 40 min after administration of domperidone (p < 0.01 vs. placebo), and returned to baseline levels within a further 40 min. Plasma somatostatin-IS levels (13.0+/-1.2 pg/ml) increased 60 min after administration of domperidone (p < 0.01 vs. placebo). Plasma gastrin-IS levels did not change significantly. These results suggest that the pharmacological effects of domperidone on gastrointestinal functions are closely related to changes in motilin-IS and somatostatin-IS levels. Domperidone significantly suppressed increases in plasma ACTH-IS and cortisol levels compared with the response to a placebo. These modulatory effects might be beneficial in stress-related diseases and suggest that this medicine has clinical pharmacological activity.     

Effects of Ninjin-to on levels of brain-gut peptides (motilin, vasoactive intestinal peptide, gastrin, and somatostatin) in human plasma

We examined the effects of Ninjin-to, a traditional Chinese (Kampo) medicine, on the levels of brain-gut peptides (motilin, vasoactive intestinal peptide (VIP), gastrin, and somatostatin) in plasma from healthy subjects. A single oral administration of Ninjin-to, at a dose of 6.0 g, caused significant increases in plasma motilin levels at 40 to 90 min and somatostatin levels at 20 to 90 min, compared with a placebo treated group. Transient elevations of gastrin levels in the placebo group were inhibited by administration of Ninjin-to, but the medicine did not alter the levels of VIP. In conclusion, these results suggest that pharmacological effects of Ninjin-to on gastrointestinal functions closely relate to changes of motilin, gastrin, and somatostatin-immunoreactive substance levels in human plasma.     

Effect of Dai-kenchu-to on levels of 3 brain-gut peptides (motilin, gastrin and somatostatin) in human plasma.

We examined the effect of Dai-kenchu-to (DKCT), a traditional Chinese (Kampo) medicine, on the levels of 3 brain-gut peptides (motilin, gastrin and somatostatin) in plasma from 24 healthy subjects. A single oral administration of DKCT, at a dose of 7.5 g, caused significant increases in plasma motilin levels (about 12 pg/ml) at 60 to 90 min, compared with a placebo-treated group. Transient elevations of gastrin levels were noted after administration of both DKCT (25.9+/-1.4 pg/ml) and placebo (23.5+/-1.3 pg/ml). DKCT did not alter the levels (about 5.7 pg/ml) of somatostatin. In conclusion, these results indicate that the action of DKCT closely relates to changes in motilin-immunoreactive substance levels in human plasma.     

红霉素对糖尿病胃轻瘫患者胃动素胃泌素及肠道菌群的影响

目的 观察红霉素对糖尿病胃轻瘫(DGP)患者胃动素、胃泌素及肠道菌群的影响.方法 将2011年9月至2013年9月本院消化内科门诊及住院收治的78例DGP患者按随机法分为观察组和对照组,对照组患者给予莫沙必利片治疗,观察组患者给予红霉素胶囊治疗.比较两组患者的疗效、血浆胃动素(MTL)和血清胃泌素(GAS)水平及肠道菌群数量.结果 治疗后观察组患者总有效率显著高于对照组患者(x2=12.889,P＜0.05),而两组患者血浆胃动素和血清胃泌素水平显著下降(均P＜0.05),且观察组中血浆胃动素和血清胃泌素水平显著低于对照组,差异均有统计学意义(t=13.865、6.272,均P＜0.05);治疗前后两组患者肠道内大肠杆菌、肠球菌、双歧杆菌、乳酸杆菌数量比较差异均无统计学意义(t=1.540、1.093、1.790、1.946,均P＞0.05);而治疗后观察组中拟杆菌数量明显多于对照组,差异具有统计学意义(t=8.073,P＜0.05).结论 红霉素治疗糖尿病胃轻瘫临床效果显著,能降低胃动素、胃泌素的分泌,对患者肠道菌群影响较小,具有良好应用价值,值得临床推广使用.     

摩腹运气功对功能性消化不良患者血浆生长抑素和胃动素的影响

目的观察摩腹运气功对功能性消化不良(FD)的疗效。方法将80例FD患者按随机数字表法分成两组,对照组(口服莫沙必利分散片、铝碳酸镁片、氟哌噻吨美利曲辛片)与治疗组(在对照组西药治疗的基础上指导摩腹运气功锻炼),每组各40例。采用FD临床疗效评价标准对治疗前及治疗后各组FD患者进行评价,采用症状积分评价治疗后临床疗效,采用放免法检测FD患者血浆生长抑素(SS)含量与血浆胃动素(MTL)含量变化,并进行组间比较。结果摩腹运气功干预后的FD患者总有效率为90%;症状总积分下降值高于对照组(P <0.05);可降低患者SS,增加MTL,与对照组比较差异有统计学意义(P <0.05)。结论摩腹运气功治疗FD疗效确切,并通过降低患者SS、增高MTL改善消化不良症状。     

Rikkunshi-to raises levels of somatostatin and gastrin in human plasma.

Rikkunshi-to, a traditional Chinese (Kampo) medicine, has been used to treat chronic hypofunctions of the gastrointestinal tract. The effects of Rikkunshi-to on the plasma levels of gut-regulated peptide (somatostatin, motilin, gastrin, and vasoactive intestinal peptide (VIP)) levels were studied in healthy subjects. A single oral administration of Rikkunshi-to caused significant increases in plasma somatostatin and gastrin levels at 60 to 240 min compared with a placebo group. On the other hand, this medicine showed no effects on motilin and VIP levels. In conclusion, these results might indicate that the pharmacological action of Rikkunshi-to is closely related to changes in somatostatin- and gastrin-immunoreactive substance levels.     

Omeprazole raises somatostatin and motilin in human plasma

Omeprazole, a proton pump inhibitor (PPI), is widely used in treatment of peptic ulcer, gastro esophageal reflux disease and eradication of Helicobacter pylori. PPIs inhibit final gastric acid secretion stage by blocking H+/K+-ATPase. But the mechanism except for gastric antisecretory effect has not understood clearly. So, we examined the effects of omeprazole on the levels of gastrointestinal peptides (somatostatin, motilin, gastrin, vasoactive intestinal peptide (VIP), substance P (SP) and calcitonin gene-related peptide (CGRP)) in plasma from healthy subjects. After a single oral administration of omeprazole, the plasma omeprazole concentration was highest at 120 min. Omeprazole caused a significant increase of plasma somatostatin-immunoreactive substance (IS) levels at 60-240 min and plasma motilin-IS levels at 120-180 min, compared with a placebo group, respectively. The physiological release of plasma gastrin-IS was reduced by the administration of omeprazole at 60 min, but the medicine did not alter the levels of VIP-, CGRP- and SP-IS. These results suggested that the pharmacological effects of omeprazole on regulation of gastrointestinal function are closely related to changes of somatostatin-, motilin- and gastrin-IS levels in human plasma.     

The effect of motilin on the rectum in healthy volunteers

AIMS: The role of motilin in the regulation of upper gastrointestinal (GI) motility is well defined. However, little is known about the effects on the distal GI tract. To investigate the effect of exogenous motilin on rectal function, barostat measurements in the rectum were performed and lower abdominal symptoms were scored. METHODS: Eight fasted, healthy volunteers were infused intravenously with synthetic motilin or placebo over 90 min in a double-blind, randomized, cross-over design. Rectum volume was measured with a barostat device during constant pressure and during isobaric distensions. Lower abdominal symptoms were scored by visual analogue scales. Plasma motilin concentrations were measured by radioimmunoassay. RESULTS: Baseline rectum volumes were similar between treatments: 185 +/- 62 mL (motilin) and 136 +/- 41 mL (placebo). During the constant pressure procedure, motilin increased rectum volume [area under the effect curve (AUEC)] by 6%[95% confidence interval (CI) -3, 16] of baseline, compared with placebo. During isobaric distensions motilin increased rectum volume (AUEC) by 43 mL (95% CI 0.4, 85; P < 0.05) and compliance by 10 mL mmHg-1 (95% CI 0.3, 20; P < 0.05) relative to placebo. Motilin did not induce changes in the sensation of rectal feelings. CONCLUSION: Exogenous motilin increased rectal compliance in healthy volunteers, without affecting rectal sensations.     

Biorhythmic changes of plasma histamine levels in healthy volunteers

The plasma histamine levels were reported to increase in early hours of the morning in asthmatic patients. It was supposed that this phenomenon would also be observed in normal volunteers. In this study using twelve normal healthy volunteers the plasma histamine levels were examined in a pharmacokinetic manner. It could be shown that plasma histamine levels flow biorhythmic changes with 3 maxima and 3 minima. The acrophases of the maxima are 12.77 +/- 0.61, 19.33 +/- 0.78 and 5.42 +/- 1.83 h. The most important rise in plasma histamine levels was found in the early hours of the morning representing about 55% of the total histamine available in plasma.     

Divalproex sodium increases plasma GABA levels in healthy volunteers

The purpose of this study was to ascertain the effects of divalproex sodium (DVP), an anticonvulsant and mood stabilizer, on plasma gamma-aminobutyric acid (GABA) levels in healthy humans. Twenty healthy volunteers with no lifetime history of psychiatric illness or family history in first-degree relatives were recruited. Each subject received DVP 1000 mg per day for 1 week. Blood samples for assay of plasma levels of GABA were taken from each subject before and after the administration of DVP. GABA concentrations were analysed using high pressure liquid chromatography with fluorescence detection after derivatization with o-phthaldialdehyde. It was found that DVP administration for 1 week resulted in a small, but significant, increase in plasma levels of GABA. Our results suggest that DVP enhances GABA activity in humans. Further treatment studies of DVP on GABA function in patients with psychiatric disorders are needed to explore the significance of the enhancing effect of DVP on GABA activity.     

Serum levels of thioridazine in psychiatric patients and healthy volunteers

Summary The rate of absorption of thioridazine varied greatly in ten healthy volunteers who took 100 mg in the morning after an overnight fast. The peak level in blood was also variable and it was reached 1 1/4 to 4 h after dosing. Maximal concentrations in the blood varied widely from 0.13 µg/ml to 0.52 µg/ml. No relation was found between the weight or sex of the subjects and the pharmacokinetics of the drug. The serum half life of thioridazine in three healthy volunteers was 9, 10 and 10 h respectively. In a group of 22 patients receiving less than 5 mg/kg body weight a day, there was a strong correlation between the dose and the morning or evening concentration of thioridazine in the blood. A positive correlation was also observed between the age of the patient and the serum level in those who received doses of less than 5 mg/kg body weight.     

Gas chromatographic-mass spectrometric determination of levodropropizine plasma levels in healthy volunteers

A gas chromatographic-mass spectrometric method for the qualitative and quantitative analysis of levodropropizine (S(-)-3-(4-phenyl-piperazin-1-yl)-propane-1,2-diol, DF 526) in plasma is described. The method proved to be highly selective and sensitive. Drug concentrations as low as 5 ng/ml could be measured. Levodropropizine plasma levels were measured in 6 healthy volunteers after administration of an acute 60 mg dose. Peak concentrations were reached between 40 and 60 min and measurable amounts of drug were present till 8 h after administration.     

Effects of salbutamol and bitolterol mesilate on pO2 levels in asthmatic patients and healthy volunteers.

The hypoxic effects of salbutamol 200 micrograms (CAS 18559-94-9) and bitolterol mesilate 740 micrograms (Biterol, CAS 30392-41-7), both administered by pressurized aerosol, were assessed by transcutaneous pO2 monitoring in 18 asthmatic subjects and in 12 normal volunteers. Unlike the latter, the asthmatics showed a highly significant difference in ptcO2 time course after the two drugs. After bitolterol mesylate the decrease in ptcO2 was much more gradual and the maximal decrease showed a 10-min time lag vs. salbutamol, which may partly explain the well known chronotropic effect of bitolterol. The clinical importance of the beta 2-induced hypoxemia may be related more to the dynamics of the ptcO2 decrease than to its absolute magnitude, which is usually fairly moderate.     

慢性肾衰竭与血浆胃泌素、胃动素的相关性分析

目的 探讨慢性肾衰竭与血浆胃泌素、胃动素的相关性.方法 选择本院2013年1～12月收治的90例慢性肾衰竭患者与9例正常健康者,以肾小球滤过率分组并与血浆胃泌素、胃动素进行相关性统计分析.结果 慢性肾衰竭组测定的血浆胃泌素、胃动素的指标均高于对照组;慢性肾衰竭五组的胃泌素与对照组比较差异有统计学意义（P＜0.01）;除GFR3、GFR4组胃动素与对照组比较差异有统计学意义（P＜0.01）,其余3组胃动素均差异无统计学意义（P＞0.05）;GFR1、GFR2、GFR3、GFR4、GFR5组及对照组的GFR与胃泌素呈正相关;GFR1、GFR2、GFR5组及对照组的GFR与胃动素呈正相关,GFR3、GFR4组的GFR与胃动素呈负相关.结论 肾脏损害可能会导致胃泌素和胃动素的升高,但是并不能证明胃泌素和胃动素的升高就是肾脏损害的严重征兆,胃泌素和胃动素是消化道疾病的测定指标,可以衡量消化系统功能的损害程度,虽然它们的分泌与肾脏损害有一定程度的相关性,但不能单纯用胃泌素与胃动素的测定指标来衡量肾脏实质的损伤.     

琥乙红霉素口崩片在健康志愿者的生物等效性

目的　研究琥乙红霉素口崩片的人体相对生物利用度和生物等效性。方法　健康志愿者20名,用随机双交叉试验方法,单剂量口服试验制剂琥乙红霉素口崩片和参比制剂琥乙红霉素片,剂量为800 mg,交叉间隔为2周。用微生物法测定血浆中红霉素的浓度。结果　单剂口服试验和参比制剂后血浆红霉素的Cmax分别为(1.16±0.38)和(1.03±0.34) mg.L-1;tmax分别为(1.04±0.30 )和(1.02±0.35) h;t1/2分别为(2.48±0.51) h和(2.51±0.36) h;AUC(0-10)分别为(4.12±1.36)和(3.80±1.17) mg.h.L-1;AUC(0-inf)分别为(4.43±1.38)和(4.12±1.20) mg.h.L-1;相对生物利用度为(109.3 ± 22.1)%。结论　试验和参比制剂具有生物等效性。     

Relationship of plasma amphetamine levels to physiological,subjective, cognitive and biochemical measures in healthy volunteers

Acute administration of the stimulant dextro-amphetamine produces multiple physiological, subjective cognitive and biochemical changes. These effects are similar to those seen in mania, and may be a useful model for mania. The aim of the present study was more fully to determine the multiple effects of dextro-amphetamine and to relate these to changes in plasma levels of the drug. In a double-blind, placebo-controlled crossover study in 25 healthy volunteers (ages 18-45), the effects of 25 mg of oral dextro-amphetamine were examined. Physiological, subjective, cognitive changes, concentrations of amino acids and metabolites of biogenic amines period were related to changes in plasma amphetamine concentrations over 500 min. Peak concentrations of dextro-amphetamine occurred at 2.5-3.5 h post-administration and levels decreased to 75% of peak value after 500 min. The results from the present study indicate that the subjective psychological, cognitive and blood pressure changes frequently did not mirror the time course of plasma levels of the drug. Thus, there was no clear-cut relationship between plasma levels and effects. In addition, dextro-amphetamine caused no significant changes in amino acids or amino metabolite concentrations. In conclusion, while dextro-amphetamine administration definitely causes several changes which are seen in mania, there remain some physiological and metabolic differences between these two conditions.     

The efect of indornethacin-induced gastric rnucosal injury on 24-h intragastric acidity and plasma gastrin concentration in healthy volunteers

Aims: To determine the influences of prostaglandin inhibition by indomethacin on 24-h intragastric acidity and plasma gastrin concentration, related to gastric mucosal injury. Methods: A pre- and post-treatment study design was employed in 10 Helicobacter pylori negative healthy male subjects. All subjects underwent upper gastrointestinal endoscopy at least 3 days before and after 7 days dosing with indomethacin 50 mg t.d.s. Mucosal damage was scored according to the Lanza method, and biopsies were taken for H. pylori status and assay of mucosal concentrations of prostaglandin (PG)E₂ and leukotriene (LT)B₄. Before and on the last day of dosing, intragastric acidity was measured by continuous 24-h pH monitoring, and plasma gastrin levels determined by radioimmunoassay in blood samples collected over the same period. Results: All subjects completed the study and no serious adverse events were reported. The mucosal injury score increased significantly from 0 (0–2) to 3.4 (0–8) (mean and range of values, P < 0.05) after dosing with indomethacin. No differences were observed in 24-h mean pH or meal stimulated plasma gastrin concentrations. Mucosal PGE₂ and LTB₄ were unchanged 8–10 h after the last indomethacin dose. Conclusions: Endogenous prostaglandins do not appear to alter intragastric acidity or gastrin secretion, in contrast to the PGE analogues, whose effects must be more pharmacological than physiological.     

Gallbladder volume as a biomarker for the motilin effect in healthy volunteers and patients with functional dyspepsia

AIM: To investigate a motilin effect on gallbladder volume in healthy volunteers and patients with functional dyspepsia. METHODS: Forty-three healthy volunteers and 10 patients with functional dyspepsia received motilin (4 pmol.min/kg) or placebo in four separate double-blind, randomized, placebo-controlled, cross-over studies. The gallbladder volume was measured by ultrasonography. Analysis of variance of the combined data of these studies was performed to investigate a motilin effect on gallbladder volume and potential differences between patients and healthy volunteers. RESULTS: The baseline gallbladder volume was similar for placebo and motilin treatment, as well as for patients and healthy volunteers. Motilin, compared with placebo, significantly decreased the gallbladder volume in healthy volunteers (P = 0.003) and patients (P < 0.0001). A linear concentration-response relationship was observed. The decrease in gallbladder volume by motilin was greater in patients (P = 0.03). The motilin effect was consistent between studies. CONCLUSION: The interdigestive gallbladder volume is a non-invasive end-point for motilin activity, displaying a consistent response across studies, a clear response to motilin and a clear concentration-response relationship. However, it is less suitable as a biomarker for future pharmacological studies on motilin agonists or antagonists as the effect is probably indirect, and a relatively large study population of 27 subjects is required to demonstrate a 15% decrease in gallbladder volume. Further investigation is required to confirm altered gallbladder motility as a feature of functional dyspepsia.