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Linezolid is an oxazolidinone antibiotic against Gram-positive bacteria. Although thrombocytopenia is a major adverse effect of linezolid, hyponatremia also often develops after linezolid administration. This study examined the frequency of hyponatremia that developed during linezolid treatment and identified its risk factors. In this retrospective, single-center, observational cohort study, 61 hospitalized patients treated with linezolid between January 2013 and January 2015 were analyzed. Hyponatremia was defined as a sodium level of ≤134 mEq/L for the duration of linezolid treatment. Its risk factors were identified via a logistic regression analysis. Hyponatremia occurred in 11 (18.0%) patients, and it was severe in a case (a sodium level of ≤128 mEq/L). Univariate and multiple logistic regression analyses identified the plasma C-reactive protein (CRP) level before the initial administration of linezolid and the concomitant use of a potassium-sparing diuretic as the independent variables associated with the development of hyponatremia. The odds ratios were 1.081 (95% confidence interval [CI]; 1.008-1.158) (p=0.028) and 11.017 (95% CI; 1.869-64.939) (p=0.008), respectively. Before linezolid treatment, the CRP levels of the hyponatremia group were significantly higher than those of the no-hyponatremia group (p

Therapeutic drug monitoring of valproic acid (VPA) is essential to prevent toxicity, but the correlation between plasma ammonia level and serum VPA concentration remains unclear. We examined the correlation of plasma ammonia level with VPA dose and serum trough concentrations of total and free VPA in Japanese patients with epilepsy. Thirty-eight data sets from 19 Japanese patients with epilepsy were analyzed. The relations of VPA dose and serum total and free VPA concentrations with plasma ammonia level, and the breakpoints of VPA parameters predicting hyperammonemia (plasma ammonia higher than 60 µmol/L) were analyzed. A significant positive correlation was observed between plasma ammonia level and VPA dose (r(s)=0.56, p=0.00062), serum trough total VPA concentration (r(s)=0.55, p=0.00086) and serum trough free VPA concentration (r(s)=0.58, p=0.00041). The breakpoints predicting hyperammonemia were VPA dose of 30.4 mg/kg, serum trough total VPA concentration of 90.9 µg/mL, and serum trough free VPA concentration of 8.65 µg/mL, with impurity reductions at 1.35, 1.35 and 2.02, respectively. These findings suggest that serum trough concentration of free VPA is the most reliable predictor for hyperammonemia, and that the risk of developing hyperammonemia may increase in patients with serum trough free VPA concentrations higher than 8.65 µg/mL.

Pantethine and fursultiamine have been evaluated for their clinical usefulness in the treatment and prevention of uncomplicated postoperative adhesive intestinal obstruction. In recent years, the actions of drugs used to treat gastrointestinal diseases have been elucidated pharmacologically from the viewpoints of gastrointestinal peptide levels. We examined the effects of pantethine and fursultiamine on plasma levels of calcitonin gene-related peptide (CGRP)-, vasoactive intestinal polypeptide (VIP)-, motilin- and substance P (SP)-like immunoreactive substances (IS) in healthy subjects. An open-labeled study was conducted on five healthy volunteers. Each subject was administered a single oral dose of pantethine, fursultiamine and placebo at intervals of one month. Venous blood samples were collected before and at 20, 40, 60, 90, 120, 180 and 240 min after each administration. Plasma peptide levels were measured using a highly sensitive enzyme immunoassay. A single oral dose of pantethine resulted in significant increases of plasma CGRP- and VIP-IS levels compared to placebo. Furthermore, areas under the plasma concentration-time curves (AUC(0-240)) of CGRP- and VIP-IS were significantly higher after pantethine administration compared with placebo. On the other hand, fursultiamine had no effect on plasma levels and AUC(0-240) of CGRP-, VIP-, motilin- and SP-IS. This study demonstrated the different effects of pantethine and fursultiamine from the viewpoint of plasma gastrointestinal peptide changes. The pharmacological effects of pantethine may be closely related to the changes in plasma CGRP- and VIP-IS levels.

Some traditional Chinese herbal (Kampo) medicines have recently been evaluated for their clinical usefulness in stress and depression. These medicines have modulatory effects on the hypothalamic-pituitary-adrenal axis and sympathetic nervous system (SNS). We examined the effects of Rikkunshi-to, Hange-shashin-to, Hange-koboku-to, and Ninjin-to on plasma levels of neuropeptide Y (NPY), which is the representative neurotransmitter of the SNS, under venipuncture stress. Rikkunshi-to and Hange-shashin-to suppressed increases in plasma NPY-immunoreactive substance levels compared with the response to a placebo. In this study, Rikkunshi-to and Hange-shashin-to altered plasma levels of NPY under venipuncture stress. These effects might be beneficial in stress-related diseases and our results suggest that these medicines have clinical pharmacologic activity.

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.

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 herbal medicine Ninjin-to has been used for the treatment of gastroenteritis, esogastritis, gastric atony, gastrectasis, vomiting, and anorexia. One of the mechanisms of the empirical effects is assumed to be due to local changes in neuropeptide levels. Sensory afferent neurons in the gastrointestinal mucosa regulate neuropeptides [calcitonin gene-related peptide (CGRP), substance P, etc.], which play various physiologic roles. To determine whether the pharmacologic effects of Ninjin-to on the gastrointestine are due to changes in gastrointestinal mucosa regulatory peptide levels, we examined the effects of Ninjin-to on the levels of CGRP-like immunoreactive substances (IS) and substance P-IS in plasma taken from five healthy subjects. A single oral administration of 6.0 g of Ninjin-to caused significant increases in plasma CGRP-IS at 40 min and 60 min, and in substance P-IS levels at 90 min, compared with a placebo group. These results may indicate that the pharmacologic actions of Ninjin-to are closely related to changes in CGRP-IS and substance P-IS levels.

Sho-hange-ka-bukuryo-to and Nichin-to, traditional Chinese herbal (Kampo) medicines have been used to treat vomiting and nausea. Traditional herbal medicines have frequently been used in the empirical treatment. Some patients who take these medicines have no organic disease but have conditions classified as non-ulcer dyspepsia (NUD). To determine the pharmacological effects of Sho-hange-ka-bukuryo-to, Nichin-to, and the two herbs (Pinelliae Tuber and Zingiberis Rhizoma, both of which are included in Sho-hange-ka-bukuryo-to and Nichin-to), we examined the effects of these medicines on the plasma levels of adrencorticotropic hormone (ACTH) and cortisol under stress conditions by repetitive blood sampling. After a single administration of Kampo medicine or a placebo, venous blood samples were taken before and 20-240 min after administration. A single administration of Sho-hange-ka-bukuryo-to caused significant suppression of an increase in plasma ACTH-immunoreactive substance (IS) levels at 120 to 180 min and tended to suppress increases in plasma cortisol levels at 240 min, compared with the response to a placebo. A single administration of Nichin-to caused significant suppression of increases in plasma ACTH-IS levels at 120 min compared with a placebo group, but had no effect on plasma cortisol levels. Pinelliae Tuber had no significant effects in plasma ACTH-IS or cortisol, but Zingiberis Rhizoma significantly suppressed the increase of ACTH-IS (120 min) and cortisol (180 min). These medicines have a modulatory effect on the hypothalamo-pituitary-adrenal (HPA) axis and autonomic nervous function. These effects might be beneficial in stress-related disease and suggest that this medicine has clinical pharmacological activity.

Hange-koboku-to (Banxia-houpo-tang), a Chinese herbal (Kampo) medicine, has been used for improvement of hoarse voice, something foreign body sensation in the throat and/or esophagus, and swallowing reflex, among other conditions. One of the mechanisms of the empirical effects is assumed to be due to local changes in neuropeptide levels locally. We investigated the effects of Hange-koboku-to on neuropeptides, calcitonin gene-related peptide (CGRP), substance P, somatostatin, and vasoactive intestinal peptide (VIP) in plasma and saliva, as well as on salivary secretion in healthy subjects. A single oral administration of Hange-koboku-to caused significant increases in substance P-immunoreactive substance (IS) (40 min) in plasma, and slightly increased in CGRP-IS and somatostatin-IS in plasma compared with placebo. In saliva neuropeptides, Hange-koboku-to caused significant increases in substance P-IS (20 min) and somatostatin-IS (40, 60 min), and a slight increase in VIP-IS. However, a single Hange-koboku-to stimulation did not have a significant effect of sialosis volume. These results seem to suggest that Hange-koboku-to improves hoarse voice, something foreign body sensation in the throat and esophagus, and swallowing reflex disorder, by stimulation of neuropeptidergic nerves locally.

Rikkunshi-to, a gastrointestinal function regulatory traditional Chinese herbal (Kampo) medicine, has recently been evaluated for its clinical usefulness in stress and depression. This medicine has modulatory effects on the hypothalamo-pituitary-adrenal axis and autonomic nervous function. We examined the effect of Rikkunshi-to and the other gastrointestinal function regulatory Kampo medicines, Hange-shashin-to, Hange-koboku-to, and Ninjin-to, on the plasma levels of adrenocorticotropic hormone (ACTH) and cortisol under stress conditions by repetitive blood sampling. Rikkunshi-to, Hange-shashin-to, and Hange-koboku-to significantly suppressed increases in plasma ACTH-immunoreactive substance (IS) levels compared with the response to a placebo. Rikkunshi-to and Hange-shashin-to significantly suppressed increases in plasma cortisol levels compared with the response to placebo. Ninjin-to had no significant effect on plasma ACTH-IS and cortisol levels. In this study, Rikkunshi-to, Hange-shashin-to, and Hange-koboku-to (partially) regulated plasma ACTH and cortisol levels under stress. These modulatory effects might be beneficial in stress-related disease and suggest that these medicines have clinical pharmacologic activity.

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.

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 (p0.01 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 (p0.01 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.

We examined the effects of Dai-kenchu-to (DKCT) on the levels of vasoactive intestinal peptide (VIP) and 5-hydroxytryptamine (serotonin; 5-HT) in plasma taken from 6 healthy subjects. A single oral administration of 7.5 g DKCT caused significant increases in plasma VIP at 30, 60 to 90 and 120 min (3.5-5.5 pg/ml), compared with the response in a placebo group (about 1.0 pg/ml). DKCT also caused significant increases in plasma 5-HT at 30 (121.8+/-7.3 ng/ml) and 60 (156.5+/-8.0 ng/ml) min, compared with the response in the placebo group (about 101 ng/ml). These results indicate that the stimulatory effect of DKCT on VIP-immunoreactive substance (VIP-IS) secretion is due, at least in part, to increased 5-HT levels in the abdomen. As a consequence, increased VIP-IS may improve feelings of coldness in the abdomen.

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.