Improvement of accessory symptoms of hypertension by TSUMURA Orengedokuto Extract, a four herbal drugs containing Kampo-Medicine Granules for ethical use: a double-blind, placebo-controlled study.

A double-blind, placebo-controlled study was conducted to evaluate the efficacy, safety, and utility of TSUMURA Orengedokuto Extract Granules for Ethical Use (TJ-15) as a treatment for the accessory symptoms of hypertension. Two capsules of the study drug were administered orally 3 times daily (i.e., before meals) for 8 weeks. Among 265 patients enrolled in the study, 134 were assigned to the TJ-15 group and 131 were assigned to the placebo group, of whom 204 patients (103 in the TJ-15 group and 101 in the placebo group) were included in the efficacy and utility analyze and 251 patients (128 in the TJ-15 group and 123 in the placebo group) were included in the safety analysis. Efficacy was significantly higher in the TJ-15 group based on the total score for the accessory symptoms of hypertensions which was the primary efficacy endpoint (Wilcoxon's rank sum test, p=0.013). When each accessory symptom of hypertension was assessed separately, efficacy was higher for hot flushes and facial suffusion in the TJ-15 group (Wilcoxon's rank sum test, p=0.034, and 0.022, respectively). There were no significant differences between the TJ-15 and the placebo groups with respect to the decrease of blood pressure or the antihypertensive effect. There was also no significant difference between the two groups with regard to the overall safety rating. The utility rating was significantly higher in the TJ-15 group than in the placebo group (Wilcoxon's rank sum test, p=0.016). In conclusion, TJ-15 was superior to placebo with respect to efficacy, safety, and utility for the treatment of accessory symptoms of hypertension.

Choto-san in the treatment of vascular dementia: a double-blind, placebo-controlled study.

In an earlier placebo-controlled study, we demonstrated that a kampo (Japanese herbal) medicine called Choto-san (Diao-Teng-San in Chinese) was effective in treating vascular dementia. To evaluate its efficacy using more objective criteria, we carried out a multi-center, double-blind study of Choto-san extract (7.5 g/day) and a placebo, each given three times a day for 12 weeks to patients suffering from this condition. The study enrolled and analyzed 139 patients, 50 males and 89 females, with a mean age of 76.6 years. Choto-san was statistically superior to the placebo in global improvement rating, utility rating, global improvement rating of subjective symptoms, global improvement rating of psychiatric symptoms and global improvement rating of disturbance in daily living activities. Such items as spontaneity of conversation, lack of facial expression, decline in simple mathematical ability, global intellectual ability, nocturnal delirium, sleep disturbance, hallucination or delusion, and putting on and taking off clothes were significantly improved at one or more evaluation points in those taking Choto-san compared to those taking the placebo. Furthermore, the change in revised version of Hasegawa's dementia scale from the beginning point in Choto-san group was tended to be higher than that in placebo group with no statistical significance. These results suggest that Choto-san is effective in the treatment of vascular dementia.

[Inhibitory effects of Hachimijiogan on micturition reflex via the locus coeruleus].

Pharmacological studies were undertaken to elucidate the role of Hachimijiogan in the micturition reflex via the locus coeruleus, using alpha-chloralose-anesthetized cats. Rhythmic contractions of the urinary bladder induced by continuous infusion of saline into the bladder were dose-dependently inhibited by intravenous injection of Hachimijiogan (10, 30 and 90 mg/kg), as well as flavoxate hydrochloride (1 and 3 mg/kg). In contrast, contraction of the urinary bladder elicited by electrical stimulation of the locus coeruleus was significantly suppressed by intravenous injection of flavoxate, but not affected by that of Hachimijiogan. These results suggest that Hachimijiogan acts on the afferent pathway from the urinary bladder to the locus coeruleus, thereby inhibiting the micturition reflex, while it has no effects on the efferent pathway from the locus coeruleus to the urinary bladder.

Acute effects of methamphetamine applied microiontophoretically to nucleus accumbens neurons in rats.

Microiontophoretic studies were performed to elucidate the acute effects of methamphetamine on the nucleus accumbens (Acc) neurons receiving input from the parafascicular nucleus (Pf) of the thalamus using rats anesthetized with chloral hydrate. Spike generation upon Pf stimulation was inhibited by conditioning stimuli applied to the ventral tegmental area (VTA), which is rich in dopamine-containing neurons, and by iontophoretic application of methamphetamine as well as dopamine. The VTA-, methamphetamine- and dopamine-induced inhibition of the spikes elicited by Pf stimulation was antagonized during simultaneous application of haloperidol. Glutamate-induced firing was also inhibited during iontophoretic application of methamphetamine and dopamine in neurons receiving input from the Pf, and the inhibition was blocked by simultaneously applied haloperidol. In the reserpine-treated animals, however, the Pf-induced spikes were not affected by methamphetamine, but inhibited by dopamine. These results indicate that methamphetamine inhibits the Acc neurons receiving input from the Pf, probably by releasing dopamine from dopaminergic nerve terminals from the VTA.

Feedback loop between locus coeruleus and spinal trigeminal nucleus neurons responding to tooth pulp stimulation in the rat.

Studies were performed to elucidate reciprocal relationships between locus coeruleus (LC) and spinal trigeminal nucleus (STN) neurons responding to tooth pulp (TP) stimulation using rats anesthetized with alpha-chloralose. LC conditioning stimulation inhibited STN field potential as well as orthodromic spike generation of STN neurons produced by ipsilateral TP stimulation, confirming the previous findings in cats that LC neurons played an inhibitory role in the orthodromic transmission in STN neurons. Forty-one out of 56 LC neurons were activated by ipsilateral TP stimulation and 12 neurons by stimulation of both ipsi- and contralateral TP. STN stimulation usually excited LC neurons with a significantly shorter latency than did TP stimulation, including three LC neurons with a latency of less than 2.0 msec. These results indicate the existence of input from TP to LC neurons via multisynapses. In addition, neurons antidromically activated by STN stimulation were found in LC. It is highly probable, therefore, that there is a feedback loop between LC and STN, which might control input from TP to STN.

Hyperdipsia induced by bilateral destruction of the locus coeruleus in rats.

Bilateral lesions in the locus coeruleus (LC) of rats induced a urinary disorder and hyperdipsia. Dilatation of the urinary bladder, urinary retention and hematuria with bleeding originating from the urinary bladder, occurred immediately after the lesioning and continued for 2-5 days. Water intake increased 4 days after the lesioning. This hyperdipsia persisted for at least 4 days and then gradually returned to the control level. Food intake decreased for the first 5 days, and then returned to the control level. Lesions in the ascending dorsal bundle (DB) originating from the LC also produced hyperdipsia, but not urinary disorder. Destruction of the ascending ventral vundle (VB) originating from the noradrenaline (NA) neurons in the medulla oblongata did not affect eating, drinking or urination. The LC- or DB-lesioning caused a significant reduction of NA in the whole forebrain except the hypothalamus, whereas VB-lesioning caused reduced NA in the hypothalamus. In LC-lesioned animals, no significant changes were observed in serum osmolarity, Na+, K+, albumin and glucose in serum, or in the excretion of urine in the water-loading test.