Predictive factors requiring high-dose evocalcet in hemodialysis patients with secondary hyperparathyroidism.

The dosage of evocalcet required to control serum parathyroid hormone (PTH) levels varies among secondary hyperparathyroidism (SHPT) patients. This post hoc analysis evaluated the dose-dependent efficacy of evocalcet on serum intact PTH (iPTH) levels, corrected calcium (Ca) and phosphate (P) levels, and safety, in an evaluation period (week 28 to week 30) by stratifying the previous phase 3 data with the final evocalcet dosages (low 1-2 mg [131 patients], medium 3-4 mg [90 patients], high 5-8 mg [92 patients]), and identified pre-treatment patient characteristics predicting the use of higher final evocalcet dosages via univariate and multivariate logistic regression models. At the end of the study at week 30, the median serum iPTH level was higher and the achievement ratio for the target range of Japanese Society for Dialysis Therapy (60-240 pg/mL) was lower in the final high-dose subgroup (216 pg/mL and 58%, respectively) than in the other subgroups (low: 149 pg/mL and 79%; medium: 149 pg/mL and 73%, respectively). Among the three subgroups, the mean serum corrected Ca and P levels demonstrated similar trends, and similar ratio of patients achieved the target range (corrected Ca, 8.4-10 mg/dL; P, 3.5-6.0 mg/dL) from week 28 to week 30. No dose-dependent safety concerns were identified. Younger age, prior cinacalcet use, higher serum levels of iPTH and corrected Ca, procollagen type 1 N-terminal propeptide, intact fibroblast growth factor-23, and larger maximum parathyroid gland volume were significantly associated with final high-dose evocalcet (p < 0.05 in all cases). Patients requiring final high-dose evocalcet had pre-treatment characteristics indicating severe SHPT, leading to a lower final achievement rate for the target PTH levels of Japanese Society for Dialysis Therapy. Therefore, the early initiation of evocalcet treatment for SHPT is critical. Trial registration: This trial was registered as follows: ClinicalTrials.gov: NCT02549391 and JAPIC: JapicCTI-153013.

A novel calcimimetic agent, evocalcet (MT-4580/KHK7580), suppresses the parathyroid cell function with little effect on the gastrointestinal tract or CYP isozymes in vivo and in vitro.

Cinacalcet hydrochloride (cinacalcet), an oral calcimimetic agent has been widely used for the management of secondary hyperparathyroidism (SHPT) in chronic kidney disease (CKD). In sharp contrast to vitamin D receptor activators, cinacalcet suppresses SHPT without inducing hypercalcemia or hyperphosphatemia. Nevertheless, some patients remain refractory to SHPT with this agent, as the dose cannot be sufficiently increased due to gastrointestinal symptoms. In order to resolve this issue, we have developed a newly synthesized calcimimetic agent, evocalcet (MT-4580/KHK7580). In a rat model of CKD induced by 5/6 nephrectomy, oral administration of evocalcet efficiently suppressed the secretion of parathyroid hormone (PTH). With regard to the gastro-intestinal effects, cinacalcet induced a significant delay in gastric emptying in rats, while evocalcet did no marked effects on it. Evocalcet also demonstrated the less induction of emesis compared to cinacalcet in common marmosets. The pharmacological effects of evocalcet were observed at lower doses because of its higher bioavailability than cinacalcet, which may have contributed to the reduced GI tract symptoms. In addition, evocalcet showed no substantial direct inhibition of any CYP isozymes in in vitro liver microsome assay, suggesting a better profile in drug interactions than cinacalcet that inhibits cytochrome P450 (CYP) 2D6. These findings suggest that evocalcet can be a better alternative to cinacalcet, an oral calcimimetic agent, with a wider safety margin.

[Effect of santalol on the sleep-wake cycle in sleep-disturbed rats].

Sandalwood oil is widely used in aromatherapy for alleviating various symptoms. Santalol, a major component of sandalwood oil, has been reported to have central nervous system depressant effects such as sedation. In the present study, we investigated the effect of santalol on the sleep-wake cycle in sleep-disturbed rats. When inhaled at a concentration of 5 X 10(-2) ppm, santalol caused a significant decrease in total waking time and an increase in total non-rapid eye movement (NREM) sleep time. In order to clarify the mechanism of action, olfactory hypofunction was caused in rats by intranasal application of 5% zinc sulfate solution, and thereafter the effects of inhalation of fragrances were evaluated. In this study, it was found that the impairment of the olfactory system showed no significant effect on the changes in sleep parameters induced by santalol. This result suggests that santalol may act via the circulatory system rather than the olfactory system. That is, santalol is thought to be absorbed into the blood through the respiratory mucosa, and then exert its action. From these results, it is concluded that santalol may be useful in patients having difficulty maintaining sleep without being affected by individual differences in perfume-related preference.

Effect of valerian extract preparation (BIM) on the sleep-wake cycle in rats.

In the present study, we studied the effect of valerian extract preparation (BIM) containing valerian extract, golden root (Rhodiola rosea L.) extract and L-theanine (gamma-glutamylethylamide) on the sleep-wake cycle using sleep-disturbed model rats in comparison with that of valerian extract. A significant shortening in sleep latency was observed with valerian extract and the BIM at a dose of 1000 mg/kg. On the other hand, valerian extract and the BIM caused no significant effects on total times of wakefulness, non-rapid eye movement (non-REM) sleep and REM sleep. Valerian extract and the BIM at a dose of 1000 mg/kg also had no significant effect on delta activity. In conclusion, it became clear that the BIM could be useful as a herbal medicine having a sleep-inducing effect without causing an alteration of the sleep-wakefulness cycle.

Effect of seed coat extract from black soybeans on radial maze performance in rats.

1. In the present study, we tested the effect of seed coat extract from black soybeans on eight-arm radial maze performance in rats. 2. Rats were fed a diet containing 5% seed coat extract from black soybeans or a normal diet for 40 days. 3. One week after the start of feeding, rats were tested for learning ability related to two types of memory, reference memory and working memory, with a partially (four of eight) baited eight-arm radial maze. 4. A significant decrease in the total number of errors was observed 30 (mean value of five trials of 26-30 days) and 35 days (30-35 days) after the intake of the diet containing seed coat extract compared with the control group. In addition, the mean number of days taken to reach this criterion was significantly decreased after the intake of the diet containing the seed coat extract. 5. The number of reference memory errors was significantly decreased 30 and 35 days after the intake of the diet containing seed coat extract. However, no significant decrease was observed in the number of working memory errors. 6. From these results, it is concluded that the intake of seed coat extract from black soybeans effectively enhances memory and learning ability, especially long-term memory, in rats.

Hypnotic activities of chamomile and passiflora extracts in sleep-disturbed rats.

In the present study, we investigated hypnotic activities of chamomile and passiflora extracts using sleep-disturbed model rats. A significant decrease in sleep latency was observed with chamomile extract at a dose of 300 mg/kg, while passiflora extract showed no effects on sleep latency even at a dose of 3000 mg/kg. No significant effects were observed with both herbal extracts on total times of wakefulness, non-rapid eye movement (non-REM) sleep and REM sleep. Flumazenil, a benzodiazepine receptor antagonist, at a dose of 3 mg/kg showed a significant antagonistic effect on the shortening in sleep latency induced by chamomile extract. No significant effects were observed with chamomile and passiflora extracts on delta activity during non-REM sleep. In conclusion, chamomile extract is a herb having benzodiazepine-like hypnotic activity.

Effects of kava-kava extract on the sleep-wake cycle in sleep-disturbed rats.

RATIONALE: Kava-kava extract may be useful as an herbal medicine for treatment of insomnia and anxiety. OBJECTIVES: The present study was undertaken to investigate the effects of kava-kava extract on the sleep-wake cycle in comparison with that of flunitrazepam using sleep-disturbed rats. METHODS: Electrodes for measurement of electroencephalogram (EEG) and electromyogram (EMG) were implanted into the frontal cortex and the dorsal neck muscle of rats. EEG and EMG were recorded with an electroencephalogram. SleepSign ver.2.0 was used for EEG and EMG analysis. Total times of wakefulness, non-rapid eye movement (non-REM) and REM sleep were measured from 09:00 to 15:00. RESULTS: A significant shortening of the sleep latency in sleep-disturbed rats was observed following the administration of kava-kava extract at a dose of 300 mg/kg, while no effects were observed on the total waking and non-REM sleep time. On the other hand, flunitrazepam showed a significant shortening in sleep latency, decrease in total waking time and increase in total non-REM sleep time. Although the effects of flunitrazepam were antagonized by the benzodiazepine receptor antagonist flumazenil, the effect of kava-kava extract was not antagonized by flumazenil. Kava-kava extract showed a significant increase in delta activity during non-REM sleep in sleep-disturbed rats, whereas a significant decrease in delta power during non-REM sleep was observed with flunitrazepam. Flumazenil caused no significant effect on the changes in delta activity induced by both kava-kava extract and flunitrazepam. CONCLUSIONS: Kava-kava extract is an herbal medicine having not only hypnotic effects, but also sleep quality-enhancement effects.