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This study was undertaken to examine the effects of the antiepileptics phenytoin and zonisamide on changes in the mineral density of the incisor and bone mineral density (BMD) of the mandibular head, and on the rate of dentin formation using histomorphometric measurements. After repeated administration of phenytoin or zonisamide to male growing rats, the mineral density of the lower incisors and mandibular head were determined by analyzing microradiographs and dentin formation rates were determined by histomorphometric measurements. Results showed a significant decrease in the mean values of BMD of the mandibular head and lower incisors in groups treated with phenytoin or zonisamide compared with the vehicle-treated group (p < 0.05). The percent rates of decrease in mineral density of the incisors for phenytoin and zonisamide were 6.8% and 4.0%, respectively. Phenytoin and zonisamide significantly reduced the dentin formation rate for the mesial and distal areas compared with the vehicle-treated group. Thus, epileptic children who are treated over a long period with antiepileptics, especially at primary school age, should ensure good oral hygiene so as not to suffer bone loss, edentulism or gingival overgrowth.

Metallothionein (MT) is induced in the liver not only by heavy metals, but also by stress such as starvation. However, the meaning of the induced MT during starvation has never been clear. In this study, we investigated the relationship between changes in hepatic MT synthesis and the hepatic damage that occurs during starvation. MT synthesis was assessed by measuring MT contents and the expression of the MT gene in the liver. The hepatic damage was assessed by measuring glutamic pyruvic transaminase (GPT) and glutamic oxaloacetic transaminase (GOT) activities in the serum. MT synthesis in the liver increased over the normal level by starvation, but decreased under the normal level by refeeding after starvation. Both GPT and GOT activities of the refeeding group were higher than those of the control group. However, MT synthesis increased by a subcutaneous injection with CdCl(2) (1 mg Cd /kg) at the same time as refeeding after starvation. At this point, GOT activity decreased until it reached the normal level. MT synthesis decreased by refeeding after starvation, and from the results found in this study, we proposed the hypothesis that the liver damage caused by refeeding after starvation might be due to the decrease in the synthesis of a sufficient amount of MT induced by metals.

To clarify the action of estrogenic endocrine disruptors on cadmium (Cd)-induced metallothionein (MT) synthesis in the liver, we investigated the effects of bisphenol A (BPA) on hepatic MT-I mRNA expression and MT contents after Cd injection. Liver damage after Cd injection was assessed by measuring glutamic-pyruvic transaminase (GPT) and glutamic-oxaloacetic transaminase (GOT) activities in the serum. It was found that BPA reduced the Cd-induced expression of MT-I mRNA and MT protein in the liver. The administration of tamoxifen, an estrogen receptor antagonist, prevented the reduction of hepatic MT content by PA. Moreover both the GPT and GOT activities of the BPA-treated groups were higher than those of the control groups. These findings suggest that BPA reduced hepatic MT synthesis after Cd injection via the estrogen receptor which resulted in increased damage to the liver.

The effects of chlorpheniramine and epinastine on dihydrocodeine were examined in mice. Orally administered dihydrocodeine (3-30 mg/kg) dose-dependently inhibited the number of capsaicin-induced coughs. The dose-dependent antitussive effects of dihydrocodeine were enhanced by each corresponding dose of chlorpheniramine or epinastine delivered at a ratio generally similar to that found in over-the-counter antitussive preparations (dihydrocodeine:histamine H1 antagonist = 3:1). The ED50 value of dihydrocodeine in combination with chlorpheniramine was nearly the same as that for dihydrocodeine in combination with epinastine. On the other hand, while combination treatment with dihydrocodeine (3 mg/kg i.p.) and chlorpheniramine (1 mg/kg s.c.) significantly potentiated place preference, no potentiation was observed with the combination of dihydrocodeine (3 mg/kg i.p.) and epinastine (1 mg/kg s.c.). These results suggest that epinastine may be a useful constituent opioid-containing antitussive preparation that would not enhance the potential for psychological dependence.

In this study, the intracerebroventricular administration of 4-methylhistamine (3 and 10 micrograms/head), a histamine H2 receptor agonist, shortened the step-through latency in the retention trial using a step-through passive avoidance task in mice. This deteriorating effect of 4-methylhistamine (3 micrograms/head) was clearly antagonized by pretreatment with zolantidine (10 mg/kg, i.p.), a histamine H2 receptor antagonist, 20 min before an acquisition trial. Zolantidine alone at the dose tested had no effect. Thus, it is likely that activation of histamine H2 receptors has a deteriorating effect on avoidance learning in mice. The present results indicate the cognitive involvement by negative modulation of histamine H2 receptors in passive avoidance task in mice.