Studies on interactions between traditional herbal and Western medicines. IV: lack of pharmacokinetic interactions between Saiko-ka-ryukotsu-borei-to and carbamazepine in rats.

The possibility of pharmacokinetic interactions between Saiko-ka-ryukotsu-borei-to extract powder (TJ-12), a widely used traditional Chinese herbal (Kampo) medicine, and carbamazepine (CBZ), an important anti-epileptic drug, was examined in rats. There were no significant differences in the serum protein binding of CBZ and carbamazepine- 10,11-epoxide (CBZ-E), its active metabolite, at two concentrations (1 and 10 Bg/ml) between twogroups pretreated orally with the vehicle andTJ-12 suspension (1 g/kg/d, p.o.) for 1 week. One-week repeated pretreatment with TJ- 12 (1 g/kg/d) did not influence liver weight, contents of cytochromes P450 and b5 in hepatic microsomes or the formation rate of CBZ-E from CBZ by its microsomes, while pretreatment with phenobarbital (80 mg/kg/d, i.p.) significantly increased these parameters. Neither a single nor 1-week repeated oral pretreatment with TJ-12 (1 g/kg/d) affected the plasma concentration-time profile and any pharmacokinetic parameter of CBZ or CBZ-E after oral administration of CBZ (50 mg/kg). These results indicated that oral co-administration of TJ-12 with CBZ has no effect ofthe pharmacokinetics of CBZ or CBZ-E in rats. Concomitant treatment with TJ- 12 and CBZ appears to be pharmacokinetically safe in humans.

A clinical evaluation of lymphangioma of the large intestine: a case presentation of lymphangioma of the descending colon and a review of 279 Japanese cases.

With the development and widespread use of colonoscopy, lymphangioma of the large intestine has recently been reported frequently. This paper presents some findings from a review of 279 cases of this disease in Japan, including a typical case that we encountered. A 69-year-old female was diagnosed as having lymphangioma of the descending colon based on the findings of a barium enema and a colonoscopy, and the lesion was successfully removed by an endoscopic resection. In the published reports, the etiology of this disease is not clear yet but the age at onset range shows a tendency toward a higher incidence in comparatively older patients and the male-to-female ratio indicates a higher incidence in males. If there is no complication, endoscopic treatment seems to be the preferable procedure for this disease.

Combined effects of red pepper and caffeine consumption on 24 h energy balance in subjects given free access to foods.

The effects of red pepper and caffeine ingestion on energy and macronutrient balances were examined in eight Caucasian male subjects. All subjects participated in two randomly assigned conditions: control and experimental (red pepper and caffeine). After ingesting a standardized breakfast, subjects ate three meals ad libitum (lunch, dinner and breakfast) and snacks which were served approximately 2 h after the lunch and dinner over a 24 h period. Two appetizers with or without 3 g red pepper) were given before lunch and dinner, and a drink (decaffeinated coffee with or without 200 mg caffeine) was served at all meals and snacks except for the after-dinner snack. It is also important to note that on the experimental day, 8.6 and 7.2 g red pepper were also added to lunch and dinner respectively. Red pepper and caffeine consumption significantly reduced the cumulative ad libitum energy intake and increased energy expenditure. The mean difference in energy balance between both conditions was 4000 kJ/d. Moreover, the power spectral analysis of heart rate suggested that this effect of red pepper was associated with an increase in sympathetic:parasympathetic nervous system activity ratio. These results indicate that the consumption of red pepper and caffeine can induce a considerable change in energy balance when individuals are given free access to foods.

Substantive differences in the assertiveness of low-income African American, Hispanic, and Caucasian women.

A sample of 115 low-income African American, Hispanic, and Caucasian women participated in 6 assertiveness role plays. A content analysis of their responses indicated that there are substantive differences in terms of what constitutes passive, assertive, and aggressive responses. The findings suggest that there are basic conceptual differences across the groups regarding connections and obligations to others. Differences in perceptions of assertiveness point to the culturally specific nature of assertiveness. Functionally, each group of women was able to stand up for themselves, yet boundaries between appropriate and inappropriate responding were placed somewhat differently across groups, depending on the situation.

Studies on interactions between traditional herbal and Western medicines. I. Effects of Sho-seiryu-to on the pharmacokinetics of carbamazepine in rats.

The effects of oral co- and pre-administration of Sho-seiryu-to extract powder (TJ-19, 1 g/kg), a widely used Kampo (traditional Chinese herbal) medicine, on the pharmacokinetics of an anti-epileptic drug, carbamazepine (CBZ), and its active metabolite (carbamazepine-10,11-epoxide, CBZ-E) after oral administration of CBZ (50 mg/kg) were examined in male rats. The simultaneous administration of TJ-19 significantly lengthened the time to reach the peak plasma concentration (Tmax), but did not influence the peak plasma concentration, area under the plasma concentration-time curve or terminal elimination half-life (t1/2). Each parameter for CBZ or CBZ-E with a single pretreatment with TJ-19 was not significantly different from that with the vehicle. Tmax and the elimination rate constant for CBZ were significantly increased by 1-week repeated pretreatment with TJ-19, by 83% (p<0.01) and 88% (p<0.001), respectively. t1/2 and the mean residence time from zero to infinity (MRT0-infinity) in the TJ-19 pretreatment group were significantly shortened, by 52 and 34% (p<0.005), respectively. No significant difference in the bound fraction of each drug at two concentrations (1 and 10 microg/ml) was observed between the control and TJ-19 pretreatment groups. These results indicate that simultaneous oral administration of TJ-19 delays the oral absorption of CBZ, while 1-week repeated pretreatment with TJ-19 accelerates the metabolism of CBZ in rats, without affecting the protein binding of CBZ.

Efficacy of two dentifrices on removal of natural extrinsic stain.

PURPOSE: To evaluate the 6-week effect on natural extrinsic dental stain from the use of a dentifrice containing 10% aluminum oxide, 1500 ppm sodium monofluorophosphate in a precipitated calcium carbonate (PCC) base or a second dentifrice containing 0.5% calcium peroxide (CP), 1500 ppm sodium monofluorophosphate in a PCC base compared to a fluoride placebo dentifrice without stain removal ingredients. MATERIALS AND METHODS: A total of 94 subjects were entered in the study, and stratified into three balanced groups according to their baseline mean Lobene Stain Index scores. The three groups were randomly assigned to use one of the two test dentifrices or the placebo dentifrice. The three groups were well balanced with regard to their mean baseline stain index scores, gender and tobacco habits. Subjects were instructed to brush their teeth twice daily (morning and evening) for 1 minute with their assigned dentifrice and a commercially available soft bristled toothbrush. Extrinsic dental stain examinations, which included mean stain area and mean stain intensity, were conducted at baseline and 6 weeks. Examinations were conducted by the same dental examiner (F.A.) on the subjects at each examination. RESULTS: After 6 weeks' use of their assigned products, those subjects in the aluminum oxide/PCC dentifrice group and those subjects in the CP/PCC dentifrice group demonstrated statistically significant improvements, as compared to the fluoride placebo dentifrice group without stain removal ingredients.

Effects of red pepper on appetite and energy intake.

Two studies were conducted to investigate the effects of red pepper (capsaicin) on feeding behaviour and energy intake. In the first study, the effects of dietary red pepper added to high-fat (HF) and high-carbohydrate (HC) meals on subsequent energy and macronutrient intakes were examined in thirteen Japanese female subjects. After the ingestion of a standardized dinner on the previous evening, the subjects ate an experimental breakfast (1883 kJ) of one of the following four types: (1) HF; (2) HF and red pepper (10 g); (3) HC; (4) HC and red pepper. Ad libitum energy and macronutrient intakes were measured at lunch-time. The HC breakfast significantly reduced the desire to eat and hunger after breakfast. The addition of red pepper to the HC breakfast also significantly decreased the desire to eat and hunger before lunch. Differences in diet composition at breakfast time did not affect energy and macronutrient intakes at lunch-time. However, the addition of red pepper to the breakfast significantly decreased protein and fat intakes at lunch-time. In Study 2, the effects of a red-pepper appetizer on subsequent energy and macronutrient intakes were examined in ten Caucasian male subjects. After ingesting a standardized breakfast, the subjects took an experimental appetizer (644 kJ) at lunch-time of one of the following two types: (1) mixed diet and appetizer; (2) mixed diet and red-pepper (6 g) appetizer. The addition of red pepper to the appetizer significantly reduced the cumulative ad libitum energy and carbohydrate intakes during the rest of the lunch and in the snack served several hours later. Moreover, the power spectral analysis of heart rate revealed that this effect of red pepper was associated with an increase in the ratio sympathetic: parasympathetic nervous system activity. These results indicate that the ingestion of red pepper decreases appetite and subsequent protein and fat intakes in Japanese females and energy intake in Caucasian males. Moreover, this effect might be related to an increase in sympathetic nervous system activity in Caucasian males.

Dietary red pepper ingestion increases carbohydrate oxidation at rest and during exercise in runners.

The effects of dietary hot red pepper on energy metabolism at rest and during exercise were examined in long distance male runners 18-23 yr of age. A standardized meal was given on the evening prior to the experiment. The subjects had a meal (2720 kJ) with or without 10 g of hot red pepper for breakfast. During rest (2.5 h after meal) and exercise (pedaling for 1 h at 150 W, about 60% VO2max, using cycling ergometry), expired gasses and venous blood were collected. The meal with hot red pepper significantly elevated respiratory quotient and blood lactate levels at rest and during exercise. Oxygen consumption at rest was slightly but nonsignificantly higher in the hot red pepper meal at 30 min after the meal. Plasma epinephrine and norepinephrine levels were significantly higher in those who had only hot red pepper at 30 min after the meal. These results suggest that hot red pepper ingestion stimulates carbohydrate oxidation at rest and during exercise.

Cholinergic changes in the hippocampus of stroke-prone spontaneously hypertensive rats.

BACKGROUND AND PURPOSE: We investigated age-related changes in the central cholinergic systems in stroke-prone spontaneously hypertensive rats (SHRSP) to examine whether the regional and progressive cholinergic changes occur and are correlated with behavioral changes in the passive avoidance task. METHODS: Tissue levels of choline (Ch) and acetylcholine (ACh) were determined in the cerebral regions, including the hippocampus, of SHRSP (at two ages: 15 to 20 and 30 to 40 weeks) that had been tested in a passive avoidance task and were compared with those of age-matched controls, Wistar-Kyoto rats (WKY). With the use of in vivo microdialysis, high K+-stimulated release of hippocampal ACh, a functional parameter of the cholinergic system, was also determined in 15- to 20-week-old SHRSP. RESULTS: We found that 15- to 20-week-old SHRSP demonstrated a markedly lower level of hippocampal Ch than age-matched WKY. The decrease in the Ch level in 15- to 20-week-old SHRSP was observed in all regions examined; however, in the hippocampus a significant difference from WKY was subsequently observed at the age of 30 to 40 weeks. The hippocampal ACh release was markedly decreased by repetitive stimulation with high K+ in 15- to 20-week-old SHRSP. Behavioral impairment in the passive avoidance task was observed in the two age groups of SHRSP, with significant and positive correlations between the hippocampal ACh levels and the response latency. CONCLUSIONS: A decrease in hippocampal Ch level was observed in both 15- to 20-week-old and 30- to 40-week-old SHRSP, accompanied by performance failure in the passive avoidance task. The abnormal release of hippocampal ACh in response to the repetitive K+ stimulation was also noted in 15- to 20-week-old SHRSP. Thus, cholinergic dysfunction in the hippocampal system may be responsible for behavioral abnormality in the passive avoidance task in SHRSP.

Effects of red-pepper diet on the energy metabolism in men.

We investigated the effects of dietary red pepper on the energy metabolism in male subjects. In the first experiment, after having a standardized dinner on the previous evening, the subjects consumed a breakfast (650 kcal) either with or without 10 g of red pepper. For 150 min after the meal, they took a rest and their expired gas was collected. During the initial 30 min after the meal, the energy expenditure tended to be higher in the red-pepper diet period than in the control diet period. For the remaining 120 min, no difference in the energy expenditure was found between the red-pepper diet period and the control diet period. However the carbohydrate oxidation was significantly higher in the red-pepper diet period than in the control diet period while the lipid oxidation was lower in the red-pepper diet period than in the control diet period for 150 min after the meal. In the second experiment, the subjects consumed a breakfast with 10 g of red pepper after an oral administration of propranolol or a placebo. The propranolol abolished the increase in energy expenditure during the initial 30 min due to the meal containing red pepper. For the remaining 120 min, no difference in energy expenditure was found between the propranolol period and the placebo period. These results suggest than an increase in the energy expenditure after the meal containing red pepper appeared only immediately after the meal ingestion and a red-pepper diet increases the carbohydrate oxidation without increasing total energy expenditure for 150 min after the meal. And an increase in the energy expenditure immediately after the meal containing red pepper is considered to be caused by beta-adrenergic stimulation.

Intrapleural perfusion hyperthermo-chemotherapy for malignant pleural dissemination and effusion.

Taking advantage of the antitumor effect of hyperthermia, we administered intrapleural perfusion hyperthermo-chemotherapy for the treatment of malignant pleural seeding or pleural effusion. This consists of irrigating the pleural space for 2 hours with 43 degrees C saline solution containing cis-platinum using specially devised extracorporeal circuits. From January 1988 through December 1993, we performed this technique in 12 patients with malignant disseminated lesions stemming from lung cancer who also underwent surgical resection of the primary lesions and in 7 patients with malignant pleural effusions who did not undergo thoracotomy or surgical resection. There were no serious clinical complications associated with this procedure. The pharmacokinetics showed that a high concentration of cis-platinum (more than 17.6 micrograms/mL in the free form) was retained in the pleural cavity during perfusion. After this therapy, the cancer cells showed marked degeneration with fibrosis in the pleural wall. The pleural effusion was well controlled in 100% of the patients. The median survival time in the 12 patients with pleural disseminated lesions who were treated with intrapleural perfusion hyperthermo-chemotherapy was 20 months. On the other hand, the median survival time in 7 patients with similar lesions who did not receive IPHC was only 6 months. Intrapleural perfusion hyperthermo-chemotherapy seems to have considerable value as an adjuvant therapy for patients with pleural dissemination who have had their primary lesions removed.

Analyses of metal ions in spider venoms in relation to insecticidal activity of clavamine.

To elucidate insecticidal activity of spider toxins, metal ions in venoms and in the bodies were determined by thin layer chromatography, spark source mass spectrometry, ion chromatography, inductively coupled plasma emission spectrometry and atomic absorption spectrometry. Two kinds of spiders were used, Nephila clavata and Nephila maculata. Metals from their venom glands were extracted with hydrochloric acid and the metal concentrations were almost the same in the two species. Many kinds of metals, Fe, Zn, Pb, Cu, Ca, Mg, Na, P and S were found at higher levels in the venoms at concentrations higher than in the bodies. The contents of metal ions were low in the dragonfly and the cicada which are considered to be preys. Clavamine, the main insecticidal component in N. clavata, was effective on larvae of a mosquito with Ca2+, Fe3+ or Pb2+, but ineffective with Mg2+, Zn2+, Fe2+ or Cu2+. It is suggested that the metal chelates play an important role in the intoxication and detoxication of the spider toxins.

Identification of a previously unknown compound as 2'-deoxycytidine found in the plasma of breast cancer patients under combined chemotherapy.

In an attempt to find an end-point for cancer chemotherapy, this study was designed to measure the adenine compounds in the plasma of breast cancer patients using HPLC with a selective reagent for adenine bases. The patients were treated by chemotherapy using cyclophosphamide, methotrexate and 5-fluorouracil. Blood was collected in tubes containing EDTA, the plasma separated by centrifugation and analysed by HPLC. An early peak due to the fluorescent derivative of an unknown compound reacted with bromoacetoaldehyde and its concentration appeared proportional to the chemotherapeutic courses of treatment. The compound in its native state without fluorescent derivatization was efficiently purified by using columns of DEAE- and CM-Sephadex. Its UV spectrum revealed maxima at 271, 280 and 272 nm in solutions of pH 7, pH 3 and pH 12, respectively. The electrophoretograms showed that it was neutral, positively and negatively charged at pH 7, pH 3 and pH 12, respectively. Thin-layer chromatograms showed that it had the same Rf as 2'-deoxycytidine (dCyd) which was confirmed by a positive reaction for deoxyribose. It was concluded that bromoacetoaldehyde formed a weakly fluorescent product with dCyd which gave rise to the early peak in the anion exchange chromatograms. From the calculation of the recovery obtained by the purification process, the cancer patients undertaking more than 12 courses had a dCyd level of approximately 20 mM while the corresponding figure in normal volunteers was less than 1 mM. These results may be useful in assessing the status of the cancer patients.

Changes of proliferative activity and phenotypes in spontaneous differentiation of a colon cancer cell line.

We examined the alterations of proliferative activity and c-myc expression of a colon cancer cell line (Caco-2) during its spontaneous differentiation. Caco-2 cells were cultured in various types of media and the degree of differentiation was monitored in terms of dome formation in cell monolayers and expression of alkaline phosphatase (ALP) activity. In Caco-2 cells cultured with Eagle's minimum essential medium (EMEM) containing 10% fetal calf serum (FCS), dome formation was demonstrated and ALP activity was markedly increased after the cells reached confluence. Five-fold reduction of c-myc mRNA and a marked decrease in S-phase cells were observed in the differentiated cells. These changes were not induced in FCS-free EMEM. The addition of insulin and transferrin to FCS-free EMEM did not induce cell differentiation or reduction of c-myc mRNA expression. When Caco-2 cells were cultured with three different serum-free media, the induction of dome formation and the increase of ALP activity were observed to varying degrees. Expression of c-myc mRNA in the cells cultured with one serum-free medium decreased to a level similar to that in fully differentiated cells cultured with EMEM containing 10% FCS. These results suggest that a spontaneous switch from a proliferative state with high c-myc expression to differentiated phenotype occurs after cells reach confluence and depends on the culture conditions.

Thermotolerance in regional hyperthermia in vivo--an experimental study using the MH134 tumor.

In the clinical application of hyperthermia, determining the thermotolerance that influences the anti-tumor effect is an important problem. The purpose of this study was to investigate the methods of induction and disappearance of thermotolerance in vivo. After transplanting MH134 cancer cells into the paws of C3H mice, local hyperthermia with warm water was administered, and the movement of thermotolerance in vivo studied in terms of the heating intervals and tumor growth times. When the first heating was applied on the 8th day after transplantation, thermotolerance appeared within 1 hour, increasing gradually to reach a maximum at 18 hours, after which it decreased gradually and disappeared after 48 hours. When the first heating was applied on the 13th day after transplantation, which fell during the rapid tumor proliferation period, the movement of thermotolerance presented a similar pattern of appearance and disappearance. The results of this study made it clear that there was no difference in the movement of thermotolerance between the two periods even though each had a different rate of tumor proliferation.

Existence of a polar digitalis-like factor in mammalian hypothalamus.

We were able to partially purify a polar digitalis-like factor from rat and bovine hypothalami based on the capacity to inhibit [3H]ouabain binding to intact human erythrocytes. This factor was characterized in reference to the digitalis-like factor that we have isolated and reported on. Hypothalamic factor shared digitalis-like activities and physicochemical properties with the one derived from human urine and mammalian plasma. These findings strongly suggest that a polar digitalis-like factor identical to the circulatory factor does exist in mammalian hypothalamus.

Effect of a spider toxin (JSTX) on excitatory postsynaptic current at neuromuscular synapse of spiny lobster.

1. We studied the blocking properties of a spider (Nephila clavata) toxin (JSTX) purified from venom on the spiny lobster neuromuscular junction. 2. When a small amount of JSTX was applied to the neuromuscular junction, the excitatory postsynaptic potential (EPSP) was partially suppressed. The amplitude of EPSPs remained at a steady level for several hours during the washing of the preparation, showing that the action of JSTX is irreversible. 3. We recorded the excitatory postsynaptic current (EPSC) from synaptic site using a macro-patch electrode. The amplitude of EPSC increased linearly with hyperpolarization of the membrane potential in the presence and absence of JSTX. 4. The decay phase time constant of EPSC and spontaneous EPSC was decreased by hyperpolarizing the membrane potential both in the absence and in the presence of JSTX. The relationship between the decay time constant and the membrane potential was not modified by JSTX. 5. It is suggested that JSTX irreversibly blocks EPSC by acting on the site that is apart from the ionic channel of the glutamate receptor molecule.

Spider toxin (JSTX) on the glutamate synapse.

A new neurotoxin (JSTX) was separated from spider (Nephila clavata, Joro spider) venom. JSTX irreversibly suppressed the excitatory postsynaptic potential (EPSP) and the glutamate potential in the lobster neuromuscular junction with high degree of specificity. The threshold concentration for suppressing EPSPs corresponds to a small fraction of the toxin in a venom gland, roughly estimated as low as 10(-10) M/l. 10(-10) M/l. In the giant synapse of squid stellate ganglion JSTX suppressed EPSPs without affecting the antidromic response. Glutamate-induced membrane depolarization was blocked by JSTX. In mammalian brain slice preparation, JSTX suppressed the orthodromic spike response but failed to affect on the antidromic spike in the hippocampal pyramidal neuron of CA1 and CA3 region. The above results strongly support the view that the squid giant synapse and synapses in the hippocampal pyramidal neuron are mediated by glutamate.

ACTH content in the anterior pituitary after the infusion of various doses of corticosterone and dexamethasone in normal and adrenalectomized rats.

It is well known that the administration of glucocorticoids inhibits the activities of hypothalamus-pituitary-adrenal axis. The present studies were undertaken to define the site of inhibition of both corticosterone and dexamethasone on this axis in rats. Infusion of 20 or 202 micrograms corticosterone over 6 hr did not change the ACTH content in the anterior pituitary and plasma ACTH levels even through the infusion markedly inhibited the hypothalamic CRF content in normal rats. The constant infusion of a relatively small dose of 20 micrograms dexamethasone inhibited the plasma ACTH level, but not the ACTH content in the anterior pituitary and the hypothalamic CRF content. In contrast to the above results, the infusion of 202 and 504 micrograms dexamethasone over 6 hr increased the ACTH contents in the anterior pituitary, but significantly reduced the hypothalamic CRF content and plasma ACTH levels. These results suggest that the mechanism of dexamethasone inhibition in the hypothalamus-pituitary-adrenal axis is the reduction of ACTH release rather than that of ACTH production in the anterior pituitary.