Prevention of retained fetal membranes and improvement in subsequent fertility with oxytocin administration in cows with assisted calving.

In dairy cows, the efficacy of oxytocin treatment for preventing retained fetal membranes (RFM) is controversial. The physiological condition of cows associated with the calving process may affect the action of oxytocin. This study aimed to elucidate the difference in the efficacy of exogenous oxytocin treatment immediately after calving among cows that received various obstetric interventions. The calving ease was recorded using a score of 1-5, and assisted birth was defined as a score of 2 or more. Cows that required calving assistance (assisted, n = 28) due to delayed calving progression had a prolonged time from calving to expulsion of the fetal membrane (P < 0.01), and impaired reproductive performance compared to cows that did not receive calving assistance (unassisted, n = 78). The effect of oxytocin treatment was determined using cows that did not expel their fetal membrane within 3 h after calving. Cows were randomly divided into the control (unassisted, n = 41; assisted, n = 22) or oxytocin group (unassisted, n = 33; assisted, n = 10). Oxytocin (50 IU) was administered intramuscularly to the cows in the oxytocin group between 3 and 6 h after calving, while no treatment was administered in the control group. In cows with assisted birth, oxytocin administration accelerated placental expulsion (P < 0.05) and improved several reproductive parameters, such as the number of services until conception (P < 0.05) and the calving to conception intervals (P < 0.05) compared to the control group. On the other hand, oxytocin administration slightly accelerated placental expulsion (P < 0.05), but failed to improve fertility in cows with unassisted birth. The results indicate that the action of oxytocin varies depending on the calving situation of the cows. Oxytocin administration during the early postpartum period could prevent RFM and improve the decline in reproductive performance associated with calving assistance.

Gender differences in self-perceived changes among Japanese workers with depression.

BACKGROUND: The number of patients living with depression continues to increase in Japan. The economic effects of depression include loss of productivity due to both absenteeism and presenteeism. Gender differences have been reported in prevalence, onset pathways and subjective symptoms of depression. AIMS: To understand how workers with major depressive disorder (MDD) perceive problems in the workplace and examine gender differences in their self-perceived levels of functioning at work, noticed during the initial stages of depression. METHODS: This is a cross-sectional study of Japanese workers with MDD. Participants' self-perceived changes in the level of functioning at work were surveyed after the diagnosis during the first visit. The relationship between gender and changes in the level of functioning at work as initially perceived by the participants themselves was analysed using the chi-square test, supplemented by a residual analysis. RESULTS: We administered the survey to 147 workers with MDD. In terms of gender differences in initial self-perceived changes in the level of functioning at work, the proportion of men reporting reduced work efficiency was significantly higher than that of women, while the proportion of women reporting deterioration in relationships with colleagues and superiors was significantly higher than that of men. CONCLUSIONS: The findings suggest that greater attention to reduced work efficiency by men and to deterioration in work relationships by women with MDD should be essential components of self-care. Managers need to pay attention to the level of functioning and provide adequate social support for employees.

Depression and occupational stress in Japanese school principals and vice-principals.

BACKGROUND: Teaching is one of the most stressful occupations. Over the last decade, about 5000 Japanese public school teachers per year have taken sick leave due to a mental illness. School principals and vice principals also face occupational stress, although few studies have examined occupational stress in these groups. AIMS: To clarify the relationship between occupational stress, role problems and depressive symptoms among school principals and vice principals in Japan. METHODS: We conducted a cross-sectional study in 2013 with data from 262 principals and 268 vice principals in Japan. We used the Japanese version of Zung's Self-Rating Depression Scale (SDS) to evaluate depressive symptoms and the Generic Job Stress Questionnaire to evaluate occupational stress and social support. We categorized SDS scores above 49 as indicating depression. We examined the relationship between depressive symptoms and perceived occupational stress using stepwise forward multivariate logistic regression analyses. RESULTS: Thirty-six (14%) principals and 81 (30%) vice-principals were categorized into the depressive group. Quantitative workload (odds ratio, OR = 6.62 [2.63-16.70]) and role ambiguity (OR = 4.94[1.57-15.53]) were associated with higher depressive scores in principals. Social support from supervisors (OR = 4.14 [1.97-8.68]) and role ambiguity (OR = 9.71 [4.08-23.14]) were associated with higher depressive scores in vice-principals. CONCLUSIONS: Clarifying job roles for principals and vice-principals, reducing quantitative workload for principals and increasing supervisory support for vice-principals may be important for mitigating depression for school principals and vice-principals in Japan.

Association between work role stressors and sleep quality.

Background: Work-related stressors are associated with low sleep quality. However, few studies have reported an association between role stressors and sleep quality. Aims: To elucidate the association between role stressors (including role conflict and ambiguity) and sleep quality. Methods: Cross-sectional study of daytime workers whose sleep quality was assessed using the Pittsburgh Sleep Quality Index (PSQI). Work-related stressors, including role stressors, were assessed using the Generic Job Stress Questionnaire (GJSQ). The association between sleep quality and work-related stressors was investigated by logistic regression analysis. Results: A total of 243 participants completed questionnaires were received (response rate 71%); 86 participants reported poor sleep quality, based on a global PSQI score ≥6. Multivariable logistic regression analysis revealed that higher role ambiguity was associated with global PSQI scores ≥6, and that role conflict was significantly associated with sleep problems, including sleep disturbance and daytime dysfunction. Conclusions: These results suggest that high role stress is associated with low sleep quality, and that this association should be considered an important determinant of the health of workers.

Dopamine D1 receptor subtype mediates acute stress-induced dendritic growth in excitatory neurons of the medial prefrontal cortex and contributes to suppression of stress susceptibility in mice.

Dopamine in prefrontal cortices is implicated in cognitive and emotional functions, and the dysfunction of prefrontal dopamine has been associated with cognitive and emotional deficits in mental illnesses. These findings have led to clinical trials of dopamine-targeting drugs and brain imaging of dopamine receptors in patients with mental illnesses. Rodent studies have suggested that dopaminergic pathway projecting to the medial prefrontal cortex (mPFC) suppresses stress susceptibility. Although various types of mPFC neurons express several dopamine receptor subtypes, previous studies neither isolated a role of dopamine receptor subtype nor identified the site of its action in mPFC. Using social defeat stress (SDS) in mice, here we identified a role of dopamine D1 receptor subtype in mPFC excitatory neurons in suppressing stress susceptibility. Repeated social defeat stress (R-SDS) reduces the expression of D1 receptor subtype in mPFC of mice susceptible to R-SDS. Knockdown of D1 receptor subtype in whole neuronal populations or excitatory neurons in mPFC facilitates the induction of social avoidance by SDS. Single social defeat stress (S-SDS) induces D1 receptor-mediated extracellular signal-regulated kinase phosphorylation and c-Fos expression in mPFC neurons. Whereas R-SDS reduces dendritic lengths of mPFC layer II/III pyramidal neurons, S-SDS increases arborization and spines of apical dendrites of these neurons in a D1 receptor-dependent manner. Collectively, our findings show that D1 receptor subtype and related signaling in mPFC excitatory neurons mediate acute stress-induced dendritic growth of these neurons and contribute to suppression of stress susceptibility. Therefore, we propose that D1 receptor-mediated dendritic growth in mPFC excitatory neurons suppresses stress susceptibility.

Longer longitudinal atrial dimension in patients with idiopathic paroxysmal atrial fibrillation: A possible cause of atrial fibrillation.

BACKGROUND: The ostium of the superior pulmonary veins or superior vena cava has been reported to be an important source of the ectopic beats that initiate paroxysmal atrial fibrillation (PAF). The structural details of the atria in patients with idiopathic PAF, however, remain unknown. METHODS: We studied 113 patients (92 men and 21 women) with idiopathic PAF and 128 normal control subjects (100 men and 28 women). None of the subjects in either group were found to have any evidence of structural cardiac disease. The echocardiographic measurements were performed in the apical 4-chamber view during end-systole of sinus rhythm. RESULTS: The longitudinal dimension of the left and right atria was longer in patients with PAF who were not administered any drugs (non-drug-taking patients) than in the control subjects (P <.001 and P <.01, respectively). However, there were no significant differences in the transverse dimension of either atrium between such patients and control subjects. The longitudinal and transverse dimensions and volume determinations of atria were greater in the patients with idiopathic PAF who were administered class 1 antiarrhythmic drugs than in non-drug-taking patients (P <.05 to.001). In non-drug-taking patients, prolongation of the atrial longitudinal dimension did not depend on either age, the total frequency of PAF, or the interval from the first episode of PAF. The longitudinal dimension of the left and right atria was longer even in the patients with a short history of PAF (<1 month) as compared with control subjects (P <.001 and.05, respectively). CONCLUSIONS: These observations suggest that there is prolongation of the longitudinal dimension in patients with idiopathic PAF independent of PAF frequency and age (and that PAF is probably a consequence of the prolongation).

[A case of remnant gastric cancer responding to neoadjuvant TS-1 therapy].

We report the case a 77-year-old male with remnant gastric cancer successfully treated with TS-1 as neoadjuvant chemotherapy. His treatment was daily oral administration of 100 mg TS-1 for 28 days. This therapy was safely carried out on an outpatient basis. The histological diagnosis of the resected stomach revealed complete disappearance of cancer cells in the stomach and the regional lymph nodes. This case suggests that TS-1 may have a potent therapeutic effect in neoadjuvant chemotherapy for recurrent gastric cancer.

Increased oxidative stress in childhood atopic dermatitis.

Atopic dermatitis (AD) is a chronic inflammatory skin disease of unknown etiology. To examine the involvement of impaired homeostasis of oxygen/nitrogen radicals in childhood AD, we compared the levels of urinary 8-hydroxy-2'-deoxyguanosine (marker of oxidative stress), nitrite/nitrate (marker of nitric oxide synthesis) and selenium (marker of selenium store) in 27 children with AD to those of 25 healthy control children. Urinary 8-hydroxy-2'-deoxyguanosine was significantly higher and nitrite/nitrate levels were significantly lower in patients with AD than in the control. Urinary selenium levels were similar in both groups. Our findings suggest that impaired homeostasis of oxygen/nitrogen radicals and increased oxidative stress are involved in the pathophysiology of childhood AD, and indicate that suppression of oxidative stress might be a potentially useful strategy for the treatment of AD.

Relationship between some chemical components of herbage, dietary preference and fresh herbage intake rate by the Japanese serow.

The serow is a native Japanese mammal and has been designated as a special natural treasure. However, it has been a pest of crops since the 1970s. Since the serow is an indigenous and protected species, it must be controlled without endangering the animal itself. To do this, it is necessary to determine if the serow selects particular crops to consume, and if so, what components of the crop plants influence this choice.In Experiment 1, we measured the preference of four serows for two crop plants and three wild plants, using the cafeteria method. The plants were offered to the animals from 09.00 to 15.30. The serows preferred crop plants to wild plants. The crude protein content of crop plants (28.0 and 32.7%) was higher than that of the other plants (P<0.05). Dry matter (DM) intakes per hour correlated positively with crude protein content (P<0.01) and negatively with nitrogen free extract content (NFE) (P<0.05) and acid detergent fibre content (ADF) (P<0.01) in the offered plants. In Experiment 2, the food intakes of 17 plants consisting of 6 crops and 11 wild plants were measured. Individual 300g samples from each plant were offered for 20min. The serows ate the crops and the forbs in preference to the tree leaves. They consumed little of the conifer tree leaves and the grasses. The dry matter intake and the ADF content were negatively correlated (P<0.05). The dry matter intake and the crude protein content were positively correlated (P=0.054). A multiple regression formula was constructed as follows: Y=1.65CP+0.56NFE+0.38DM-57.45,R(2)=0.54,P=0.016The feeding characteristics suggest that crops might be selected and ingested by the serows because of their higher crude protein, NFE and the dry matter contents.

Efficacy of Influenza Vaccine in Elderly Persons in Welfare Nursing Homes: Reduction in Risks of Mortality and Morbidity During an Influenza A (H3N2) Epidemic.

BACKGROUND: The effect of influenza vaccination on the occurrence and severity of influenza virus infection in a population residing in nursing homes was studied through a program by the Osaka Prefectural Government, which is the first and official support for influenza vaccination of the elderly population during an influenza A (H3N2) epidemic in JAPAN: METHODS: A cohort study located in the Osaka Prefecture, Japan, followed the outcomes of elderly nursing home residents who received influenza vaccinations (n = 10,739) in comparison with control subjects who did not receive influenza vaccinations (n = 11,723) and monitored clinically the onset of serious morbidity and mortality of influenza illness. Subjects were 22,462 persons older than 65 years who resided in 301 welfare nursing homes in the Osaka Prefecture, Japan during an influenza A (H3N2) epidemic in 1998 to 1999. RESULTS: Of 22,462 individuals living in 301 nursing homes, 10,739 received either one dose (2027 subjects) or two doses (8712 subjects) of inactivated, subunit trivalent influenza vaccine. Through the period from November 1998 to March 1999, there were 950 cases of influenza infection diagnosed clinically with cases by virus isolation and/or serology. There were statistically significantly fewer clinical cases of influenza, hospital admissions due to severe infection, and deaths due to influenza in the vaccinated cohort (256 cases, 32 hospital admissions, and one death) compared with the unvaccinated controls (694 cases, 150 hospital admissions, and five deaths). Vaccination was equally effective in those who received one dose of vaccine as in those who received two doses. No serious adverse reactions to vaccination were recorded. Thus, influenza vaccination is safe and effective in this population and should be an integral part of the routine care of persons aged 65 years and older residing in nursing homes. CONCLUSIONS: This study provides an analysis of the clinical efficacy of influenza vaccination in a large cohort of nursing home residents in JAPAN: Annual influenza vaccine administration requires the attention of all nursing home attendants, physicians, and public health organizations.

Application of an in vivo brain microdialysis technique to studies of drug transport across the blood-brain barrier.

There is a wide range of methods available for studying the transport of drugs across the blood-brain barrier (BBB) which is equipped with several systems to transport drugs as well as endogenous nutrients and waste products. The in vivo brain microdialysis technique, which allows direct sampling of the brain interstitial fluid (ISF), is a powerful means of characterizing influx and efflux transport across the BBB. In this paper, we review our results from the successful application of this technique to BBB drug transport studies. The drugs investigated include novel and CNS-active peptides, some agents that are actively removed from the brain ISF across the BBB, and a brain-directed prodrug.

Brain receptor binding characteristics and pharmacokinetic-pharmacodynamic analysis of thyrotropin-releasing hormone analogues.

Thyrotropin-releasing hormone (TRH) receptor binding in the rat brain after intravenous (i.v.) injections of novel TRH analogues, taltirelin and montirelin, was examined and the data were analyzed in relation to their plasma concentrations which were simultaneously determined. Taltirelin and montirelin inhibited specific [3H]-Me-TRH binding in the rat brain and their Ki values were 311 and 35.2 nM, respectively. The i.v. injection of taltirelin and montirelin (0.1-3 mg/kg) produced a significant reduction in [3H]-Me-TRH binding sites (Bmax values) in the rat brain. The reduction by both agents tended to reach a maximum after 60 min and lasted up to at least 120 min. On the other hand, the i.v. injection of both agents had little significant effect on the apparent dissociation constant (Kd) for [3H]-Me-TRH in the rat brain. Plasma concentrations of taltirelin and montirelin in rats peaked immediately after i.v. injection, and thereafter they decreased with t 1/2 of 23.0 and 14.1 min, respectively. Counter-clockwise hysteresis between the plasma concentration and receptor occupancy of these agents was observed after the i.v. injection of taltirelin and montirelin, and the temporal delay between plasma concentration and brain receptor occupancy was successfully minimized using the "effect compartment" model in combination with the "linear-effect" model. We concluded that taltirelin and montirelin exert a fairly potent effect following sustained occupation of brain TRH receptors under in vivo condition. Thus, both agents could be clinically useful for the treatment of CNS disorders.

Vaccine effectiveness for influenza in the elderly in welfare nursing homes during an influenza A (H3N2) epidemic.

Influenza vaccine effect on the occurrence and severity of influenza virus infection in a population residing in nursing homes for the elderly was studied as a cohort study during an influenza A (H3N2) epidemic in Japan. Of 22,462 individuals living in 301 welfare nursing homes, 10,739 voluntarily received inactivated, sub-unit trivalent influenza vaccine in a programme supported by the Osaka Prefectural Government. There were statistically significantly fewer cases of influenza, hospital admissions due to severe infection, and deaths due to influenza in the vaccinated cohort compared to the unvaccinated controls. No serious adverse reactions to vaccination were recorded. Thus influenza vaccination is effective for preventing influenza disease in persons aged 65 years and over, and should be an integral part of the care of this population residing in nursing homes.

Disposition and alpha(1)-adrenoceptor binding characteristics of JTH-601 and its metabolites in rat tissues.

The present study was performed to characterize the disposition and alpha(1)-adrenoceptor binding of JTH-601, a novel alpha(1L)-adrenoceptor antagonist, and its metabolites (beta-D-glucopyranosyl uronic acid, JTH-601-G1; hydrogen sulfate, JTH-601-S1) in the rat prostate and other tissues. JTH-601, JTH-601-G1, and JTH-601-S1 inhibited competitively specific [(3)H]tamsulosin binding in the prostate, submaxillary gland, and spleen of rats in vitro, and the inhibitory effect of JTH-601 was 2. 5 to 6.4 times more potent than that of its metabolites. JTH-601 and its metabolites inhibited dose dependently in vivo specific [(3)H]tamsulosin binding in the particulate fraction of the prostate, aorta, submaxillary gland, and spleen of rats. Compared with that of JTH-601, the in vivo inhibitory effect of JTH-601-G1 was 1.9 to 2. 9 times more potent, and the effect of JTH-601-S1 was 1.3 to 3.2 times less potent. Based on the ratios of ID(50) values, JTH-601 and JTH-601-G1 appeared to be 4.0 to 6.9 times more selective than prazosin as far as the alpha(1)-adrenoceptors in the prostate and submaxillary gland versus the spleen or aorta were concerned. The total radioactivity in rat tissues after i.v. injection of [(3)H]JTH-601-G1 was considerably lower than that of [(3)H]JTH-601. The plasma concentration of [(3)H]JTH-601-G1 at 10 min after i.v. injection in rats was 3 times higher than that of [(3)H]JTH-601, and conversely, the concentration in the prostate was 3 times lower. Although in vivo [(3)H]JTH-601-G1 binding at 10 min was significantly lower than that of [(3)H]JTH-601 in most rat tissues, there was comparable binding between these radioligands in the prostate and vas deferens. Specific binding of [(3)H]JTH-601, at 60 min after i.v. injection compared with that at 10 min, was considerably reduced in rat tissues except the prostate and vas deferens, both of which showed relatively sustained binding. In conclusion, the present study has shown that JTH-601 and its metabolites bind to alpha(1)-adrenoceptors in rat tissues in vivo and that JTH-601-G1 retains the prostatic alpha(1)-adrenoceptor subtype selectivity of its parent compound.

[Follow-up study related to raising low-birth-weight infants relationship among physical growth, mental development and child-rearing anxiety].

OBJECTIVE: In order to clarify relationship among physical growth, mental development of low-birth-weight (LBW) infants and child-rearing anxiety of mothers, a follow-up study was accomplished for LBW cases from birth to three years of age in a regional group. METHODS: A self-administered questionnaire survey was conducted for mothers whose premature infants were born from April 1992 through March 1993 and whose existence was confirmed from April 1995 through March 1996 in Fukui prefecture. A control group was selected from mature infants whose gestation was 37 weeks or more, who were born in the same year and in the same region. The questionnaire was focused on fetal and child growth, as well as child-rearing anxiety. RESULTS: Of the subjects, while including only 6% very LBW infants, the percentage of full-term LBW infants was 55.3% and that of pre-term LBW infants was 44.7%. In the former group, the mean birth weight (MBW) was 2,319 g, the percentage of females was 63.3%, firstborn children was 59.2%, and light-for-dates (LFD) infants due to intrauterine growth retardation 76.9%. In the latter group, the MBW was 1,983 g, the percentage of females was 52.9%, that of firstborn children was 44.5%, and LFD infants was 14.3%. The growth of the LBW infants through the age of three fell into the same category of growth as the upper portion (1,250-1,499 g) of the very LBW infants rather than that of the mature infants. While the growth of appropriate-for-dates (AFD) infants at full-term were normal, that of LFD infants and pre-term infants was insufficient, and the percentage of those demonstrating catch-up of mature infants was less than 80%. The group of pre-term infants was retarded in the gross motor skills, but not language understanding and pronunciation of two-word sentences. The child-rearing anxiety in mothers who delivered pre-term infants was extremely severe after child birth. As the child grew older, however, the feeling of uneasiness was reduced. Mothers who were delivered of full-term LBW infants did not exhibit any fluctuation in child-rearing anxiety during the first three years. CONCLUSION: Fetal size affects growth progress of children. The prognosis of LBW infants is not satisfactory and mothers who deliver full-term LBW infants continue to worry about their child's growth.

Efficacy of influenza vaccine in the elderly: reduction in risks of mortality and morbidity during an influenza A (H3N2) epidemic for the elderly in nursing homes.

The effect of influenza vaccination on the occurrence and severity of influenza virus infection in elderly nursing home residents was studied during an influenza A (H3N2) epidemic in Japan. Of 22,462 individuals living in 301 welfare nursing homes, 10,739 received inactivated (subunit) influenza vaccine. Through the period November 1998 to March 1999, there were 950 cases of influenza infection diagnosed clinically, with virus isolation and/or serology. There were statistically significantly fewer cases of influenza, hospital admissions due to severe infection, and deaths due to influenza in the vaccinated cohort compared with the unvaccinated controls. No serious adverse reactions to vaccination were recorded. Thus influenza vaccination is safe and effective in this population, and should be an integral part of the routine care of persons aged 65 years and over residing in nursing homes.

In vivo specific binding characteristics and pharmacokinetics of a 1,4-dihydropyridine calcium channel antagonist in the senescent mouse brain.

PURPOSE: To characterize the in vivo specific binding and pharmacokinetics of a 1,4-dihydropyridine (DHP) calcium channel antagonist, PN 200-110, in the senescent brain, using senescence-accelerated prone mice (SAMP8) and senescence-resistant mice (SAMR1). METHODS: Blood, brain, and heart samples were taken periodically from SAMR1 and SAMP8 following intravenous injection of (+)-[3H]PN 200-110, and the concentration of (+)-[3H]PN 200-110 in the plasma and tissues was determined. In addition, the in vivo specific binding of (+)-[3H]PN 200-110 in the brains of SAMRI and SAMP8 was measured periodically after intravenous injection of the radioligand. RESULTS: There was very little significant difference between SAMR1 and SAMP8 in terms of the half-life (t(1/2)), total body clearance (CL(tot)), steady-state volume of distribution (Vd(ss)). and AUC for the plasma concentration of (+)-[3H]PN 200-110 after intravenous injection of the radioligand. The brain concentration (AUCbrain) for (+)-[3H]PN 200-110 and the brain/plasma AUC ratio (AUCbrain/AUCplasma) were significantly lower in SAMP8 than in SAMR1, and the heart concentration (AUCheart) and the heart/plasma AUC ratio (AUCheart/AUCplasma) were similar in both strains. Also, the brain/plasma unbound AUC ratio (AUCbrain/AUCplasma-free) for (+)-[3H]PN 200-110 was significantly lower in SAMP8 than in SAMRI. The in vivo specific binding (AUCspecific binding, maximal number of binding sites: Bmax) of (+)-[3H]PN 200-110 was significantly lower in brain particulate fractions of SAMP8 than SAMR1. CONCLUSIONS: The concentration and in vivo specific binding of (+)-[3H]PN 200-110 was significantly reduced in the senescent brain. The simultaneous analysis of the concentrations of centrally acting drugs and the in vivo specific binding in the brain in relation to their pharmacokinetics may be valuable in evaluating their CNS effects.

Attenuation of KATP channel-opener induced shortening of repolarization time by alpha 1-adrenoceptor antagonist during ischemia in canine heart.

The purpose of the study was to determine whether a new KATP channel opener, Y 26763 (Y), can influence the electrophysiological properties in the ischemic myocardium as well as to determine whether the blunting effect of the alpha 1-adrenoceptor antagonist bunazosin (BN) on an ischemia-induced shortening of repolarization time can be related to the KATP channel activity. The anterior descending branch of the left coronary artery was ligated four times for 5 minutes, separated by 15 minutes of reperfusion (stages 1-4) to test the dose-dependent effect of drugs on repolarization. Dogs received either vehicle (n = 9), Y (0.4, 2.0, and 4.0 micrograms/kg at stages 2, 3, and 4, respectively, with 0.4 microgram/kg/min drip infusion at each of stages 2-4, n = 7), BN (0.1 mg at each of stages 2-4, n = 8), or a combination of these two drugs (BN + Y, the same dose of BN and Y in groups BN and Y, respectively, n = 9). Drugs were administered into the left atrium. The monophasic action potential (MAP) and regional electrograms were recorded. The MAP90 and the duration of the slow deflections (DSD) of the regional electrogram were used as markers of repolarization. The Vmax of the MAP and the rapid deflections (DRD) of the regional electrogram were used as markers of conduction. Y augmented an ischemia-induced shortening of MAP90 and DSD in proportion to an increase in the dose given and the plasma concentration (P < .05-.01), especially at the epicardial site. BN and BN + Y blunted the ischemia-related shortening of MAP90 and DSD, causing a reduction in repolarization time dispersion between the ischemic and normal zones. There were no significant changes in the Vmax or DRD in the ischemic zone between periods before and after an increase in each drug dose in the four groups. None of the seven dogs developed ventricular tachycardia (VT)/ventricular fibrillation (VF) in the Y group, whereas two of the eight dogs in the BN group, three of the nine dogs in the BN + Y group, and three of the nine dogs in the control group developed VT/VF. These results suggest that the alpha 1-adrenergic blocker bunazosin blunts the shortening effect of KATP channel activator on repolarization time, and that the KATP channel opener Y may be antiarrhythmic, although the repolarization time dispersion during myocardial ischemia is increased.

Brain distribution of 6-mercaptopurine is regulated by the efflux transport system in the blood-brain barrier.

6-mercaptopurine (6-MP) has been used clinically for 40 years to maintain remission in patients with acute lymphoblastic leukemia (ALL). However, central nervous system (CNS) relapses frequently occur in patients with ALL who continuously receive anticancer drugs, including 6-MP, during remission maintenance therapy. The cause of such CNS relapse is not well understood. One possible reason may involve the restricted distribution of 6-MP in the brain. This study, therefore, investigates the blood-brain barrier (BBB) transport which largely regulates 6-MP distribution in the brain using a quantitative microdialysis technique and centers on the efflux transport of 6-MP across the BBB. The brain tissue, cerebrospinal fluid (CSF), or hippocampal interstitial fluid (ISF) concentration of 6-MP was very low compared with the unbound plasma concentration, suggesting that 6-MP distribution in the brain is highly restricted. Kinetic analyses of this BBB transport showed that the efflux clearance from brain ISF to plasma across the BBB (CLout) is approximately 20-times greater than the influx clearance from plasma to brain (CLin). The CLout was significantly reduced by 1mM N-ethylmaleimide (NEM), a sulfhydryl-modifying agent, suggesting the participation of transport protein in the efflux of 6-MP across the BBB. In addition, efflux transport was inhibited by an intracerebral infusion of probenecid (1.5 mM), p-aminohippuric acid (PAH, 3.0 mM), benzoate (3.6 mM), or salicylate (3.7 mM) administered through a microdialysis probe, but neither choline (0.8 mM) nor tetraethylammonium (TEA, 0.7 mM) had any effect. These data suggest that the restricted 6-MP brain distribution may be ascribed to efficient efflux from the brain, possibly via both the organic anion transport system, shared with probenecid and PAH, and the monocarboxylic acid transport system, shared with benzoate and salicylate.