Influence of oral adsorbent AST-120 on anticonvulsive effect of zonisamide in rats.

The influence of oral adsorbent AST-120 (Kremezin) on the anticonvulsive effect and pharmacokinetics of zonisamide was investigated. Oral administration of zonisamide (50 mg/kg) blocked the appearance of the tonic extension induced by maximal electroshock seizure. This effect of zonisamide was inhibited by the oral coadministration of AST-120 (5 g/kg). In pharmacokinetics study, the serum zonisamide concentration after coadministration of zonisamide and AST-120 was significantly lower than that of single administration of zonisamide. However, the anticonvulsive effect of zonisamide was not affected by the administration of AST-120 1.5 h after zonisamide administration. In this condition, the serum zonisamide concentration was not changed. In the in vitro study, AST-120 completely adsorbed zonisamide. These findings suggest that when AST-120 is administered concurrently with zonisamide, a significant inhibition of the anticonvulsive effect of zonisamide occurs, and the decrease in serum zonisamide concentration by the adsorption effect of AST-120 is related to this phenomenon.

Arrhythmogenic properties of disordered breathing during sleep in patients with cardiovascular disorders.

The purpose of this study was twofold: to establish an ECG respiration monitoring system, and to evaluate the clinical usefulness of this system. Our purpose was to determine how many patients with cardiovascular disorders may have unrecognized sleep apnea and whether such apneic episodes are an important cause of cardiac arrhythmias. The study group included 81 patients, age range 40-95 years, and 13 healthy males, age range 52-72 years. The 24-h ECG respiration recordings were obtained with the two-channel holter recorder. Airflow at the nose using a nasal thermister or chest wall movement by impedance pneumography was recorded as respiration record on the second channel. Sleep apnea was observed 69% and 77-100% in the control subjects and patients with cardiovascular disorders, respectively. Episodes of sleep apnea were most frequent in the patients with old myocardial infarction. Grading of apneas was defined according to the length of apnea. Short duration apneas were observed only in the control subjects, but longer apneic episodes were observed in patients with cardiovascular disorders. Bradyarrhythmias observed were to be relative to apneic episodes longer than 20 s, while ventricular arrhythmias were observed only in the patients with old myocardial infarction, coincident with apneas lasting longer than 40 s. Atrioventricular conduction disturbances were also observed to be related to the occurrence of sleep apnea. These results suggest that 24-h ECG respiration monitoring is useful not only for the observation of sleep apneic episodes, but also in clarifying the relationship between cardiac arrhythmias and apneic episodes.

Effects of age and blood pressure on the cardiovascular responses to the Valsalva maneuver.

The present study was performed to obtain basic information as to the influences of two fundamental variables, age and blood pressure, on the circulatory responses during the Valsalva maneuver. Although a positive linear relationship between age and resting systolic blood pressure was present in the study population of 90 normal and uncomplicated hypertensive subjects, the pressure overshoot and the change in R-R intervals during phase 4 in the Valsalva maneuver were significantly inversely related to age or resting systolic blood pressure independently of each other variable. Furthermore, age was related negatively to the maximum R-R interval in phase 4 and positively to the decline of blood pressure post-Valsalva release in phase 3 even after adjusting for the effect of blood pressure, but age-independent relationships between these two indexes and resting systolic blood pressure were not statistically significant. The data indicate that changes in circulatory responses to the Valsalva maneuver occur with aging and high blood pressure, suggesting that the sympathetic vasoregulation and the baroreflex control of heart rate in the maneuver are impaired by these two variables. Such alterations appear to be more strongly related to age than to blood pressure level.

Differences in age-independent effects of blood pressure on baroreflex sensitivity between normal and hypertensive subjects.

Inter-relationship between age, systolic blood pressure and baroreflex sensitivity index derived from the Valsalva manoeuvre was investigated in either combined or separated groups of normal and hypertensive subjects. Both in the total population as a whole and in each blood pressure subgroup, the baroreflex sensitivity index was significantly inversely related to age and to systolic blood pressure. Furthermore, age was significantly related to systolic blood pressure except in the hypertensive group. Partial correlation analysis showed that, in the total and hypertensive population, the baroreflex sensitivity index was significantly related to age and systolic blood pressure independently of each other variable. In the normal group, however, the baroreflex sensitivity index was not related to systolic blood pressure after adjusting for the effect of age, but remained significantly related to age independently of systolic blood pressure. The estimates of relative effects of the two variables on baroreflex sensitivity by multiple regression analysis were consistent with these results. Thus a prevailing concept of the inhibitory effect of blood pressure on baroreflex function may be accurate exclusively in hypertensive patients, and baroreflex function appears to be more sensitive to age-related changes in this system than to those related to blood pressure level, particularly in non-hypertensive normal subjects.

Use of a computer in analysis of heart rate and blood pressure response to the Valsalva maneuver.

The relationship between systolic blood pressure (SBP) and R-R interval (RR) in phase II of the Valsalva maneuver was analyzed with the use of a nonlinear relation. The nonlinear relation introduced here includes time derivatives of SBP and RR, and is a natural extension from the linear one which defines the linear baroreflex sensitivity index (BRSI). The model equations of SBP and RR derived from the nonlinear relation predicted well the observed changes of SBP and RR in 11 normotensive subjects and 16 hypertensive patients. Two of the parameters of the relation were related to the activity of the compensatory mechanism, and discriminated well the hypertensives from the normotensives. For this analysis an interactive system of regression analysis has been developed to reduce the difficulties in the case of nonlinear regression curve fitting. The regression curves can be monitored on a graphic terminal during every regression step. The values of nonlinear parameters can be obtained easily and systematically with use of the system.

Age-related changes of baroreflex function, plasma norepinephrine, and blood pressure.

Interrelationships between age, baroreflex sensitivity, plasma norepinephrine levels, and systolic blood pressure were assessed in a group of 54 normal subjects ranging in age from 14 to 77 years. Baroreflex sensitivity was measured by the change in R-R intervals per unit change in systolic blood pressure during phase 4 of the Valsalva maneuver. All correlations among these four variables were statistically significant (p less than 0.05 or 0.01). To investigate possible causal relationships between age-related changes of baroreflex sensitivity, plasma norepinephrine levels, and blood pressure, partial correlative analysis was then performed. After the effect of age was eliminated, plasma norepinephrine levels were found to be related positively to blood pressure (r = 0.29, p less than 0.05) and negatively to baroreflex sensitivity (r = -0.34, p less than 0.05). The increase in plasma norepinephrine levels could be causally related to the elevation of blood pressure, as plasma norepinephrine levels could provide an index of sympathetic activity. Furthermore, baroreflex sensitivity was found to be negatively related to age (r = -0.44, p less than 0.01) independent of plasma norepinephrine levels, whereas plasma norepinephrine levels were no longer related to age (r = 0.10) after adjusting for the effect of baroreflex sensitivity. This finding suggests that an increase in plasma norepinephrine levels with age could be mediated by the age-related change of baroreflex sensitivity.(ABSTRACT TRUNCATED AT 250 WORDS)

Hybrid biosynthesis of derivatives of protylonolide and M-4365 by macrolide-producing microorganisms.

Biotransformation of a macrolide antibiotic and a related compound was studied using various macrolide-producing microorganisms grown in the presence of cerulenin, an inhibitor of de novo synthesis of the aglycone moiety. Protylonolide (1) was transformed into 5-O-(4'-O-propionylmycarosyl)protylonolide (2) by a leucomycin-producing strain, Streptoverticillium kitasatoensis KA-429. M-4365 G2 (3) was bioconverted into M-4365 G3 (4), 9-dihydro M-4365 G3 (5), 3-O-acetyl M-4365 G3 (6) and 3-O-acetyl-9-dihydro M-4365 G3 (7) by a spiramycin-producing strain, Streptomyces ambofaciens KA-1028. Forosaminylated derivatives of M-4365 G2 were not obtained using this microorganism. M-4365 G2 was converted into 3-O-acetyl M-4365 G2 (8) by Stv. kitasatoensis strain KA-429 and a carbomycin-producing strain, S. thermotolerans KA-442. These results suggest that the substrate specificity of mycaminose- and forosamine-binding enzymes is high in Stv. kitasatoensis and S. ambofaciens, respectively, while that of the 3-hydroxyl acylating enzyme and mycarose-binding enzyme is low in these microorganisms. The bioconversion products showed lower antibacterial and antimycoplasmal activities than those of M-4365 G2.

Herbimycin B, a new benzoquinonoid ansamycin with anti-TMV and herbicidal activities.

A new benzoquinonoid ansamycin, herbimycin B was isolated from the culture broth of Streptomyces hygroscopicus No. AM-3672, a herbimycin A-producing strain. Herbimycin B showed potent anti-TMV activity. Herbicidal effect of herbimycin B was less than that of herbimycin A.