A study of the pharmacokinetic and metabolic interactions between theophylline and enoxacin was carried out under steady-state conditions in seven healthy male volunteers. Sustained-release theophylline formulation (200 mg twice daily) was given as monotherapy and coadministration of enoxacin. The total and free concentrations of theophylline in the plasma and the excreted concentration of theophylline and its metabolites in the urine were measured by a high-performance liquid chromatographic method. The mean steady-state plasma theophylline concentration significantly increased by approximately 3-fold after coadministration of enoxacin. Significant decrease in the total body clearance of theophylline was found (63%) but plasma protein binding of theophylline remained unchanged. There were a significant increase in urinary theophylline and a decrease in urinary 3-methylxanthine after coadministration of enoxacin. A decrease in the total body clearance during coadministration of enoxacin is likely to have resulted from inhibition of the 1-demethylation metabolic pathway. Further studies were needed to determine the relationship between the side effects induced by enoxacin and the theophylline dosage or its plasma concentration since side effects were experienced in all the subjects concomitantly administered enoxacin.

Adult↗

PubMed1988

[Aspergilloma in tuberculous cavities].

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Adult↗

PubMed1988

[The natural history of bronchial asthma].

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Aging↗

PubMed1988

Myocardial salvage by a novel thromboxane A2 synthetase inhibitor in a canine coronary occlusion-reperfusion model.

The effects of the new thromboxane A2 (TXA2) synthetase inhibitor sodium 6-(2-[1-(1H)-imidazolyl]methyl-4,5-dihydrobenzo[b]thiophene)carboxylate (RS-5186), 10 mg/kg i.v., on infarct size, polymorphonuclear leukocytes (PMNs) infiltration, gross myocardial hemorrhage and ventricular arrhythmias were studied using a canine coronary occlusion (2 h)-reperfusion (5 h) model. Infarct size (IS) and risk area (RA) were determined by a dual staining technique. 60 min before coronary occlusion dogs were randomly assigned to either the RS-5186 treated group (n = 11) or the control group (n = 15). RS-5186 reduced infarct size (RS-5186: 26.3 +/- 2.4% of RA (mean +/- SEM) vs control: 50.7 +/- 5.9%, p less than 0.01), and also reduced the area of gross myocardial hemorrhage (RS-5186: 3.9 +/- 2.6% of IS vs control: 22.4 +/- 4.0%, p less than 0.01). The drug also decreased the intensity of PMNs infiltration into the infarcted area (p less than 0.05). However, RS-5186 had no significant influence on the incidence of ventricular arrhythmias. These results suggest that the new thromboxane A2 synthetase inhibitor RS-5186 might be useful in salvaging ischemic myocardium.

Animals↗

PubMed1988

Effect of a novel thromboxane A2 synthetase inhibitor on ischemia-induced mitochondrial dysfunction in canine hearts.

This study was designed to determine the effect of sodium 6-(2-[1-(1H)-imidazolyl]methyl-4,5-dihydrobenzo[b] thiophene)carboxylate (RS-5186), a new thromboxane A2 (TXA2) synthetase inhibitor, on mitochondrial function and lysosomal integrity in ischemic myocardium. 17 anesthetized mongrel dogs were divided into 2 groups. In the control group (n = 11), the left anterior descending arteries (LAD) of the dogs were occluded for 2 h and physiological saline was infused until the end of the experiment. In the RS-5186 treated group (n = 6), 25 min prior to LAD occlusion, RS-5186, 10 mg/kg, was injected for 10 min. 2 h after occlusion, mitochondria were prepared from both ischemic and non-ischemic areas, which were confirmed by Evans' blue dye, and mitochondrial function (respiratory control index: RCI, and the rate of oxygen consumption in state III respiration: St.III O2) was measured polarographically with succinate as substrate. Fractionation of myocardial tissue from both ischemic and non-ischemic areas was also performed, and the activities of lysosomal enzymes (N-acetyl-beta-glucosaminidase: NAG, beta-glucuronidase: beta-gluc) of each fraction were measured. 2-h LAD occlusion induced a significant greater decrease in mitochondrial function from the ischemic area of the control group (RCI: 2.80 +/- 0.45, St.III O2: 133.5 +/- 35.6 natoms/mg protein/min) compared with those from the non-ischemic area (RCI: 4.49 +/- 0.46, St.III O2: 344.0 +/- 31.9).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1988

Noninvasive carcinoma of the gallbladder arising in localized type adenomyomatosis.

We report a case of noninvasive carcinoma of the gallbladder arising in the surface mucosa of localized type adenomyomatosis. It was first detected as a polypoid lesion during routine examination with ultrasonography. The gross appearance of the resected specimen showed localized type adenomyomatosis with multiple cysts containing mucin at the fundus of the gallbladder. Microscopic study revealed noninvasive carcinoma in its surface mucosa associated with papillary adenoma in the cyst wall. The occurrence of carcinoma in adenomyomatosis is very rare, and only a few cases have been reported in the literature. Although it has been generally accepted that there is no fear of malignant transformation of adenomyomatosis, the present case suggested that it might be a possible candidate for carcinoma.

Adenocarcinoma↗

PubMed1987

Role of phospholipase in the genesis of doxorubicin-induced cardiomyopathy in rats.

The role of phospholipase on the mechanism of doxorubicin-induced cardiomyopathy was investigated in the heart mitochondria of Wistar rats. In the in vivo study, rats were divided into 3 groups: 1, the control group, untreated; 2, the doxorubicin 1-day group, in which doxorubicin (4 mg/kg) was injected s.c. once; and 3, the doxorubicin 4-day group, in which doxorubicin (4 mg/kg) was injected once a day for 4 consecutive days. In each group, the level of lipid peroxides and the phospholipase activity, the phospholipid content, and the enzymic activities in the respiratory chain were measured. The doxorubicin 4-day group showed significant increases of lipid peroxide level and phospholipase activity and an inhibition of mitochondrial respiratory function compared with the control group, while the doxorubicin 1-day group showed no significant difference. In the in vitro study, Experiment 1, intact rat heart mitochondria were incubated with 0.1 unit of phospholipase A2. After the incubation, the enzymic activities of the respiratory chain were disturbed in the same manner as in the in vivo experiment. In Experiment 2, rat heart mitochondria were incubated with ascorbate and ferrous sulfate. The experiment demonstrated the elevation of phospholipase activity associated with lipid peroxidation. These results suggested that the enhanced phospholipase activity caused by lipid peroxidation is responsible for the mechanism of doxorubicin-induced cardiomyopathy.

Animals↗

PubMed1987

Argyrophil cells in normal endometrial glands.

Normal endometrium from one hundred normal cases were examined histologically, using sections stained with the Grimelius method. Endocrine cells were demonstrated in 4 cases. Immunohistochemically, these cells were positive for anti-serotonin and anti-somatostatin antisera. Argyrophil granules were also observed in supranuclear or subnuclear regions of glandular cells in 17 cases, and argyrophilia was present in the apical region including the brush borders or microvilli of glandular cells in 6 cases. In these latter 23 cases argyrophilia seemed to be nonspecific, having no relation to endocrine type secretory granules, judging from the electronmicroscopic observations on the silver-impregnated sections. The presence of endocrine cells and the pattern of argyrophilia in glandular cells were similar to those found previously in endometrial glandular adenocarcinomas with argyrophil cells. This is the first report on the occurrence of endocrine cells in normal endometrial glands.

Adult↗

PubMed1987

Effects of acute pressure overload on prostacyclin release and myocardial blood flow in canine hearts: inhibition of prostacyclin synthesis with 15-hydroperoxy-eicosatetraenoic acid.

This study was undertaken to evaluate the effects of acute pressure overload on prostacyclin (PGI2) release and the influences of 15-hydroperoxy-eicosatetraenoic acid (15-HPETE), an inhibitor of PGI2 synthetase, and indomethacin, an inhibitor of cyclo-oxygenase, in canine hearts. Gradual stenosis of the ascending aorta was performed in 24 anesthetized open-chest dogs. The mongrel dogs were divided into three groups, which received indomethacin, 15-HPETE, and no drug. Changes in the hemodynamics, regional myocardial blood flow (MBF) by the method of H2 gas clearance, and plasma immunoreactive 6-keto-prostaglandin (PG) F1 alpha level in the descending aorta (AO) and great cardiac vein (GCV) were measured. Five minutes after aortic stenosis, the plasma immunoreactive 6-keto-PGF1 alpha level in the GCV and MBF increased from 162 +/- 23 to 289 +/- 37 pg/ml and from 87 +/- 5 to 107 +/- 8 ml/min/100 g, respectively, and the calculated coronary vascular resistance (CVR) decreased significantly from 0.93 +/- 0.08 to 0.77 +/- 0.08 mmHg/ml/min/100 g. These significant changes persisted thereafter. Continuous infusion of 15-HPETE (66 pg/kg/min) into the coronary artery simultaneously prevented significant changes in MBF and the plasma immunoreactive 6-keto-PGF1 alpha level in the GCV and CVR. Intravenous infusion of indomethacin (5 mg/kg), on the other hand, induced a significant decrease in the plasma immunoreactive 6-keto-PGF1 alpha level in both the GCV and AO; significant changes in MBF 5 to 15 min after aortic stenosis and CVR were not affected. From these results, it is suggested that PGI2 plays an important role in the regulation of coronary blood flow in canine hearts with acute pressure overload.(ABSTRACT TRUNCATED AT 250 WORDS)

6-Ketoprostaglandin F1 alpha↗

PubMed1987

Relaxant effects of forskolin on guinea pig tracheal smooth muscle.

We investigated the relaxant effects of forskolin, a diterpene derivative isolated from the roots of Coleus forskohlii, on guinea pig airway smooth muscle by measuring the isometric tension of tracheal smooth muscle in vitro and transcutaneous Po2 during the histamine inhalation test (HIT) in vivo. Forskolin (10(-9)-10(-5) M) caused dose-dependent relaxant effects on resting tone and on leukotriene C4 (10(-7) M)-, leukotriene D4 (10(-7) M)-, and carbachol (3 X 10(-6) M)-induced contraction of tracheal smooth muscle. Moreover, with propranolol pretreatment the relaxant effect of forskolin on tracheal smooth muscle did not change, whereas with the same pretreatment the relaxant effect of isoproterenol diminished. Forskolin (10(-8)-10(-6) M) raised tissue cyclic AMP levels dose-dependently in tracheal smooth muscle (6.7-359.9 pmol/mg protein). Forskolin (1 mg/kg) administered subcutaneously raised the respiratory threshold of (RT-histamine in the HIT. The determination of the RT-histamine by measuring tcPo2 was possible without anesthesia. These results suggest that forskolin relaxes airway smooth muscle in guinea pigs in vitro and in vivo by raising tissue cyclic AMP levels and that its actions are independent of beta-adrenoceptors.

Animals↗

PubMed1987

The role of phospholipase in beta-agonist-induced down regulation in guinea pig lungs.

It has been observed that repeated and prolonged beta-agonist treatment causes the impairment of beta-adrenergic function, so-called "desensitization" or "down regulation". To clarify the mechanism of down regulation, the following experiment was performed using guinea pig lungs. Animals were divided into four groups: In the metaproterenol groups, guinea pigs were treated with metaproterenol (10 mg/kg/day) by intraperitoneal injection once a day for 1 day or for 7 successive days In the control groups, guinea pigs were treated with saline by the same procedure as in the metaproterenol groups. In the group treated with metaproterenol for 7 days, there was a 45% reduction in the number of beta-adrenoceptors and a 62% reduction in adenylate cyclase activity, compared with those of the control group. However, there were no significant changes in the dissociation constant (Kd) of the receptors. On the other hand, no reduction in the number of beta-adrenoceptors and adenylate cyclase activity was observed in the group treated with metaproterenol once a day for 1 day, compared with those of the control group. Phospholipase (PLase) activity in the lung microsomes of guinea pigs injected with metaproterenol for 1 day and for 7 days was elevated by 14.4 and 33.1%, respectively, compared with that of the control groups. Phospholipid contents of lung membranes prepared from the animals treated with metaproterenol for 7 days were significantly decreased compared with those of the control group, though in the group treated with metaproterenol once a day for 1 day, phospholipid contents did not differ from those of the control. Lung membranes treated with PLase A2 revealed decreases both in the number of beta-adrenoceptors and adenylate cyclase activity, dose dependently. These results and the fact that membrane phospholipids are involved in the beta-adrenoceptor system suggest that down regulation observed during beta-agonist administration is, at least in part, attributed to degradation of phospholipids of lung membranes by the persistent activation of PLase in the tissue.

Adenylyl Cyclases↗

PubMed1987

Cardiac alpha 1 and beta adrenoceptors in rabbits: effects of dietary sodium and cholesterol.

To investigate the effects of dietary sodium and cholesterol on alpha 1 and beta adrenoceptors in hearts, male Japanese white rabbits were treated with either deoxycorticosterone acetate (DOCA) (50 mg/week sc) plus 1% saline in drinking water, frusemide (10 mg/2 days im), or cholesterol enriched diet (2%, w/w) for eight weeks. Using myocardial membrane preparations, characteristics of alpha 1 and beta adrenoceptors were assessed by a radioligand binding assay using 3H-prazosin and 125I-iodocyanopindolol (125I-CYP) as radioactive ligands respectively. Although the treatment with DOCA and salt induced a small but significant increase in the mean arterial blood pressure, other treatments did not affect blood pressure. None of these interventions affected body weight, ventricular weight, ratio of ventricular weight to body weight, or protein yield of membrane preparations. Neither the number nor the affinity of cardiac alpha 1 adrenoceptors (Bmax 15.1(1.7) fmol X mg protein-1, KD 0.63(0.13) nmol X litre-1 for controls) was affected by any of the treatments given. In contrast to alpha 1 adrenoceptors, the number of beta adrenoceptors (Bmax) decreased significantly from 109.9(9.6) fmol X mg protein-1 for controls to 54.8(5.2) and 52.7(6.9) for rabbits treated with DOCA salt and cholesterol respectively. KD values of beta adrenoceptors for 125I-CYP decreased significantly with cholesterol treatment from 22.5(2.5) to 13.6(2.7) pmol X litre-1. Salt depletion produced by frusemide administration did not affect either the number or the affinity of beta adrenoceptors. These results suggest that changes in the sensitivity of tissues to catecholamines induced by the administration of DOCA salt and cholesterol enriched diet are due to alterations in beta adrenoceptors in the heart.

Animals↗

PubMed1987

Mechanism of isoproterenol induced myocardial damage.

To study the harmful effects of isoproterenol on myocardium rats were injected with isoproterenol 10 or 0.1 mg.kg-1 or with isoproterenol 10 mg.kg-1 after an injection of propranolol 20 mg.kg-1. Endogenous phospholipase activity in heart homogenate and tissue adenosine triphosphate concentrations were determined 1, 7, and 15 h after isoproterenol injection. The activities of three segments (NADH-cytochrome c reductase, succinate-cytochrome c reductase, and cytochrome c oxidase) of the electron transport chain in heart mitochondria were also measured in the same manner. In the group given isoproterenol 0.1 mg.kg-1 the tissue adenosine triphosphate concentration was decreased after 1 h but returned to control value after 15 h. No significant change in phospholipase activity or in the activities of the three segments in mitochondria was observed throughout the study. In the group given isoproterenol 10 mg.kg-1 the tissue adenosine triphosphate concentration was significantly decreased after 1 h and did not return to control values after 15 h. Phospholipase activity was increased and the activities of NADH-cytochrome c reductase and cytochrome c oxidase were significantly decreased after 15 h. The activity of succinate-cytochrome c reductase was not affected. In the propranolol group, pretreatment with propranolol protected against a reduction in adenosine triphosphate after isoproterenol 10 mg.kg-1. Propranolol also prevented activation of phospholipase and maintained the activities of the three segments of mitochondria throughout the study. In an in vitro study mitochondria prepared from intact rat hearts were incubated with 0.1 unit phospholipase A2.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Triphosphate↗

PubMed1987

Time dependent conversion of creatine kinase MM isoforms in man.

Subforms of creatine kinase MM isoenzyme (isoforms, pI: MMA = 7.95, MMB = 7.76, MMC = 7.54) in human myocardium and serum were quantified by chromatofocusing. Creatine kinase MMA was a dominant isoform (greater than 94% of MM) in normal (n = 3) and in both infarcted and non-infarcted myocardium (n = 2). To investigate isoform conversion in vitro partially purified MMA was incubated with human plasma at 37 degrees C for 24 h (n = 5). Creatine kinase MMB (0%, 47%, 44% of MM at 0, 12, 24 h respectively) and MMC (0%, 22%, 42%) sequentially appeared in incubation media whereas MMA (100%, 31%, 14%) disappeared rapidly with a mean disappearance rate of -0.00169(0.00021)(SD) min-1. Individual differences in conversion velocity were small (SD less than 5%). To investigate isoform conversion in vivo serum isoforms were analysed in patients with acute myocardial infarction (n = 7). MMA was first dominant (A:B:C = 54:34:12%) in the early stage (6-9 h after the onset of chest pain) followed by MMB dominant (19:42:39%) in the middle stage (24-35 h), and MMC dominant (6:22:72%) in the late stage (54-60 h). Changes in isoform proportion were time dependent regardless of serum creatine kinase activity. These findings are consistent with canine isoform conversion reported previously except that in man the velocity of conversion was slower than in the dog. Thus analysis of serum creatine kinase MM isoforms may allow the onset of acute myocardial infarction to be precisely dated. Moreover, determination of MMA, the isoform native to myocardium with a short serum half life, may be useful in the prompt diagnosis of myocardial infarction.

Creatine Kinase↗