[Leukocyte adsorption and removal for the treatment of ulcerative colitis].
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Adult↗
Biomedical subjects
Y Sawada
Publications and source records attributed to Y Sawada.
Pharmacokinetic-pharmacodynamic analysis of the arrhythmogenic potency of a novel antiallergic agent, ebastine, in rats.
Ebastine (EBS), a novel nonsedative antiallergic agent, is similar to terfenadine in its chemical structure. However, clinical arrhythmogenicity of EBS remains controversial. In this study, we evaluated the possible arrhythmogenic potency of EBS as assessed by QT prolongation from a pharmacokinetic-pharmacodynamic viewpoint in comparison with that of terfenadine. EBS was intravenously infused into anesthetized rats at a rate of 3.0 or 10 mg/kg/h for 60 min, and electrocardiographic effects were continuously monitored from lead II. The plasma concentrations of EBS and its major metabolite, carebastine, were also measured under the same conditions. When intravenously administered, EBS exhibited QT prolongation in an infusion rate-dependent manner, with a lag time. Pharmacokinetic-pharmacodynamic analysis of EBS based on the effect-compartment model revealed values of EC50, Emax and EC(10 ms), (where 10 ms of QT prolongation was evoked) of 0.73 microg/mL, 12.5 ms and 2.90 microg/mL, respectively. The EC(10 ms) value of EBS was five times higher than that of terfenadine reported previously (Ohtani et al., J. Pharm. Pharmacol., 49, 458-462 (1997)). In conclusion, EBS was suggested to be less arrhythmogenic than terfenadine.
Animals↗
Mechanism of the uricosuric action of the anti-inflammatory drug E3040 used to treat inflammatory bowel disease I: study using a rat model of hyperuricemia.
E3040, a new class of anti-inflammatory drug, was found to reduce the plasma uric acid level in the first phase of clinical studies. In the present study, the mechanism of the uricosuric action of E3040 was investigated using the hyperuricemia model rat. The fractional excretion of uric acid (FEurate), an indicator of the excretion of uric acid in the renal tubules, at 30, 60 and 90 min after administration of E3040 (50 mg kg(-1)) was significantly elevated as compared with that in the control. This elevation of the FEurate by E3040 was dose-dependent. Although the FEurate was elevated spontaneously 30 min after administration of E3040-sulfate (E-Sul) and glucuronide (E-Glu) (100 mg kg(-1), respectively), the value was not significantly different from the control. Based on these results, it was suggested that E3040 has a uricosuric action, probably in the proximal tubules, and the uricosuric action after administration of E3040 may be mainly due to the parent drug. Concerning the tissue distribution, the kidney concentration of E-Sul after i.v. administration of the E3040 (50 mg kg(-1)) was higher than that of the parent drug (kidney/plasma ratio approximately 2).
Animals↗
Contribution of P-glycoprotein to bunitrolol efflux across blood-brain barrier.
In this study, we investigated the mechanism of the blood-brain barrier (BBB) transport of bunitrolol (BTL), as a model of beta-blocker, in vivo and in vitro. In order to define the contribution of P-glycoprotein (P-gp) to the active efflux of BTL from brain to blood, we examined the in vivo brain distribution of BTL in mdr1a(-/-) mice with a disrupted mdr1a gene. After intravenous administration of BTL to mdr1a(-/-) mice, the brain concentration and Kp value of BTL were significantly increased as compared with those in mdr1a(+/+) mice. Next, the contribution of the mdr1a P-gp to in vitro uptake of BTL was compared in LV500 cells and L cells (mouse mdr1a-expressing cells and host cells, respectively). The intracellular accumulations of [3H]vinblastine and BTL by LV500 cells were lower than those by L cells, but were significantly increased by verapamil, a P-gp inhibitor. Furthermore, the BTL uptake by KB-VJ300 cells, which express human P-gp, was also significantly lower than that by KB host cells, and was increased by verapamil. The steady-state uptake of BTL by LLC-GA5-COL300 cells, expressing human P-gp, was significantly increased in the presence of 20 microM cyclosporin A (another P-gp inhibitor), which had no effect in the LLC-PK1 host cells. On the other hand, the steady-state intracellular accumulation of BTL by MBEC4 cells, which express mdr1b P-gp instead of mdr1a P-gp, was not significantly changed in the presence of verapamil. This finding suggested that BTL is not a good substrate for mdr1b P-gp. In conclusion, our results suggest that BTL is transported from brain to blood by mdr1a P-gp in mice and by MDR1 in humans, and this presumably accounts for the low brain distribution of BTL.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
Effect of itraconazole on the pharmacokinetics of digoxin in guinea pigs.
The effect of itraconazole (ITZ) on the pharmacokinetics of digoxin (DGX) was investigated in guinea pigs. The plasma concentrations of DGX in guinea pigs following treatment with ITZ (20 mg/kg intraperitoneally (i.p.)) after intravenous (i.v.) administration of DGX (0.125 mg/kg) were significantly higher than in the controls. The percentage cumulative excretion (6.9%) of DGX in bile of the ITZ-treated group up to 6 h after administration of DGX was significantly reduced (p < 0.05) compared with 10.5% in the control. The percentage cumulative excretion (3.1%) of DGX in urine of the ITZ-treated group up to 6 h after administration was also one third that in the controls. The total, biliary, renal and metabolic clearances for DGX in the ITZ-treated group were significantly reduced, while the V(dss) was unaffected. The plasma unbound fraction of DGX (ranged 47-58%) in the ITZ-treated group was generally similar to that in the controls (50-57%). The blood-to-plasma concentration ratio of DGX (range 1.28-1.42) in the absence of ITZ did not change in the presence of ITZ. Based on these results, the pharmacokinetic interaction between DGX and ITZ may be due not only to a reduction in the renal clearance but also to a reduction in the metabolic clearance of DGX by ITZ.
Animals↗
Mechanism of the uricosuric action of E3040, a drug used to treat inflammatory bowel disease II: study using DBA/2N mice.
In the initial phase of clinical studies, it was shown that E3040, a new type of anti-inflammatory drug, reduced plasma uric acid levels. The present study describes a comparison of the excretion of uric acid in the proximal tubules of the kidney after administration of E3040 and its conjugates, sulphate and glucuronide, with that of other general uricosuric agents in DBA/2N mice. The aim of this investigation was to elucidate the mechanism for the uricosuric action of E3040. It was found that E3040 increased the excretion rate of uric acid in a dose-dependent manner, and the excretion rates following 10 and 50 mg/kg doses were significantly greater than that of the control group. The paradoxical effect observed with probenecid was not seen in the E3040 dose-response curve for the uric acid excretion rate. Neither E3040-sulphate nor E3040-glucuronide increased the excretion rate of uric acid significantly, even at a high dose, such as 200 mg/kg. In the pyrazinoic acid suppression test, the uric acid excretion rate after concomitant administration of E3040 and pyrazinoic acid was significantly higher than that after administration of pyrazinoic acid alone, and the rate after concomitant administration was 30% of the level after administration of E3040 alone. The change in the excretion rate of uric acid after concomitant administration of E3040 and pyrazinoic acid was similar to that of AA193, a selective inhibitor of the presecretory reabsorption of uric acid. From these results, it appears that E3040 may exert its uricosuric action by reducing the presecretory reabsorption of uric acid rather than increasing its secretion.
Animals↗
A new method to evaluate ischemic heart disease: combined use of rest thallium-201 myocardial SPECT and Tc-99m exercise tetrofosmin first pass and myocardial SPECT.
We developed a new diagnostic method for simultaneously evaluating myocardial ischemia, myocardial viability and ventricular function in less than 90 minutes by combined use of rest thallium-201 (Tl) SPECT and exercise Tc-99m tetrofosmin (TF) first pass and SPECT. The subjects were 9 healthy controls, 19 angina pectoris patients, and 19 old myocardial infarction patients, in all of whom coronary angiography had been performed. Rest Tl myocardial SPECT was performed first, and was followed by exercise TF myocardial SPECT. We also performed first pass radionuclide angiography by TF during maximum exercise on a bicycle ergometer to assess the left ventricular ejection fraction (LVEF). The total examination time was less than 90 minutes. SPECT diagnosis was performed by semi-quantitative analysis. LVEF below 55% was regarded as abnormal. In the patients with angina pectoris, analysis according to the coronary artery showed that the diagnostic accuracy of SPECT was 85.0% for ischemia in the region of the left anterior descending branch (LAD), 87.5% for the left circumflex branch (LCX) and 77.8% for the right coronary artery (RCA). The accuracy of diagnosis for angina pectoris was 82.1%, as determined by SPECT alone, and rose to 89.3% when the LVEF levels were also taken into consideration. In the patients with old myocardial infarction, the diagnostic accuracy of SPECT was 84.2% for the LAD, 92.3% for the LCX and 85.0% for the RCA. Analysis by patients showed that the accuracy of diagnosis for myocardial infarction was 85.7%, as determined by SPECT alone. The diagnostic accuracy, however, rose to 89.3% when the LVEF levels also were taken into consideration. In conclusion, it was demonstrated that this combined diagnostic method was highly reliable for evaluating ischemic heart disease within a short time.
Aged↗
Nonpeptide mimic of bradykinin with long-acting properties.
Kinins, members of a family of peptides released from kininogens by the action of kallikreins, have been implicated in a variety of biological activities including vasodilation, increased vascular permeability, contraction of smooth muscle cells and activation of sensory neurons. However, investigation of the physiological actions of kinins have been greatly hampered because its effects are curtailed by rapid proteolytic degradation. We examined the pharmacological characteristics of the first nonpeptide bradykinin receptor agonist 8-[2,6-dichloro-3-[N-[(E)-4-(N-methylcarbamoyl)cinnamidoacetyl+ ++]-N-methylamino]benzyloxy]-2-methyl-4-(2-pyridylmethoxy)quinolin e (FR190997). FR190997, whose structure is quite different from the natural peptide ligand, but is similar to the nonpeptide antagonists FR165649, FR167344 and FR173657, potently and selectively interacts with the human B2 receptor and markedly stimulates inositol phosphate formation in transfected Chinese hamster ovary (CHO) cells. FR190997 induces concentration-dependent contraction of isolated guinea pig ileum. In vivo, FR190997 mimics the biological action of bradykinin and induces hypotensive responses in rats with prolonged duration, presumably as a consequence of its resistance to proteolytic degradation. Therefore, FR190997 is a highly potent and subtype-selective nonpeptide agonist which displays high intrinsic activity at the bradykinin B2 receptor. This compound represents a powerful tool for further investigation of the physiology and pathophysiology of bradykinin receptors.
Animals↗
Neopterin and biopterin concentrations in cerebrospinal fluid in controls less than 1 year old.
Neopterin and biopterin concentrations were measured in cerebrospinal fluid (CSF) and urine samples from controls less than 1 year old. This is the first time for CSF reference data for controls less than 1 year old to be reported. The ratio of neopterin to biopterin in CSF 0-30 days (n = 48) of age in control samples was 0.65 +/- 0.31 (SD), which was far lower than that in urine over the same time period, 4.0 +/- 1.9 (SD), (n = 51). This finding is very important when diagnosing 6-pyruvoyltetrahydropterin synthase (PTPS) deficiency and peripheral form of PTPS deficiency in the neonatal period. Our CSF reference data for controls should be useful in the diagnosis of PTPS deficiency.
Age Factors↗
Pharmacodynamic analysis of the electrocardiographic interaction between disopyramide and erythromycin in rats.
Disopyramide (DP) is known to induce QT prolongation and Torsades de Pointes (TdP) when administered concomitantly with erythromycin (EM). To define and evaluate quantitatively the arrhythmogenic risk of the concomitant administration of DP and EM, we investigated the influence of EM on the pharmacokinetics and pharmacodynamics of DP in rats. The time profiles of change in QT interval and plasma concentration of each drug were evaluated during and after constant intravenous infusion of DP (6.0 or 15.0 mg/kg/h), EM (4.0 or 8.0 mg/kg/h), and coadministration of DP and EM (DP 6.0 mg/kg/h plus EM 4.0 mg/kg/h). Each agent induced QT prolongation at plasma concentrations within the therapeutic range in humans. DP-induced QT prolongation was proportional to its plasma concentration. In the case of EM, the Emax model with an "effect compartment" could explain the relationship between plasma EM concentrations and changes in QT interval. Although coadministration of EM with DP gave enhanced QT prolongation compared to dosing with DP alone, EM did not affect the pharmacokinetics of DP. In conclusion, it was shown that a pharmacodynamic interaction contributes to the electrocardiographic adverse reaction (i.e., QT prolongation) induced by coadministration of DP and EM in rats.
Animals↗
Problems and our solutions for implementing telemedicine systems.
There are several problems on the practical use of telemedicine, for example, the difficulties involved in promoting communication between medical facilities, uncooperative clinicians, and the absence of high-speed circuits and high-resolution CRT. From the Japanese point of view, we suggest ways to resolve these problems. We will analyze and propose scenarios for realizing successful communications among medical institutions, medical communication and its characteristics, barriers to the promotion of communications among medical institutions, second-opinion centers, and separate satellites and separate circuits. We also mention the World Wide Web for teleconsultation, provision of assistance to people with data handicaps via a communications satellite, and assistance to programs designed for training telemedicine specialists. Using a communication satellite, we offer programs that explain preventive medicine, support activities for nursing at home, explain the risks of fast food, and support activities for the handicapped and women in a simple manner to computer illiterates.
Communication↗
Analysis of antiplatelet effect of ticlopidine in humans: modeling based on irreversible inhibition of platelet precursors in bone marrow.
The relationship between plasma concentration of ticlopidine and its inhibitory effect on platelet aggregation in human was analyzed using a pharmacokinetic/pharmacodynamic (PK/PD) model. The data of plasma concentration and inhibitory effect on platelet aggregation were taken from the literature. A two-compartment open model was fitted to plasma ticlopidine concentrations. Assuming that ticlopidine acts on platelet precursors in the bone marrow, the apparent reaction rate constant of ticlopidine and platelet precursors (K), apparent transformation rate constant of platelet precursors (kr) and apparent elimination rate constant of platelets (ke) were estimated. The estimated values +/- S.D. were 1.01 +/- 1.08 ml micrograms-1 hr-1 for K, 0.265 +/- 0.259 hr-1 for kr and 0.0747 +/- 0.0112 hr-1 for ke. The antiaggregation effects of ticlopidine on platelets after administration of 100, 200, and 300 mg (bid for 8 days) were simulated using the PD parameters of K, kr, and ke. While the antiaggregation effect reached steady state within 3-4 days without dose dependency of the interval, the maximum effect increased with dose. Furthermore, changing the elimination rate constant of ticlopidine from the central compartment in the model significantly changed the duration of inhibitory effect of ticlopidine on platelet aggregation. Therefore, the reported long duration of antiplatelet effect after discontinuation of ticlopidine, which is believed to be irreversible binding to the platelet, might have been partially caused by the delayed plasma elimination after a long therapy of ticlopidine. On the other hand, the mean life-span of platelets in the blood estimated by 1/ke after administration of ticlopidine was 14 hr, far below the life-span of platelets in the blood. For a more detailed analysis of the antiplatelet effect of ticlopidine, the possible contribution of reversible binding of the drug to glycoprotein IIb/IIIa should be considered in future PK/PD models.
Blood Platelets↗
The time course of the change in antibody titres in herpes gestationis.
The time course of the change in antibody titres was examined postpartum after treatment in two patients with herpes gestationis. The first patient, a 29-year-old woman seen first in the 32nd week of her first pregnancy, had an exudative erythema, and developed an itchy erythema with small tense vesicles on the trunk and legs after delivery in the 40th week of pregnancy. The second patient, a 28-year-old woman seen first in the 28th week of her first pregnancy, had an itchy exudative erythema, small tense vesicles and crusts on the legs. After a Caesarean section in the 40th week of pregnancy performed because of cardiac complications in the fetus, the skin lesions extended to the trunk and extremities. Direct immunofluorescence revealed linear depositions of IgG and C3 at the basement membrane zone (BMZ) and indirect immunofluorescence was positive at the epidermal side of the BMZ in 1 mol/L NaCl-split skin in both cases. In patient 1, prednisolone, 20 mg/day, administered 4 months after delivery, gave rapid improvement (within 1 week) of the skin lesions; in patient 2, minocycline, 200 mg/day, administered 2 weeks after delivery, gave improvement within 2 weeks. Immunoblotting against epidermal extracts revealed the presence of antibodies directed to the 180 kDa bullous pemphigoid antigen in both sera. Indirect immunofluorescence and immunoblot were positive for at least 2 months in patient 1 and for 5 months in patient 2 after disappearance of the skin lesions.
Adult↗
The seborrhoeic pattern of dermatomyositis.
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Adolescent↗
An infant with severe atopic dermatitis and progressive hepatomegaly due to fatty liver.
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Adolescent↗
Helical crus reconstruction using a postauricular chondrocutaneous flap.
The authors describe a helical crus reconstruction technique using a postauricular chondrocutaneous flap vascularized by the postauricular vessels. They used this procedure on 7 patients who had developed a large defect on the helical crus following surgery. In each patient the flap design was adjusted to fit the form of the defect. All flaps were in easy reach of the defect and all flaps survived without any complications. The reconstructed ears had good three-dimensional form, and the color and texture match was satisfactory. The flap donor site was not noticeable because it was hidden behind the ear. Constriction did not occur and a good form was maintained. Neither deformity due to scar contracture nor absorption of the cartilage was observed.
Aged↗
Stahl's ear caused by an abnormal intrinsic auricular muscle.
Stahl's ear in a 12-year-old girl was treated surgically. During the operation, we discovered that the transverse muscle had an abnormal course, and we concluded that this muscle had caused the deformity. Treatment was accomplished by cartilage incision and transposition of the muscle to its normal position. After 3 years of follow-up, the reconstructed ear has maintained a good appearance. The etiology of Stahl's ear is unknown. Although various techniques have been reported for the reconstruction of Stahl's ear, the course of the intrinsic auricular muscles have not been confirmed by surgeons during the operation. We think that this case provides insight into the etiology of Stahl's ear and provides guidance for a new surgical treatment.
Child↗
Functional reconstruction using a depressor anguli oris musculocutaneous flap for large lower lip defects, especially for elderly patients.
Described here is a new technique to reconstruct large lower lip defects using one or two musculocutaneous island flaps, which includes an innervated depressor anguli oris muscle and has a facial artery in its pedicle. Vermilion is simultaneously reconstructed using a mucosal transposition flap. Three patients who had a total lower lip defect and five patients who had a defect larger than one-half of the lower lip were treated by our procedure. All the flaps survived completely without any signs of vascular stasis. In six patients, sphincter function and sensation appeared within 3 months after surgery. In one patient who needed a total lower lip reconstruction, the depressor anguli oris muscle was atrophic and the motor nerve could not be found. This patient could not regain motion. One other patient complained of a sialorrhea accompanied by sensory loss; however, his sensation improved within 6 months after surgery. All of the reconstructed lower lips were large enough to enable the patient to wear dentures and were of a cosmetically acceptable appearance 1 year after surgery.
Aged↗