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Biomedical subjects

M Kato

Publications and source records attributed to M Kato.

At least 703 records · Page 39Linked to original sources
PubMed1998

Long-term effect of recombinant human insulin-like growth factor I on metabolic and growth control in a patient with leprechaunism.

Leprechaunism is the most severe form of insulin resistance, manifesting with abnormal glucose metabolism and retarded growth. In the present study, we investigated the biological actions of recombinant human insulin-like growth factor I (rhIGF-I) in fibroblasts derived from a patient with leprechaunism. In the same patient, we also investigated the pharmacokinetics of IGF-I and the long-term effect of rhIGF-I treatment on metabolic control and physical growth. The patient's fibroblasts showed normal binding of IGF-I, normal phosphorylation of the beta-subunit of the IGF-I receptor, and normal [3H]thymidine incorporation in response to IGF-I. The fibroblast studies suggested that the patient would respond to IGF-I therapy, but certainly did not exclude the possibility of IGF-I resistance in vivo. Administration of recombinant human GH at the dose of 2.0 IU/kg for 3 consecutive days induced a minimal response of serum total IGF-I and IGF-binding protein-3 (IGFBP-3), suggesting partial GH resistance. To increase the serum total IGF-I level, we administered rhIGF-I with combination therapy of intermittent and continuous s.c. injection. This sustained the serum total IGF-I level, but not the serum IGFBP-3 level, within the normal range. The patient was treated with combination therapy of rhIGF-I by both s.c. injection and continuous s.c. infusion for 6 yr and 10 months. Administration of rhIGF-I at total daily dose of 1.6 mg/kg maintained her growth rate and hemoglobin A1c level nearly within the normal range. These findings suggest 1) that this leprechaun patient has an IGF-I-deficient state and partial GH resistance, as reflected by impaired production of IGF-I and IGFBP-3; 2) that rhIGF-I treatment works effectively for preventing postnatal growth retardation and normalizing glucose metabolism in patients with extreme insulin resistance; 3) that this treatment requires relatively higher dose of rhIGF-I; and 4) that treatment appears to be safe and devoid of adverse effects.

Blood Glucose↗
PubMed1998

Multimodality visual evoked potentials in evaluating visual dysfunction in optic neuritis.

Visual information is processed via multiple, parallel channels. The present study examined the clinical feasibility of multimodality visual evoked potentials (VEPs) in optic neuritis. We recorded transient VEPs to 30' checkerboard patterns, chromatic and achromatic sinusoidal gratings and apparent motion, and steady-state VEPs to achromatic gratings in 15 normal controls and 14 patients. VEPs to 30' checks were abnormal in 10 eyes (7 patients); however, considering all five modalities, abnormal responses were seen in 20 eyes (12 patients). Abnormality rates were not equal among the visual stimuli, which thus suggested possible dysfunction of individual subdivisions in the visual pathways. We conclude that use of multimodality VEPs may increase both understanding of the pathophysiology of the visual pathways and diagnostic yield.

Adult↗
PubMed1998

Fragile X syndrome. Clinical, electroencephalographic and neuroimaging characteristics.

We studied 11 patients (9 males) with cytogenetic diagnosis of fragile X syndrome (FXS) with the purpose of investigating the neural circuitry involved in this condition. The ages ranged from 8 to 19. All the individuals presented large ears, elongated faces and autistic features. Ten patients had severe mental retardation. Attention disorder was found in 10 individuals. Electroencephalographic recordings were abnormal in 6 of 10 patients examined, showing focal epileptiform discharges predominantly in frontal and parietal areas. All patients underwent magnetic resonance imaging studies which were abnormal in 8 of them. The most important abnormalities were reduction of the cerebellar vermis and enlargement of the IV ventricle. Single photon emission computerized tomography (SPECT) was performed in 7 patients and was abnormal in all of them, the most frequent finding being a hypoperfusion of the inferior of the frontal lobes. Based on the clinical picture, neuropsychological findings and functional and structural imaging studies we suggest that FXS presents with a dysfunction involving a large area of the central nervous system: cerebellum-basal frontal regions-parietal lobes. The literature points to a disturbance involving the same neural circuitry in patients with autism.

Adolescent↗
PubMed1998

Preferential use of branched-chain amino acids as an energy substrate in patients with liver cirrhosis.

We analyzed basal energy metabolism in 20 healthy volunteers and 41 cirrhotic patients by indirect calorimetry. Subjects were then given either glucose, branched-chain amino acids (BCAA) or fatty acids as an energy substrate. Resting energy expenditure (REE), nonprotein respiratory quotient (npRQ), and oxidation rates of glucose (% CHO), protein (% PRO) and fat (% FAT) were analyzed. REE and %FAT were significantly higher and % CHO and %PRO were significantly lower in cirrhosis than in controls. These changes correlated with disease severity. Glucose and BCAA were utilized efficiently as energy substrates and reduced %FAT in cirrhosis. Energy efficacy (increased energy expenditure/energy equivalent of the supplemented nutrient) was significantly higher in BCAA (96 +/- 16%) than in glucose (41 +/- 8%) (p<0.01) and fatty acids (27 +/- 13%) (p<0.05). Patients with cirrhosis have an increased energy requirement. BCAA seems to be the preferred substrate to meet this demand, because its energy efficacy is higher than glucose or fatty acids in cirrhosis.

Amino Acids, Branched-Chain↗
PubMed1998

Effect of adenosine triphosphate on human coronary circulation.

We investigated in humans the effects of adenosine triphosphate (ATP), administered by intracoronary bolus (4-16 microg) or intravenous infusion (25-200 microg/kg/min), on coronary and systemic hemodynamics and electrocardiogram (ECG) variables. All patients had normal epicardial coronary arteries. The maximal coronary blood flow velocity (CBFV) was determined with intracoronary bolus of papaverine. A 12 microg bolus of ATP (n=12) caused maximal coronary hyperemia similar to that caused by papaverine. Intracoronary boluses caused a small brief decrease in arterial pressure but no significant changes in HR or ECG variables. Intravenous infusion of ATP at 150 microg/kg/min (n=15) caused a decrease in the coronary resistance index similar to that caused by papaverine, but the rate of increase in CBFV by ATP was smaller than that caused by papaverine. No patients had a significant change in ECG variables, but some patients (40%) had a serious decrease in arterial pressure. These studies suggest that maximal coronary vasodilation can be achieved safely with intracoronary ATP administration and that intravenous infusions at 150 microg/kg/min cause near-maximal coronary hyperemia in most patients.

Adenosine Triphosphate↗
PubMed1998

The herbal medicine sho-saiko-to inhibits the growth of malignant melanoma cells by upregulating Fas-mediated apoptosis and arresting cell cycle through downregulation of cyclin dependent kinases.

The anti-tumor effect and its mechanism of the herbal medicine sho-saiko-to were investigated on a murine malignant melanoma cell line (Mel-ret). Sho-saiko-to induced apoptotic cell death of Mel-ret cells with a definite increase of cell surface Fas antigen and Fas ligand (FasL). Sho-saiko-to arrested Mel-ret cells in G1 phase by decreasing the expression of cyclin-dependent kinase (cdk) 4 and its homologue cdk6. Kinase activities of cdk4 and cdk6 were identified to be downregulated by sho-saiko-to. Ingredient analysis revealed that baicalin is likely the main active constituent in the upregulation of Fas antigen and Fas ligand, while glycyrrhizin is the main constituent in the inhibition of cdks.

Animals↗
PubMed1998

[Biological and clinical analyses of the mechanism of growth retardation and the effect of recombinant human insulin-like growth factor-1 (rhIGF-1) treatment on glucose metabolism and growth in leprechaunism with severe insulin resistant diabetes].

Leprechaunism is the most severe form of insulin resistant diabetes and accompanied with growth retardation. Previously, we identified two mutations of insulin receptor (IR) gene in a patient with leprechaunism. In the present study, we assessed the biological actions of IGF-1 in the patient's fibroblasts and investigated short and long term effects of recombinant human IGF-1 (rhIGF-1) treatment on glucose metabolism and growth in the patient. The patient's fibroblasts had normal binding of IGF-1, normal phosphorylation of the beta-subunit of IGF-1 receptor (IGF-1R) and normal incorporation of thymidine in response to IGF-1. The subcutaneous administration of rhIGF-1 at the single dose of 0.4 mg/kg revealed a half life of IGF-1 as short as 90 minutes, and her serum IGFBP-3 level was extremely low. She was treated with rhIGF-1 for about 6 years by both subcutaneous injection (SI) before each meal and continuous subcutaneous infusion (CSI). The administration of rhIGF-1 at the total daily dose of 1.6 mg/kg sustained serum total IGF-1 level within normal range and maintained her growth rate and HbA1c level within nearly normal ranges. Therefore, the treatment with rhIGF-1 was thought to be effective in lowering plasma glucose levels in the patient because these mutant IRs had no dominant negative effects on endogenous IGF-1 Rs. The results suggested that the treatment with a high dose of rhIGF-1 by both SI and CSI is effective for preventing the postnatal growth retardation and normalizing glucose metabolism in patients with genetic form of extremely severe insulin resistant diabetes and that IGF-1 deficient state and partial GH resistance such as the impairment of the production of IGF-1 and IGFBP-3 may contribute to the growth retardation.

Abnormalities, Multiple↗
PubMed1998

Pharmacokinetics of erythropoietin in genetically anemic mice.

We examined the pharmacokinetics of recombinant human erythropoietin (rh-EPO) in genetically anemic mice (W/Wv genotype) to clarify its disposition mechanism in hematopoietic injury such as occurs in aplastic anemia. After rh-EPO was administered to W/Wv and control (+/+ genotype) mice once a day for 1 week at different doses, both the hematocrit (Hct) and tissue uptake clearance (CLup) of 125I-rh-EPO by spleen and bone marrow in the femur were estimated on the eighth day. The hematocrit increased on eighth day, depending on the dose administered. Compared with +/+ mice 10 times more rh-EPO was needed in W/Wv mice to produce an almost equivalent pharmacological effect. In +/+ mice, the CLup of 125I-rh-EPO by spleen increased to 4-fold that of controls after treatment with rh-EPO, 4.8 microg/kg, whereas that by bone marrow remained unchanged, irrespective of the dose administered. On the other hand, the increase in both the Hct and CLup in spleen was minimal in W/Wv mice. The CLup by bone marrow and spleen in both types of mice showed saturation with similar Km values (389-619 pM), comparable with the dissociation constant of the EPO receptor. In addition, the Hct correlated with the sum of the CLup by bone marrow and spleen in both types of mice, and the correlation lines were superimposable. These results suggest that the pharmacological receptors govern the saturable tissue uptake not only in normal mice but also in those that are anemic.

Animals↗
PubMed1998

[Effect of positive end-expiratory pressure on respiration and hemodynamics in dogs with pulmonary edema caused by increased membrane permeability].

The effect of PEEP on the extravascular lung water, respiratory mechanics and hemodynamics were studied in dogs with oleic acid-induced pulmonary edema. The dogs were randomized into one of three groups according to PEEP of 0, 5 and 10 cmH2O, 60 minutes after oleic acid (0.1 ml.kg-1) injection. PEEP improved oxygenation accompanied by increased FRC and DLco. However, oxygen delivery decreased in association with the decreased cardiac index caused by application of PEEP. PEEP failed to decrease the extravascular lung water volume measured by double-indicator dilution technique after lung edema formation.

Animals↗
PubMed1998

In vivo characterization of T-794, a novel reversible inhibitor of monoamine oxidase-A, as an antidepressant with a wide safety margin.

T-794 is a new reversible inhibitor of MAO type A. In order to predict its clinical utility as an antidepressant, we examined its pharmacological profile (i.e., MAO inhibitory activity, antidepressant-like activity and safety) in vivo in rodents. The p.o. administration of T-794 potentiated L-5-hydroxytryptophan-induced symptoms with ED50 = 1.01 mg/kg (mice) or 1.15 mg/kg (rats), and L-dopa-induced behavior with ED50 = 5.90 mg/kg (mice), whereas it did not alter the effect of beta-phenylethylamine even at 100 mg/kg (mice). In the L-5-hydroxytryptophan test in rats, the activity of T-794 (at twice the dose of ED50) disappeared by 8 h; the duration of action was similar to that of moclobemide. These results confirm the previous biochemical results that MAO-A inhibition by T-794 is highly selective and of short duration. T-794 was effective in three animal models of depression: reserpine reversal (mice, rats), behavioral despair test (mice) and learned helplessness (rats). In these tests, it had potency similar to or greater than moclobemide, tranylcypromine or imipramine. The p.o. administration of T-794 (30 mg/kg) did not affect the pressor effect of tyramine in anesthetized rats, whereas moclobemide (30 mg/kg) and tranylcypromine (6 mg/kg) potentiated the effect. Acute toxicity of T-794 proved to be very low (maximal tolerated dose > 2 g/kg p.o.) in contrast to brofaromine (maximal tolerated dose = 150 mg/kg p.o.). Unlike tricyclic antidepressants, T-794 did not prevent the oxotremorine-induced tremor even at 100 mg/kg p.o.; in this it demonstrated a lack of the anticholinergic activity. These results suggest that T-794 is an effective and particularly safe antidepressant and that it may make an important contribution in the treatment of depressive disorders.

Animals↗
PubMed1998

Comparison of antiplatelet effects of two nitric oxide-donating agents, FR146801 and FK409.

In the present study, we examined the antiplatelet effects of the two nitric oxide (NO)-donating agents, (+/-)-N-[(E)-4-ethyl-3-[(Z)-hydroxyimino]-6-methyl-5-nitro-3-he ptenyl]-3-pyridinecarboxamide (FR146801). a more stable analog of FK409 ((+/-)-(E)-4-ethyl-2-[(E)-hydroxyimino]-5-nitro-3-hexenamide ), and FK409 in in vitro and in vivo experiments. FR146801 and FK409 inhibited ADP- and collagen-induced platelet aggregation in human and rat platelet-rich plasma in a concentration-dependent manner, however, the inhibitory effect of FR146801 was weaker than that of FK409. In human washed platelets (WP), FR146801 and FK409 inhibited collagen-induced platelet aggregation in a concentration-dependent manner. The inhibitory effects of FR146801 and FK409 on platelet aggregation were closely reflected by the increase in the intraplatelet cGMP level. This intensely suggests that the antiplatelet activities of FR146801 and FK409 are due to NO-released from them. In the rat extracorporeal shunt model, FR146801 inhibited thrombus formation dose-dependently and its inhibition was significant at 10 mg/kg, p.o. FK409 suppressed thrombus formation significantly at 1.0 mg/kg, p.o., at which it induced significant hypotension, whereas FR146801 did not show any significant hypotensive effect even at 10 mg/kg, p.o. These results suggest that FR146801 has desirable antiplatelet effects both in vitro and in vivo and that its in vivo antiplatelet effect is more selective than its hypotensive effect, while FK409 does not show a selective antiplatelet effect in vivo.

Animals↗
PubMed1998

GBV-C/HGV infection in chronic hepatitis C patients: its effect on clinical features and interferon therapy.

A novel virus (GBV-C/HGV) may be associated with some liver diseases including fulminant hepatitis and acute and chronic hepatitis. On the other hand, many investigations showed that this infection does not contribute to liver disease. GBV-C/HGV has been found to occur in association with infection with other hepatitis viruses. We investigated the effect of GBV-C/HGV infection on the clinical features and interferon treatment in patients with chronic hepatitis C. A total of 262 hepatitis C virus (HCV) RNA positive patients with chronic hepatitis were examined in this study. The detection of serum GBV-C/HGV RNA was done by RT-PCR using specific primers from the NS5 regions. Interferon-alpha was given at a dose of 6 MU/day for 16 or 24 weeks. A responder was defined as a patient with ALT normalization and HCV RNA disappearance after treatment. GBV-C/HGV RNA was detected in 28 (11%) patients. No significant difference was detected in clinical features (age, sex, liver-related biochemical tests, and histological examination) between the 28 GBV-C/HGV-positive patients and the GBV-C/HGV-negative patients. Using interferon therapy for hepatitis C, the responder rates of GBV-C/HGV-positive and -negative patients were 14% and 20%, respectively. Of the 28 patients with GBV-C/HGV RNA, GBV-C/HGV RNA was tested after interferon therapy in 16 and of these GBV-C/HGV RNA was not detected in nine patients after therapy. These findings suggest that GBV-C/HGV infection dose not affect the clinical features in patients with HCV and the efficacy of interferon therapy for chronic hepatitis C.

Adolescent↗
PubMed1998

Activation of human liver 3alpha-hydroxysteroid dehydrogenase by clofibrate derivatives.

The NADP+-dependent dehydrogenase activity of a predominant isoenzyme of human liver 3alpha-hydroxysteroid dehydrogenase was activated by antihyperlipidemic drugs, such as bezafibrate and clinofibrate, and by clofibric acid and fenofibric acid (active metabolites of clofibrate and fenofibrate, respectively). The optimal pH of the activation by the drugs was about 7.5, and the concentrations giving maximum stimulation (1.8- to 2.4-fold) were 100, 50, 400 and 50 microM for bezafibrate, clinofibrate, clofibric acid and fenofibric acid, respectively. Clofibrate and fenofibrate acted as weak inhibitors, and the clofibric acid derivatives that lack the chloro group, methyl group on the alpha-carbon or carboxyl group greatly decreased the stimulatory effects. The activation by the drugs increased both Km and kcat (turnover number) values for the coenzyme and substrates. Kinetic analysis with respect to NADP+ showed that bezafibrate, clinofibrate, clofibric acid and fenofibric acid were nonessential activators showing dissociation constants of 32, 6, 103 and 11 microM, respectively. The combined activators experiments with one of the above drugs and sulfobromophthalein, a known activator specific for this enzyme, and comparison of their effects on the activities of mutant enzymes (with Met replacing Lys-270 or Arg-276) indicated that sulfobromophthalein and the drugs bind to an identical site on the enzyme. These results suggest that the long-term therapy with the antihyperlipidemic drugs influences the metabolism of steroid hormones, bile acids and several ketone-containing drugs mediated by the enzyme.

Alcohol Oxidoreductases↗
PubMed1998

[Clinical evaluation of intermittent hepatic arterial infusion therapy for metastatic liver tumor of gastric and colorectal cancer].

Eleven patients with liver metastasis from gastric cancer were treated by intermittent arterial infusion using OK-432 and recombinant IL-2 in combination with anticancer drugs. The direct effects for liver metastasis were PR 3 (response rate 30%), MR 2, NC 3, PD 1 and NE 1. Papillary adenocarcinoma showed a highly effective rate. The mean survival period was 326 days and the 50% survival period was 318 days. Out of 4 patients who underwent surgical resection for metastatic liver tumor, one showed recurrence, and the other is now healthy without any sign of recurrence for 8 years after the operation. In 7 patients with liver metastasis from colorectal cancer, intermittent arterial infusion therapy using Leucovorin, CDDP and 5-FU was performed. The direct effects were CR 2, PR 1, MR 1, PD 2, NE 1; the mean survival period was 478 days, and the 50% survival period 556 days. Out of 8 patients who underwent liver resection for metastasis, all patients remained alive for 687 mean survival days without liver recurrence. No severe side effects were noted in either therapy.

Adenocarcinoma, Papillary↗