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Biomedical subjects

K Nakatsuka

Publications and source records attributed to K Nakatsuka.

At least 19 recordsLinked to original sources
PubMed1998

Short-term effects of nicardipine and propranolol on ocular and systemic hemodynamics in healthy Japanese subjects.

Ocular perfusion is a critical factor in ischemic ocular diseases, and blood flow in the ophthalmic artery has a pronounced effect on perfusion. To evaluate the effects of dihydropyridine calcium channel blocker and nonselective beta-adrenergic antagonist on ocular perfusion, we investigated the short-term effects of single oral doses of nicardipine (40 mg) and propranolol (40 mg) on the blood flow velocity in the ophthalmic artery, intraocular pressure (IOP), systemic blood pressure, and heart rate in nine healthy Japanese male volunteers in a double-blind, placebo-controlled study using color Doppler imaging. Parameters were evaluated before and 60 and 120 minutes after administration. Nicardipine significantly increased the maximum systolic velocity and time-averaged blood flow velocity compared with placebo without significant increase in the resistance index. Propranolol had no significant effects on Doppler parameters. Propranolol exhibited a great reduction in IOP from placebo values. Systolic blood pressure and heart rate were significantly reduced by propranolol. Nicardipine significantly increased heart rate. These results suggest that nicardipine increased ophthalmic blood flow, but propranolol did not.

Adrenergic beta-Antagonists↗
PubMed1998

Interaction between timolol eyedrops and oral nicardipine or oral diltiazem in healthy Japanese subjects.

OBJECTIVE: Timolol is widely used for the topical therapy of glaucoma. Adverse cardiovascular effects include slowing of the heart rate and weakening of myocardial contractility. We investigated pharmacodynamic interactions with respect to cardiovascular and ocular responses between timolol ophthalmic solution and either nicardipine, which does not directly inhibit cardiac conduction, or diltiazem, which does. METHODS: Two studies utilized a randomized, double-blind, Latin-square, placebo-controlled design involving four separate treatments given at least 1 week apart. Eight healthy male Japanese volunteers received a single drop of 0.5% timolol or artificial tears in each eye with or without a single oral dose of nicardipine (40 mg), and with or without a single oral dose of diltiazem (60 mg). Subjects exercised on a bicycle ergometer before and 1.5 and 3 h after dosing. At these times, heart rate and blood pressure were measured at rest and after exercise. The intraocular pressure was measured at rest. RESULTS: One drop of 0.5% timolol per eye significantly reduced the exercise-induced increase in heart rate and blood pressure, and intraocular pressure at rest. The timolol ophthalmic solution suppressed the reflex sympathetic cardiac stimulation that resulted from the primarily vasodilative action of nicardipine. No additional reduction in heart rate occurred when the ophthalmic timolol solution was administered in conjunction with diltiazem. The concomitant use of timolol and nicardipine or diltiazem did not induce an additional reduction in intraocular pressure. Oral nicardipine or diltiazem did not reduce intraocular pressure. Care should be taken when using topical timolol in patients with cardiovascular or respiratory diseases.

Administration, Oral↗
PubMed1998

Protective effects of a human 18-kilodalton cationic antimicrobial protein (CAP18)-derived peptide against murine endotoxemia.

CAP18 (an 18-kDa cationic antimicrobial protein) is a granulocyte-derived protein that can bind lipopolysaccharide (LPS) and inhibit various activities of LPS in vitro. The present study examined the protective effect of a synthetic 27-amino-acid peptide (CAP18(109-135)) from the LPS-binding domain of CAP18 against antibiotic-induced endotoxin shock, using highly LPS-sensitive D-(+)-galactosamine (D-GalN)-sensitized C3H/HeN mice. The antibiotic-induced endotoxin (CAZ-endotoxin) was prepared from the culture filtrate of Pseudomonas aeruginosa PAO1 exposed to ceftazidime (CAZ). Injection of CAP18(109-135) protected the mice injected with LPS or CAZ-endotoxin from death and lowered their tumor necrosis factor (TNF) levels in serum in a dose-dependent manner. Treatment with CAZ caused death of the D-GalN-sensitized P. aeruginosa PAO-infected mice within 48 h, while injection with CAP18(109-135) rescued the mice from death. In the mice rescued from death by injection with CAP18(109-135), endotoxin levels in plasma and TNF production by liver tissues were decreased but the numbers of viable infecting bacteria in their blood were not decreased significantly and remained at the levels in CAZ-treated mice. These results indicate that CAP18(109-135) is capable of preventing antibiotic-induced endotoxic shock in mice with septicemia and that the effect is due to its LPS-neutralizing activity rather than to its antibacterial activity.

Animals↗
PubMed1998

Paget's disease of bone: evidence for a susceptibility locus on chromosome 18q and for genetic heterogeneity.

Paget's disease of bone is a common condition characterized by bone pain, deformity, pathological fracture, and an increased incidence of osteosarcoma. Genetic factors play a role in the pathogenesis of Paget's disease but the molecular basis of the disease remains unclear. Previous genetic linkage studies have mapped the rare Paget's disease-like bone dysplasia familial expansile osteolysis (FEO) to chromosome 18q21-22, and recent work has shown evidence of linkage between this locus and Paget's disease in one family. Here we studied the relationship between the 18q21-22 locus and Paget's disease in eight large multiplex families from diverse ethnic backgrounds with inherited Paget's disease. Paget's disease was inherited as an autosomal dominant trait in all families, with high penetrance by the sixth decade. Analysis of seven highly polymorphic markers from chromosome 18q21-22 showed positive summated two-point log10 odds ratio (lodscores) of +2.97 with the marker D18S42 at a recombination fraction (theta) = 0.05, and of +2.95 with the marker D18S60 at theta = 0.00, values which are close to the cut-off of +3.0, which is generally accepted as evidence of linkage. Segregation analysis of the haplotypes and formal statistical analysis using the HOMOG program provided evidence for genetic heterogeneity, however, with evidence for linkage in five families and against linkage in the remaining three families (chi square 8.82; df = 2; p < 0.025). Multipoint linkage analysis in the five linked families showed lodscores of above +3.5 across the whole susceptibility region and a maximum summated lodscore of 3.89 at the marker D18S465. In the three nonlinked families, negative multipoint results were obtained for the whole region, with lodscores below -2.0 in one family, excluding this as a candidate locus for the disease. Our studies demonstrate the importance of hereditary factors in the pathogenesis of Paget's disease and confirm evidence of linkage between Paget's disease and chromosome 18q21-22 in some families. This raises the possibility that Paget's disease and FEO may share a common molecular basis, perhaps due to different mutations in the same gene or family of genes. Data from three families did not support evidence of linkage to 18q21-22 however, indicating that Paget's disease is genetically heterogeneous and suggests the presence of at least one additional locus which remains to be discovered.

Chromosome Aberrations↗
PubMed1998

[A case of segmental sunset glow fundus following a choroidal tumor-like lesion].

This paper presents a very rare case of segmental sunset glow fundus following a choroidal tumor-like lesion in a 59-year-old woman. She complained of metamorphopsia in her left eye. Funduscopic examination disclosed a pale yellowish choroidal tumefaction, superotemporal to the macula. She was initially thought to have a choroidal tumor. However, in spite of systemic investigation, a diagnosis could not be made. Gradually the lesion became flattened but spread to the periphery. Iridocyclitis with Koeppe's nodule occurred but regressed after treatment with a topical steroid. Three months after the initial onset of the lesion, funduscopy showed a red area, the "sunset glow", in the superior temporal quadrant. This case resembles Harada disease because of the red coloration in the fundus, iridocyclitis with Koeppe's nodule, and human leukocyte antigen (HLA)-DR4 positivity. But other findings were not compatible with the criteria of Harada disease. It seems that the present lesion has not been reported in the past.

Choroid↗
PubMed1998

Metabolism-based inactivation of penile nitric oxide synthase activity by guanabenz.

Guanabenz (Wytensin) was shown to inactivate nitric oxide synthase (NOS) activity in vitro and in vivo. In in vitro studies with the use of a cytosolic fraction from penile tissue, the inactivation was found to depend on NADPH, time, and the concentration of guanabenz. The L-, but not the D-, isomer of arginine could protect from the inactivation, suggesting an active site-directed event. The kinetics of inactivation could be described by an apparent dissociation constant for the initial reversible complex (Ki) and a pseudo first-order inactivation constant (kinact) of 38.5 microM and 0.179 min-1, respectively. In in vivo studies, guanabenz was shown to inhibit penile cytosolic NOS activity in a dose- and time-dependent manner. Treatment of rats with guanabenz (5 mg/kg/day) for 4 days caused a decrease of approximately one-half in the NOS activity of the penile cytosolic fraction with a concomitant loss in the amount of immunodetectable NOS protein. Treatment for 4 days at a dose of 0. 5 mg/kg/day showed a similar decrease in activity, whereas a dose of 0.05 mg/kg/day showed no effects. Due to the multitude of processes that are regulated by NO, the inactivation of NOS is a potential mechanism to be considered in a variety of biological effects associated with drugs.

Animals↗
PubMed1998

[Biochemical markers of bone metabolism].

Markers of bone metabolism can be utilized for selection of treatment and/or evaluation of the treatment, and possibly decision-making to start treatment. Resorption markers are sensitive to detect changes in bone metabolism but show higher day-to-day variation, and formation markers are less sensitive but show less fluctuation. Among these markers, deoxypyridinoline, NTx, and CTx are utilized for short-term judgement of efficacy during the early phase of anti-resorptive treatment, such as bisphosphonate and hormone replacement therapy. The coefficients of day-by-day variations in these resorption markers are 8-14%. Thus, 20 (approximately 30)% or more change in marker levels may be necessary to detect the efficacy in individual patients on anti-resorptive therapy. The formation markers can be utilized for monitoring the degree of excessive suppression during the late phase of treatment by anti-resorptive treatment, possibly later than 6 months following initial treatment.

Biomarkers↗
PubMed1997

Temporal variation in the effects of ophthalmic timolol on cardiovascular and respiratory functions in healthy men.

This study examined the effects of ophthalmic timolol and time of administration on cardiovascular and respiratory functions in healthy young male volunteers. Eight participants (mean age +/- standard deviation, 22 +/- 0.9 years) received either 50 microL of 0.5% timolol or placebo in the lower conjunctival sacs of both eyes in the morning or evening. Intraocular pressure, blood pressure, heart rate, and respiratory functions, including percent forced expiratory volume in 1 second and peak expiratory flow rate, were then measured for 3 hours after drug administration. Timolol reduced intraocular pressure and cardiovascular function at both administration times. However, a timolol-induced reduction in respiratory function was observed only in the evening: percent forced expiratory volume in 1 second, peak expiratory flow rate, and expiratory flow rate at 75% vital capacity were reduced by 3%, 7%, and 12%, respectively, 3 hours after administration. These results indicate that ophthalmic timolol reduces cardiovascular and respiratory functions in healthy young male subjects and that bronchial sensitivity to timolol differs between morning and evening.

Adrenergic beta-Antagonists↗
PubMed1997

[Effects of long-term administration of alfacalcidol on bone mass and bone metabolism in patients with primary osteoporosis--comparison with calcium preparations].

Long-term administration of active vitamin D3 can reduce the loss of bone mass and the incidence of fractures in Japanese whose intake of calcium (Ca) is low. In a crossover study, we examined the safety and efficacy of 1 alpha (OH)D3 and combination therapy with a Ca preparation. We measured bone mass, the incidence of fractures and bone metabolism in 33 elderly patients with a high risk of fracture (mean age: 77.5 %/- 7.8 (SD) years). Subjects were randomly assigned to receive calcium lactate alone for 12 months after 12 months of combination therapy with 1 alpha (OH)D3 (1 microgram/day) (A-C group, 17 patients) or to take calcium lactate alone for 12 months and then undergo 12 months of combination therapy with 1 alpha(OH)D3 (C-A group, 16 patients). These subjects were followed for 24 months. In the A-C group, the bone mineral density (BMD) of the lumbar spine (L2-4 BMD) measured 6 months after the start of 1 alpha (OH)D3 administration was 3% higher than the baseline value. In the C-A group, L2-4 BMD measured 6 months after the start of calcium lactate administration had decreased by approximately 2%. The rate of decrease was the same 12 months after the start of administration. The differences in L2-4 BMD between the two groups 6 and 12 months after the start of administration were significant (p = 0.023 and p = 0.005, respectively). In the A-C group, the mean BMD of the distal one-third radius measured 6 months after the start of administration had increased by 5%, but the increase was 1% when measured 12 months after the start of administration. In the C-A group, there were no such changes. The incidence of vertebral fracture during combination therapy with 1 alpha(OH) D3 and Ca preparations in the A-C group was significantly lower than that in the C-A group (chi square test, p < 0.05). The serum Ca level in the C-A group gradually increased, as measured 6 and 12 months after the start of combination therapy with 1 alpha(OH) D3 and Ca preparations, although these changes were within the reference range. There was no hypercalciuria. Serum intact parathyroid hormone levels had decreased from 26.5 +/- 11.3 pg/ml and 30.7 +/- 10.3 pg/ml to 19.8 +/- 9.7 pg/ml and 25.5 +/- 9.6 pg/ml in the A-C group and the C-A group, respectively, by 6 months after the start of administration. The rate of decrease was significantly higher in the A-C group (p = 0.004). These findings suggest that long-term administration of 1 alpha(OH)D3 is safe even when combined with administration of Ca preparations, and that this agent inhibits parathyroid function, and thus prevents loss of bone mass and reduces the incidence of vertebral fracture.

Aged↗
PubMed1997

[Serum bone Gla-protein increases following short-term oral administration of active vitamin D3 in the elderly with vitamin D deficiency].

Serum bone Gla-protein (BGP) is produced by osteoblasts in a vitamin K-dependent process. It is well known that serum BGP levels increase after oral administration of active vitamin D3 in postmenopausal women and patients with chronic renal failure before dialysis. These findings indicate that active vitamin D3 increases the BGP production by osteoblasts. In the present study, a daily oral dose of 2 micrograms of 1 alpha (OH)D3 was administered to 10 elderly males (age, 75.0 +/- 10.9 years) and 8 young males (age, 29.0 +/- 3.2 years) to compare the changes in serum BGP levels between the two groups. None of the subjects had severe renal or hepatic dysfunction or abnormalities in calcium (Ca) metabolism. Serum BGP and 1,25(OH)2D levels in both groups were measured before the initial administration, at 24 h and at 1, 2 and 3 weeks after the start of administration. Serum parathyroid hormone (m-PTH), alkaline phosphatase (ALP), Ca and phosphorus levels were also measured in the elderly group. Serum BGP levels before the initial administration were 4.63 +/- 1.8 ng/ml in the elderly group and 4.33 +/- 0.92 ng/ml in the young group, with no significant difference between the two groups. In both group serum 1,25(OH)2D levels were slightly increased at 24 h after administration. In the elderly group serum BGP levels increased significantly to 11.5 +/- 3.0 ng/ml, an increase of approximately 250%, 1 week after the initial administration and the increase was maintained for up to 3 weeks after the administration commenced. However, no changes in serum BGP levels were noted in the young group. In the elderly group serum m-PTH levels were 544 +/- 257 pg/ml, almost the upper normal limit, before, and decreased slightly after, the administration of 1 alpha (OH)D3. Serum ALP levels also decreased slightly after the administration and serum Ca levels were slightly increased, however, the changes were within normal limits. We conclude that osteoblastic function is activated after short-term administration of active vitamin D3 in vitamin D deficient elderly subjects.

Administration, Oral↗
PubMed1997

Rheumatoid synovial fibroblasts are stimulated by the cellular adhesion to T cells through lymphocyte function associated antigen-1/intercellular adhesion molecule-1.

OBJECTIVE: To determine if T cells stimulate synovial fibroblasts to produce inflammatory cytokines through cellular adhesion in synovitis of rheumatoid arthritis (RA). METHODS: Immunohistochemical staining, flow microfluorometry, adhesion assay, ELISA, and Northern blot analysis to determine production of interleukin-1beta (IL-1beta) from RA synovium and RA synovial fibroblast-like cell line. RESULTS: We observed the following novel features of cellular adhesion of T cells to synovial fibroblasts, which suggest a role for induction of cytokine production in synovial fibroblasts: (a) CD11a (lymphocyte function associated antigen-1 alpha) positive T cells accumulated around CD54 [intercellular adhesion molecule (ICAM-1)] positive synoviocytes in active RA synovium, shown by immunohistochemical studies: (b) synovial fibroblastic cell line E11 expressed a single adhesion molecule ICAM-1, the expression of which was not affected by IL-1beta; (c) E11 adhered to phorbol myristate acetate (PMA) activated T cells within 30 min, not resting T cells, and its adhesion was completely inhibited by anti-LFA-1 monoclonal antibody (Mab); (d) pretreatment of E11 with IL-1beta did not affect the adhesion of E11 to PMA activated T cells; (e) IL-1beta production and IL-1beta mRNA transcription from E11 were induced by the addition of T cells in a cell number dependent manner and the induced production and transcription were inhibited by anti-LFA-1 Mab. CONCLUSION: T cells infiltrating the synovium may play a pivotal role in the pathogenesis of RA, by inducing IL-1beta production of synovial fibroblasts by sequential events, namely, T cell-synoviocyte cellular adhesion through LFA-1/ICAM-1, signal transduction, and production of IL-1beta induced by the cellular adhesion.

Arthritis, Rheumatoid↗
PubMed1997

[A case of congenital retinoschisis with unexpected appearance and spontaneous regression].

A case of congenital retinoschisis, with both unexpected appearance and spontaneous regression, is reported. The patient, a 22-year-old man, had been diagnosed with congenital retinoschisis when he was 11 years old. The ocular fundus showed bilateral foveal retinoschisis and peripheral retinoschisis in the right eye. Early in November 1991, he visited our hospital and complained of a visual field defect in the left eye. The ocular fundus of the left eye showed high ballooning retinoschisis. However, two weeks later, the ballooning retinoschisis had completely disappeared. Appearance and regression of peripheral retinoschisis of congenital retinoschis in an adult is a very rare occurrence.

Adult↗
PubMed1996

Cross-linking of intercellular adhesion molecule 1 (CD54) induces AP-1 activation and IL-1beta transcription.

Leukocytes adhere to target cells through their integrins and play a crucial role in self-defense, inflammation, and differentiation. Intercellular adhesion molecule-1 (ICAM-1; CD54) is a representative ligand for integrins and is expressed on many cell types, some of which are targets for leukocyte adhesion. Recent studies suggest that adhesion molecules function not only as a cellular glue, but also as a signal transducer. However, it remains to be clearly defined whether engagement of ICAM-1 is able to induce activation signals in target cells. In rheumatoid synovium, synovial cells are known to express abundant ICAM-1 and produce multiple inflammatory cytokines, such as IL-1beta. In this study, we provide the first evidence that ICAM-1 engagement induces activation of the transcription factor AP-1 and transcription of the IL-1beta gene using a specific Ab to cross-link ICAM-1 on a rheumatoid synovial cell line (E11 cells). This evidence includes ICAM-1 cross-linking-dependent induction of 1) in situ IL-1beta transcription and protein synthesis, 2) transiently transfected chloramphenicol acetyltransferase (CAT) reporter plasmids containing both the IL-1beta LPS-responsive enhancer (between -3134 and -2729) as well as multiple copies of an AP-1 site from this enhancer (between -3117 and -3111), and 3) the binding of a Jun/Fos family complex to this AP-1 site. Thus, ICAM-1 not only functions as a glue for integrin binding, but also as a transducer for AP-1 activation signals important for IL-1beta gene transcription.

Animals↗
PubMed1996

Comparison of three intravenous regimens of clodronate in Paget disease of bone.

We compared the effects of three different regimens of intravenous clodronate in a retrospective study of 60 patients with Paget disease. A total dose of 1500 mg of clodronate was given as 300 mg for 5 consecutive days (n = 20), 1500 mg as a single infusion (n = 20), or 300 mg as a single infusion for 5 consecutive months (n = 20). The response to treatment and the duration of the effect were assessed from sequential changes in the activity of serum alkaline phosphatase. Treatment with clodronate induced a significant response in 85% of patients. The response rate was comparable in patients treated with 5 daily infusions (90%), with a single infusion (75%), and with 5 monthly infusions (90%). The median duration of response from the start of treatment was 11 months for those treated with five daily infusions and 12 months for the other two regimens. At one year, 22, 40, and 44% of patients had maintained their response in the daily, single, and monthly infusion regimen, respectively (NS). Six patients (32%) treated with 5 daily infusions achieved a remission (complete response) compared with 3 patients treated with a single infusion and 5 monthly infusions, respectively (16 and 15% respectively, NS). Patients attaining a complete response had a significantly longer duration of response compared with partial responders (median time 15.0 versus 11.5 months, respectively, p < 0.05). We conclude that intravenous clodronate (total dose 1500 mg) suppresses disease activity in the majority of patients with Paget disease of bone. The degree and duration of response were similar for the three regimens. Thus, in the treatment of Paget disease, the choice of regimen is a matter of convenience.

Aged↗
PubMed1996

Duration of response with oral clodronate in Paget's disease of bone.

We studied retrospectively 51 patients with Paget's disease of bone treated with oral clodronate, 1600 mg daily given for 1 (n = 23), 3 (n = 13), or 6 months (n = 15), to compare the effect of a variable length of treatment on the response rate to treatment and the duration of disease suppression. Activity of alkaline phosphatase and urinary hydroxyproline excretion were measured before treatment at monthly intervals for a year and every 3 months thereafter until biochemical relapse. Before treatment, patients given the three regimens had similar disease activity as judged by serum alkaline phosphatase and urinary hydroxyproline values. There was no significant difference in the time to response between groups (median = 2 months). The proportion of patients attaining normal values of alkaline phosphatase activity was significantly higher in patients treated for 6 months (71%, p < 0.03) compared with those treated for 1 or 3 months (23% and 39%, respectively). The time to relapse from the start of treatment was significantly shorter in patients treated for 1 month compared with those treated for 3 or 6 months (median = 11, 18, and 23 months, respectively). Thus, at 2 years all patients treated for 1 month had relapsed, whereas 31% and 40% were still relapse-free in patients receiving treatment for 3 and 6 months, respectively. The length of treatment was the only variable identified by stepwise linear regression that significantly affected the duration of response. We conclude that oral clodronate (1600 mg daily) suppresses disease activity in the vast majority of patients with Paget's disease of bone. The magnitude of the response and its duration depend on the duration of treatment or the total dose administered, so that several months of treatment with oral clodronate are required when a durable response is desired.

Administration, Oral↗