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Biomedical subjects

M Takenaga

Publications and source records attributed to M Takenaga.

At least 19 recordsLinked to original sources
PubMed2004

A single treatment with microcapsules containing a CXCR4 antagonist suppresses pulmonary metastasis of murine melanoma.

Biodegradable poly D,L-lactic acid (PLA, molecular weight: ca. 5000) microcapsules containing a CXCR4 antagonist (4F-benzoyl-TE14011) were prepared (4F-benzoyl-TE14011-PLA), and their anti-metastatic activity was evaluated in mice. A single subcutaneous administration of 4F-benzoyl-TE14011-PLA significantly reduced the number of colonies formed by pulmonary metastasis of B16-BL6 melanoma cells expressing CXCR4. The same dose of 4F-benzoyl-TE14011 in a single or a series of treatments affected little. The substance 4F-benzoyl-TE14011 dose-dependently suppressed B16-BL6 cell growth. In the cells cultured with SDF-1, a more potent suppression was observed. 4F-Benzoyl-TE14011 was rapidly released from 4F-benzoyl-TE14011-PLA for an initial period, both in vitro and in vivo. A steady release was thereafter observed. Therefore, this drug release profile might contribute to prevention of melanoma metastasis at the steps involving the migration and cell growth. These results also show that a sustained drug release formulation could be a useful drug delivery system for CXCR4 antagonists.

Animals↗
PubMed2002

Insulin-loaded biodegradable PLGA microcapsules: initial burst release controlled by hydrophilic additives.

We investigated the controlled release of human insulin at an initial stage from poly(DL-lactic-co-glycolic acid) (PLGA, M(w) 6600) spherical matrices. PLGA microcapsules were prepared by the novel solvent evaporation multiple emulsion process. When the crystalline insulin was dispersed in dichloromethane as solid-in-oil (S/O) dispersion, it was found that most of insulin molecules were inlaid on the surface of PLGA microcapsules. Consequently, insulin-loaded PLGA microcapsules exhibited marked rapid release of insulin within several hours in both in vivo and in vitro experiments. On the other hand, the addition of glycerol or water in the primary dichloromethane dispersion results in drastically suppressed initial release. It was found by SEM observation that water- or glycerol-in-oil (W/O or G/O) type mini-emulsion droplets with a mean diameter of 300-500 nm were formed in this primary solution. This phenomenon can be theoretically presumed to occur because insulin and PLGA molecules, having amphiphilic properties, converge on the interface between the hydrophilic additive and dichloromethane. Hence, insulin molecules heterogeneously located in the inside of PLGA microcapsules, not on the surface, would be gradually released with PLGA hydrolytic decomposition. As an additional effect of glycerol, the initial burst was further suppressed due to the decrease of the glass transition temperature of PLGA from 42.5 to 36.7 degrees C. Since the annealing of PLGA molecules took place at around 37 degrees C, the porous structure of microspheres immediately disappeared after immersion in PBS or subcutaneous administration. The insulin diffusion through the water-filled pores would be effectively prevented. The strict controlled initial release of insulin from the PLGA microsphere suggested the possibility of utilization in insulin therapy for type I diabetic patients who need construction of a basal insulin profile.

Animals↗
PubMed2001

Marked hypotensive and blood flow-increasing effects of a new lipo-PGE(1) (lipo-AS013) due to vascular wall targeting.

Lipo-AS013 is being developed as an improved formulation of lipo-PGE(1), which is widely used in clinical practice in Japan and some Asian countries. We have previously reported that lipo-AS013, which is a lipid microsphere (LM) preparation of a chemically stable and lipophilic PGE(1) prodrug (AS013, Fig. 1), slowly releases small amounts of the active ingredient (AS013) in human plasma. In the present study, to estimate the vascular wall targeting ability and efficacy of lipo-AS013, we determined the hypotensive and blood flow-increasing effects of lipo-AS013, lipo-PGE(1), PGE(1)CD, and AS013. Lipo-AS013 was found to have longer-lasting hypotensive and blood flow-increasing effects than the other agents. The two LM preparations, lipo-PGE(1) and lipo-AS013, had a markedly stronger effect than PGE(1)CD and AS013 alone, demonstrating the benefit of drug delivery using LM. In spontaneously hypertensive rats (SHR), lipo-AS013 also had a significant hypotensive effect. To confirm vascular wall targeting by lipo-AS013, the localization of PGE(1) in the aorta and neovascular capillaries of rat was investigated by immunostaining. The results indicated that lipo-AS013 was more efficient at delivering the active ingredient (AS013) to the vessel wall. In conclusion, lipo-AS013 could supersede lipo-PGE(1) and PGE(1)CD in clinical use.

Alprostadil↗
PubMed2001

Clinical manifestations of influenza a myocarditis during the influenza epidemic of winter 1998-1999.

OBJECTIVES: The clinical features of myocarditis that developed during the influenza epidemic of winter 1998-1999 were investigated to emphasize the need for medical attention to this disease. METHODS: Nine patients were treated under diagnoses of acute myocarditis during the winter of 1998-1999. Five (two males and three females, mean age 52 +/- 18 years) were examined with myocarditis associated with influenza A. The diagnosis of influenza A myocarditis was based on electrocardiographic and echocardiographic abnormalities, increased creatine kinase levels and at least a four-fold increase in influenza A virus titers using paired sera. RESULTS: All patients had preceding flu-like symptoms and fever. Cardiac involvement developed between 4 and 7 days after the onset of influenza symptoms. Dyspnea progressively worsened in three patients, one went into shock and one had persistent fever, cough and mild dyspnea without apparent cardiac symptoms. Three patients had ST elevation associated with Q waves and one had complete left bundle branch block. The creatine kinase levels were abnormally increased and global wall motion of the left ventricle on echocardiography was decreased in all patients. Two patients had diagnoses of fulminant myocarditis. One patient died of pneumonia following cerebral infarction, but the left ventricular dysfunction normalized in the remaining four patients. CONCLUSIONS: Cardiac involvement occurred between 4 and 7 days after the onset of influenza symptoms, and worsening dyspnea was the most common symptom. Electrocardiography, echocardiography and creatine kinase levels should be checked to determine the potential for cardiac involvement when patients present with suspected influenza associated with worsening dyspnea or prolonged weakness. Increasing the awareness of influenza myocarditis may help in the earlier identification and treatment of this disease during influenza epidemics.

Adult↗
PubMed2000

Effect of a soluble pseudo-receptor on verotoxin 2-induced toxicity.

To neutralize the toxicity of verotoxin (VT) produced by Escherichia coli type O-157, a soluble pseudo-receptor (Lyso Gb3) was synthesized with the deacylated form of the natural receptor, globotrisylceramide (Galalpha 1-4Galbeta1-4-glucosylceramide; Gb3). In this study, we evaluated the characteristics and pharmacological effects of Lyso Gb3, using VT2. It was confirmed that Lyso Gb3 specifically recognized VT2. Lyso Gb3 itself had little influence on the in-vitro growth of Vero cells, but markedly augmented VT2-induced cytotoxicity. In addition, the VT2-induced killing of mice was not decreased, but was, rather, increased by Lyso Gb3. These results indicate that the soluble pseudo-receptor Lyso Gb3 recognized VT2. However, it did not reduce, but, rather, enhanced, VT2-induced toxicity in the presence of the natural receptor, although Lyso Gb3 alone had no toxicity.

Animals↗
PubMed2000

[Recurrent pulmonary embolism from left subclavian thrombosis: a case report].

A 38-year-old woman was admitted to our hospital because of pulmonary thromboembolism. Thrombolysis therapy resulted in initial improvement in symptoms and laboratory data. However, 4 months later, pulmonary thromboembolism recurred despite antiplatelet and anticoagulation therapy. Contrast venography and venous ultrasonography of both upper and lower extremities revealed subtotal occlusion and venous thrombosis of the left subclavian vein with collateral vessels, but no evidence of lower extremity venous thrombosis. She had no history of subclavian venous catheterization, neoplasm, hypercoagulability or other predisposing cause of thrombus formation. Operative ligation of the left subclavian vein was performed at the junction with the internal jugular vein. White thrombus was identified within the venous lumen. She was well without recurrent pulmonary thromboembolism or venous insufficiency for 10 months after the operation. Surgical interruption of the subclavian vein may be effective to prevent recurrent pulmonary thromboembolism in patients with recurrent pulmonary thromboembolism due to venous thrombosis of the upper extremity despite therapeutic anticoagulation.

Adult↗
PubMed1999

Endogenous calcitonin gene-related peptide suppresses vasoconstriction mediated by adrenergic nerves in rat mesenteric resistance blood vessels.

The role of perivascular calcitonin gene-related peptide (CGRP)-containing nerves in the modulation of adrenergic nerve-mediated vasoconstrictions was studied in the rat perfused mesenteric vascular bed. A frequency-dependent vasoconstriction induced by periarterial nerve stimulation (1-6 Hz) of the bed was significantly potentiated by perfusion of 1 microM CGRP-(8-37) (CGRP receptor antagonist) or to a similar extent after treatment with 500 nM capsaicin. In the preparations treated with capsaicin, CGRP-(8-37) caused a small potentiation of periarterial nerve stimulation-induced vasoconstriction. Exogenous CGRP (0.1-1 nM) concentration-dependently attenuated the augmented vasoconstriction in response to periarterial nerve stimulation after treatment with capsaicin. However, exogenous CGRP (1 nM) did not attenuate the periarterial nerve stimulation-induced vasoconstriction in the bed untreated with capsaicin. These results suggest that endogenous CGRP, which is released from CGRP-containing nerves, suppresses the adrenergic nerve function involved in mechanisms regulating the tone of resistant blood vessels.

Animals↗
PubMed1999

Differential hormonal profiles of adrenomedullin and proadrenomedullin N-terminal 20 peptide in patients with heart failure and effect of treatment on their plasma levels.

BACKGROUND: Adrenomedullin (AM) is a potent vasodilatory peptide discovered in human pheochromocytoma tissue. Proadrenomedullin N-terminal 20 peptide (PAMP) processed from an AM precursor is also a novel hypotensive peptide which inhibits catecholamine secretion from sympathetic nerve endings. HYPOTHESIS: The present study sought to examine the relationships between the two peptides and other clinical parameters by measuring the plasma AM and PAMP concentrations in 98 patients with heart failure. METHODS: In all, 98 patients [65 men and 33 women, aged 58.2 +/- 11.0 years, mean +/- standard deviation (SD)] with heart failure and 26 healthy volunteers (12 men and 14 women, aged 54.1 +/- 8.6 years) were examined in this study. Heart failure was secondary to previous myocardial infarction in 58 patients, valvular disease in 28, cardiomyopathy in 9, and congenital heart disease in 3. All patients were classified into two groups of class I or II (Group 1) and class III or IV (Group 2) according to the New York Heart Association (NYHA) functional classification. RESULTS: Both plasma AM and PAMP concentrations in the patients were significantly higher than those in healthy volunteers. In addition, plasma AM and PAMP concentrations in patients in class III or IV of New York Heart Association (NYHA) classification were significantly higher than those in NYHA class I or II. The elevated plasma concentrations of these peptides in patients in NYHA class III or IV significantly decreased in response to the treatment for 7 days. There was a significant correlation between plasma AM and PAMP, though the plasma concentration of PAMP was one-fifth to one-seventh of that of AM in patients and controls. The plasma AM concentration correlated significantly with the plasma concentrations of atrial and brain natriuretic peptides, epinephrine, and right atrial pressure, whereas such a relationship was not noted for the plasma PAMP concentration. CONCLUSIONS: Judging from the difference in not only the biological actions but also the hormonal profiles between AM and PAMP, they may differentially modulate the cardiovascular system in patients with heart failure, although they are processed from the same precursor.

Adrenomedullin↗
PubMed1999

Effect of lecithinized superoxide dismutase (PC-SOD) on experimental pulmonary metastasis in mice.

The inhibitory effect of lecithinized superoxide dismutase (PC-SOD) on pulmonary metastasis in mice was investigated. In an experimental pulmonary metastasis model employing Meth A-T cells, significant and dose-dependent inhibition was observed after i.v. pre-administration of PC-SOD. Unmodified SOD (U-SOD) was also effective, but a 10-times higher dose was necessary to be significant. The pulmonary accumulation of Meth A-T cells labeled with 5-[125I]iodo-2'-deoxyuridine was not reduced by either PC-SOD or U-SOD, and neither of the compounds decreased pulmonary MPO activity. However, PC-SOD increased pulmonary SOD activity for longer, compared with U-SOD. In vitro addition of PC-SOD dose-dependently suppressed the growth of Meth A-T cells, while U-SOD had little effect. The combination of PC-SOD and S-nitroso-N-acetyl-D,L-penicillamine (SNAP), a nitric oxide (NO)-generating agent, had an additive effect. It was also found that PC-SOD prevented a decrease of pulmonary NOx level following tumor cell inoculation. It was concluded that PC-SOD possessed antimetastatic activity, and its potency was superior to that of U-SOD. These results suggest that PC-SOD may prevent the excessive formation of oxygen radicals and peroxynitrite (ONOO-) which cause cell damage and facilitate tumor metastasis.

Animals↗
PubMed1999

[Neuronal control of mesenteric circulation].

The mesenteric circulation plays an important role in maintenance of systemic blood pressure and regulation of tissue blood flow. The tone of the mesenteric artery and resistance blood vessels are mainly regulated by sympathetic adrenergic nerves through the release of neurotransmitter noradrenaline and also controlled by nonadrenergic noncholinergic (NANC) nerves and possibly by parasympathetic cholinergic nerves. Noradrenaline and adrenergic cotransmitters including neuropeptide Y and adenosine triphosphate act as a vasoconstrictor neurotransmitter for sympathetic nerves. While, dopamine, calcitonin gene-related peptide and acetylcholine act as a vasodilator neurotransmitter for adrenergic, NANC and cholinergic nerves, respectively. In the mesenteric circulation, these nerves containing various neurotransmitters and cotransmitters interact and modulate each other via feedback autoregulatory mechanisms and neuromodulation of various vasoactive substance to regulate vascular resistance.

Animals↗
PubMed1999

Lipid microsphere preparation of a lipophilic ceramide derivative suppresses colony formation in a murine experimental pulmonary metastasis model.

Ceramide is a well-known regulator of apoptosis and cell growth. In this study, we synthesized lipophilic ceramide derivatives to incorporate into lipid microspheres (LM) and their activity was evaluated in vivo. Cera 03, a lipophilic ceramide derivative synthesized from membrane-permeable C2-ceramide, caused potent growth inhibition and DNA fragmentation of Meth A-T tumor cells in vitro. Its potency was similar to that of C2-ceramide. Both compounds increased the proportion of apoptotic cells. Cera 02, the diacetylated form of natural ceramide (Cer), also suppressed in vitro cell growth with a similar or higher potency to that of Cer, but both were far less potent than C2-ceramide and Cera 03. LM containing Cera 03 (Lipo-Cera 03) could not totally prevent metastatic incidence of Meth A-T cells, but reduced pulmonary metastatic nodules in number. Intravenous injection of Lipo-Cera 03 (1 mg/kg of Cera 03) produced about 35% inhibition, while Lipo-Cera 02 had no significant effect. In conclusion, Lipo-Cera 03 may have potential as an antimetastatic drug and may also be a useful tool for researching the role of ceramides in vivo.

Animals↗
PubMed1999

[One-hour protocol stress myocardial scintigraphy: prospective study of diagnostic accuracy for the detection of coronary artery stenosis].

A one-hour protocol for stress myocardial scintigraphy using technetium-99m-tetrofosmin (Tc-tetrofosmin) was compared with coronary arteriography for the detection of coronary artery stenosis in 90 consecutive patients without prior myocardial infarction, revascularization procedure or vasospastic angina. Tc-tetrofosmin stress myocardial scintigraphy acquired a rest image 20 min after intravenous administration of Tc-tetrofosmin (185 MBq, 1/5 vial) using a three-head gamma camera collecting 20-sec views over 360 degrees. The stress test using bicycle ergometer was performed and administration of Tc-tetrofosmin (740 MBq, 4/5 vial) was repeated at the peak stress point. The stress image was acquired 15 min after the second injection with 5-sec views over 360 degrees. Coronary arteriography revealed the presence of significant coronary artery stenosis (> 75%) in 56 vessels of 45 patients, including 35 patients with single-vessel disease, 5 with two-vessel disease, 2 with three-vessel disease, and 3 with left main trunk disease. The overall sensitivity and specificity for the detection of coronary artery disease by visual analysis were 91.1% and 77.8%, respectively, and by quantitative analyses (using bull's-eye method) were 95.6% and 91.1%, respectively. The individual stenotic vessel sensitivities in the right coronary artery, left anterior descending artery, and left circumflex artery were 84.6%, 90.9%, and 78.6%, respectively. The specificities were 97.3%, 95.9%, and 100.0%, respectively. These results suggest that stress myocardial scintigraphy using the present new protocol is a promising approach for the detection of coronary artery stenosis.

Angina Pectoris↗
PubMed1998

Microparticle resins as a potential nasal drug delivery system for insulin.

The application of various resins for the nasal delivery of insulin was examined in rabbits. Intranasal administration of human insulin (28 U, 1 mg) mixed with fractionated sodium polystyrene sulfonate powder (an anionic resin with a particle size of 20-45 microns) caused a rapid increase of the plasma insulin level 413.0 +/- 71.7 microU/ml (mean +/- S.D.) after 15 min, while intranasal administration of insulin alone caused little increase. The blood glucose level decreased from 118.8 +/- 18.5 mg/dl to 65.8 +/- 13.8 mg/dl at 45 min after administration. These results were superior to those obtained with the unfractionated resin. Styrene-divinylbenzene copolymer (a nonionic resin; 20-45 microns fraction) showed similar enhancement of nasal insulin absorption. In contrast, polyacrylester (a nonionic resin; 20-45 microns fraction) and cholestyramine (a cationic resin) did not promote insulin absorption. These results suggest that some resins may be useful for nasal delivery of insulin.

Administration, Intranasal↗
PubMed1998

Magnetic resonance imaging of Bland-White-Garland syndrome--a case of anomalous origin of the left coronary artery from the pulmonary trunk in a 22-year-old woman.

Selective right coronary angiography in a 22-year-old woman demonstrated an enormous right coronary artery, with the contrast medium opacifying to the left coronary artery through a well-developed collateral circulation and draining into the pulmonary artery. The diagnosis of anomalous origin of the left coronary artery from the pulmonary trunk [also known as Bland-White-Garland (BWG) syndrome] was thus established. Magnetic resonance imaging (MRI) showed a dilated right coronary artery arising from the aorta, the left coronary artery from the pulmonary trunk but not from the aorta, and well-developed channels in the interventricular septum. MRI could be a useful tool for diagnosing anomalous origin of the left coronary artery from the pulmonary trunk.

Coronary Vessel Anomalies↗
PubMed1998

Effect of pacing rate in pacing therapy in hypertrophic obstructive cardiomyopathy.

The effects of dual-chamber pacing therapy in patients with hypertrophic obstructive cardiomyopathy (HOCM) have been reported in short- and long-term studies. Almost all of these studies have reported that the key factor in pacing therapy is the setting of the atrioventricular (AV) interval. However, studies focusing on the effects of pacing rate on the hemodynamic state are rare. In this study, cardiac catheterization was performed in 2 patients during temporary pacing at various rates and AV intervals. When the pacing rate was increased slightly (to 70-90/min), AV sequential pacing decreased peak subaortic pressure gradient and increased systolic aortic pressure without increase in pulmonary capillary wedge pressure, left ventricular end-diastolic pressure, and the time constant of isovolumetric relaxation. In another case, of a patient who became refractory to AV sequential pacing therapy at an optimum AV interval, pacing at a slightly higher rate relieved syncope. Thus, AV sequential pacing therapy performed at a slightly higher rate than normal in a patient with HOCM may lead to a decreased subaortic pressure gradient and relief of symptoms without noticeable deterioration in cardiac function.

Adult↗
PubMed1998

Angiotensin inhibits neurotransmission of calcitonin gene-related peptide-containing vasodilator nerves in mesenteric artery of spontaneously hypertensive rats.

The role of angiotensin (Ang) in neurotransmission of calcitonin gene-related peptide (CGRP)-containing vasodilator nerves in perfused mesenteric vascular beds isolated from spontaneously hypertensive rats (SHR) (8- and 15-week-old) and age-matched Wistar Kyoto rats (WKY) was investigated. In both SHR and WKY preparations precontracted by continuous perfusion of Krebs' solution containing 7 microM methoxamine plus 5 microM guanethidine, periarterial nerve stimulation (PNS; 1 and 2 Hz) produced a frequency-dependent vasodilation, which was abolished by 100 nM tetrodotoxin and 500 nM CGRP(8-37) (CGRP receptor antagonist). The PNS-induced vasodilation in the SHR decreased with age and was smaller than that in the WKY. The neurogenic vasodilation in the SHR but not WKY was significantly inhibited by N-acetyltetradecapeptide renin substrate (RS, 100 and 500 nM), AngI (50 and 100 nM) and AngII (50 and 100 nM). The inhibitory effects of RS, AngI and AngII were abolished by the AngII receptor antagonist, [Sar1,Ile8]AngII (500 nM). The effect of RS and AngI was inhibited by captopril (5 microM) and temocapril (500 nM). AngII (100 nM) had no effect on vasodilator response to exogenously infused CGRP (100 pmol). PNS (2 Hz) of perfused mesenteric vascular beds increased the release of CGRP-like immunoreactivities (CGRP-LI) in the perfusate, which was less in 15-week-old SHR than in age-matched WKY. AngII (100 nM) significantly inhibited the neurogenic release of CGRP-LI in the SHR but not in the WKY. These results suggest that exogenous and locally converted AngII, via AngII receptors, modulates the neurotransmission of CGRP-containing vasodilator nerves by inhibiting CGRP release from the nerve.

Angiotensin I↗