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Biomedical subjects

Hirohisa Horinouchi

Publications and source records attributed to Hirohisa Horinouchi.

At least 19 recordsLinked to original sources
PubMed2006

PEGylated albumin-heme as an oxygen-carrying plasma expander: Exchange transfusion into acute anemia rat model.

Poly(ethylene glycol) (PEG) conjugated recombinant human serum albumin (HSA) incorporating the synthetic iron-porphyrin (FeP) [PEGylated albumin-heme, PEG(HSA-FeP)] is a unique albumin-based oxygen carrier as a red blood cell (RBC) substitute. The physiological responses to an exchange transfusion with PEG(HSA-FeP) into an acute anemia rat model were investigated. After a 65% isovolemic hemodilution with HSA, a 30% volume of the circulatory blood was withdrawn, affording a hemorrhaged state. The circulation parameters, blood parameters, renal cortical oxygen partial pressure [PtO(2)(R)], and muscle tissue oxygen partial pressure [PtO(2)(M)] were continuously monitored. The intravenous infusion of PEG(HSA-FeP) restored the reduced levels of the mean arterial pressure, heart rate, respiration rate, mixed venous PO(2), and arterial PCO(2). The increased arterial PO(2) and pH also returned to their basal values. These effects were almost to the same extent as those observed after the administration of the RBC suspension. The relatively low recovery in PtO(2)(R) and PtO(2)(M) might be due to the Langmuir-type oxygen binding profile of PEG(HSA-FeP) (Hill coefficient: 1.0). All the animals survived during the experiments. In contrast, those injected with HSA died within 41 min. The PEG(HSA-FeP) solution is an oxygen-carrying plasma expander which can be used as a resuscitative fluid for hemorrhagic shock.

Acute Disease↗
PubMed2006

Early pulmonary resection for Mycobacterium avium complex lung disease treated with macrolides and quinolones.

BACKGROUND: The purpose of this study was to examine the postoperative outcomes of patients with Mycobacterium avium complex (MAC) lung lesions persisting despite treatment with multiple antibiotics. METHODS: Patients with localized pulmonary lesions persisting despite extensive state-of-the art antimicrobial chemotherapy became candidates for surgical resection. Twenty-two patients who were expected to retain sufficient postoperative pulmonary function were included in this study. These patients received chemotherapy for 2 to 37 months (mean, 17). Surgical procedures were lobectomy (n = 15), segmentectomy (n = 4), and partial lung resection (n = 6). Three patients underwent bilateral resections. RESULTS: Mycobacterium avium complex causing bronchiectasis or cavitary lesions was detected preoperatively in all 22 patients. There was no major operative morbidity or mortality. Postoperative chemotherapy was continued for 6 to 35 months. All patients were alive and well at follow-ups ranging from 6 to 164 months (median, 46). Both vital capacity and forced expiratory volume in 1 second after surgery were maintained at 89% and 84% of the preoperative values, respectively. Mycobacterium avium complex disappeared from sputum after surgery in all patients. In 1 patient, 4 months after resection of a cavitary lesion, MAC-positive sputum presumed to be from the contralateral lung lesion became negative during continuation of chemotherapy. CONCLUSIONS: The long-term outcomes of patients operated on for MAC resistant to antimicrobial chemotherapy were excellent. For such patients, we recommend surgery before the disease becomes exceedingly advanced and nonresectable. Additionally, in extensive disease, the excision of large cavitary bacterial foci may assist the medical management of contralateral lesions.

Adult↗
PubMed2006

Hemoglobin-vesicles as a transfusion alternative.

Phospholipid vesicles or liposomes encapsulating purified and concentrated human hemoglobin (Hb-vesicle, HbV) have been developed as a transfusion alternative. They are void of blood-type antigens and infectious viruses; they are stable and suitable for long-term storage. The cellular structure of HbV (particle diameter, ca. 250 nm) prevents direct contact of Hb with the blood components and the endothelial lining shielding cells from the side effects of Hb molecules. Microcirculatory observations show that the cellular structure of HbV is important to control reactions with endothelium-derived vasorelaxation factors. Animal studies of extreme hemodilution and resuscitation from hemorrhagic shock attest to the sufficient oxygen transporting capacity of HbV. Studies of biodistribution and metabolism reveal that HbVs are captured eventually in the reticuloendothelial system, and degraded within one week. In a joint collaboration partnership of academia, a biotech venture company and a corporation, we plan to produce HbV with good manufacturing practices, and to start preclinical and, finally, clinical trials within a few years.

Animals↗
PubMed2006

Acute 40 percent exchange-transfusion with hemoglobin-vesicles (HbV) suspended in recombinant human serum albumin solution: degradation of HbV and erythropoiesis in a rat spleen for 2 weeks.

BACKGROUND: Hemoglobin-vesicles (HbVs; diameter, 251 +/- 81 nm) are artificial O(2) carriers. Their efficacy for acute exchange transfusion has been characterized in animal models. However subsequent profiles of recovery involving the degradation of HbV in the reticuloendothelial system (RES) and hematopoiesis remain unknown. STUDY DESIGN AND METHODS: Isovolemic 40 percent exchange transfusion was performed in 60 male Wistar rats with HbV suspended in 5 g per dL recombinant human serum albumin (rHSA; HbV/rHSA, [Hb] = 8.6 g/dL), stored rat RBCs suspended in rHSA (sRBC/rHSA), or rHSA alone. Hematological and plasma biochemical analyses and histopathological examination focusing on the spleen were conducted for the subsequent 14 days. RESULTS: The reduced hematocrit (Hct) level (26%) for the HbV/rHSA and rHSA groups returned to its original level (43%) in 7 days. Plasma erythropoietin was elevated in all groups: the rHSA group showed the highest value on Day 1 (321 +/- 123 mIU/mL) relating to the anemic conditions (HbV/rHSA, 153 +/- 22; sRBC/rHSA, 63 +/- 7; baseline, 21 +/- 3). Simultaneously, splenomegaly occurred in all the groups as HbV/rHSA > rHSA > sRBC/rHSA. Histopathologically, the accumulated HbV in the spleen was undetectable by Day 14, but hemosiderin was deposited in slight quantities for both the HbV/rHSA and sRBC/rHSA groups. Considerable amounts of erythroblasts were apparent in the spleens of both the rHSA and the HbV/rHSA groups. CONCLUSION: HbVs were phagocytized and degraded in RES, a physiological compartment for the degradation of RBCs, and the elevated erythropoietic activity resulted in the complete recovery of Hct within 7 days in the rat model.

Animals↗
PubMed2006

Fluid resuscitation with hemoglobin-vesicle solution does not increase hypoxia or inflammatory responses in moderate hemorrhagic shock.

The aim of the present study was to compare the hypoxic and inflammatory effects of transfusing hemoglobin-vesicles (HbV) or lactated Ringer's (LR) solution on several organs in a hemorrhagic shock model. Hemorrhagic shock was induced in 48 anesthetized rats by withdrawing 28 mL/kg blood. The animals were resuscitated by replacing the blood with an equal volume of HbV solution or three times the volume of LR solution. The heart, lung, liver, kidney and spleen were extracted at different time points following resuscitation, and mRNA expression levels of hypoxia-induced factor 1-alpha (HIF-1alpha) and tumor necrosis factor-alpha (TNF-alpha) were determined. Blood lactate concentrations in the HbV group rapidly returned to baseline levels, whereas elevated lactate concentrations in the LR group were prolonged. There were no significant differences between the two resuscitation groups in terms of HIF-1alpha and TNF-alpha expression in the organs examined. HIF-1alpha and TNF-alpha expression in the lungs was significantly greater than in other organs. Our results suggest that resuscitation from hemorrhagic shock with HbV did not increase hypoxic or inflammatory effects in major organs, compared with resuscitation using LR solution, despite prolonged elevation of blood lactate.

Animals↗
PubMed2006

[Prognosis of surgically treated thymic epithelial tumors].

This study was performed to clarify the prognosis of patients with surgically treated thymic epithelial tumors. The records of 131 patients who underwent surgical treatment during 1985-2005 were retrospectively reviewed. Pathologic review was done according to the WHO classification of tumors of the thymus. Patients characteristics were: 76 male and 55 fimale; average age 53 (range 20-80) years; tumor stage was stage I in 42, stage II in 43, stage III in 23, stage IVa in 15, stage IVb in 1, and thymic carcinoma (squamous cell carcinoma) in 7 based on Masaoka's staging. There were 7 cases of type A, 23 of type AB, 30 of type B1, 27 of type B2, 29 of type B3, and 15 of type C. Surgical procedures performed were 5 partial resections, 5 tumoretomies, 5 thymectomies, 65 extended thymectomies, 4 tumorectomies plus adjunctive resections of surrounding tissue, and 51 extended thymectomies plus tumorectomies plus adjunctive resections of surrounding tissue including the pleura, pericardium, lung, and great vessels. Five-, 10-, and 15-year survival rates by Masaoka stage were 100%, 100%, and 100% in stage I; 100%, 100%, and 87.5% in stage II; 100%, 87.5%, and 87.5% in stage III; 71.1%, 53.3%, and 53.3% in stage IVa; and 42.9%, 42.9%, and 0% in thymic carcinoma. The prognosis of patients with stage IVa and thymic carcinoma was thus significantly poorer compared with that in the other groups. According to the WHO classification, the 5-year survival rate of type A was 100%, and the 5-, 10-, and 15-year survival rates were 100%, 100%, and 100% in type AB; 100%, 100%, and 75.0% in type B1; 92.6%, 86.4%, and 86.4% in type B2; 95.5%, 95.5%, and 81.8% in type B3; and 57.1%, 42.9%, and 0% in type C. The survival rate of patients with type C was the poorest and there was a significant difference between type C and all other groups. The prognosis of patients with thymic epithelial tumors after resection is thought to be determined by histologic classification and clinical invasiveness. In particular, patients with type B3 and type C thymomas should be considered for multidisciplinary treatment.

Adult↗
PubMed2005

The sealing effect of fibrin glue against alveolar air leakage evaluated up to 48 h; comparison between different methods of application.

OBJECTIVE: There is little experimental evidence to show how much positive airway pressure fibrin sealants can actually withstand, and in particular, how this effect changes over time. In the present study, we experimentally evaluated the sealing effect of fibrin glue against alveolar air leakage up to 48 h after application. METHODS: Beagles were used (n = 48). Under thoracotomy, approximately 5 x 10 mm defects (2 mm depth) were made on the lung surface. Fibrin glue sealants were applied to this defect in three ways. In rubbing and spray method, fibrinogen was rubbed, followed by spraying of both fibrinogen and thrombin solutions. In double layer method, fibrinogen was dripped, followed by thrombin. Collagen fleece, coated with fibrinogen and thrombin (TachoComb) was also tested. The minimum positive airway pressure which produced air leakage was measured for each sealed defect (seal breaking pressure, cmH2O) at 0, 3, 6, 12, 24, and 48 h after application (n = 6 at each time point). RESULTS: The seal-breaking pressure increased over time in all of the application methods. At 6 h, differences between methods were not significant but three defects in RS reached 70 cmH2O, the maximum pressure tested, compared with none in other two methods. At 12h, the seal-breaking pressure was significantly higher in RS compared with the other two methods (rubbing and spray method vs TachoComb; 66+/-3 vs 47+/-17, P = 0.047, rubbing and spray method vs double layer method; 66+/-3 vs 42+/-18, P = 0.024). Beyond 24 h, sealing pressure reached close to 70 cmH2O in all the methods. CONCLUSIONS: The results show that the sealing effect of fibrin glue is relatively unstable up to 12h after its application. Rubbing and spray method may help the fibrin seal to reach its full strength faster compared with the other two methods.

Aerosols↗
PubMed2004

Exchange transfusion with synthetic oxygen-carrying plasma protein "albumin-heme" into an acute anemia rat model after seventy-percent hemodilution.

Recombinant human serum albumin (rHSA) incorporating the synthetic heme "albumin-heme" is an oxygen-carrying plasma protein that has the potential to be a red blood cell substitute. The physiological responses to a 30% exchange transfusion with two types of albumin-heme (rHSA-FecycP, rHSA-FepivP) solutions after 70% isovolemic hemodilution with 5 g/dL rHSA were investigated using anesthetized rats. The circulation parameters, blood parameters, renal cortical oxygen pressure (pO2), and muscle tissue pO2 were carefully monitored for 60 min after the injection. The declined mean arterial pressure and the mixed venous partial pO2 significantly recovered to 70.8 and 91.9% of the basal values by intravenous infusion of albumin-hemes, respectively. The lowered renal cortical pO2 also increased, indicating oxygen transport by this synthetic hemoprotein. The administration of albumin-heme into the acute anemia rat model after hemorrhage improved the circulatory volume and resuscitated the shock state. Both rHSA-FecycP and rHSA-FepivP transported oxygen through the body.

Anemia↗
PubMed2004

Exchange transfusion with entirely synthetic red-cell substitute albumin-heme into rats: physiological responses and blood biochemical tests.

Recombinant human serum albumin (rHSA) incorporating 2-[8-[N-(2-methylimidazolyl)]octanoyloxymethyl]-5,10,15,20-[tetrakis[alpha,alpha,alpha,alpha-o-(1-methylcyclohexanoyl)amino]phenyl]porphinatoiron(II) [albumin-heme (rHSA-heme)] is an artificial hemoprotein which has the capability to transport O(2) in vitro and in vivo. A 20% exchange transfusion with rHSA-heme into anesthetized rats has been performed to evaluate its clinical safety by monitoring the circulation parameters and blood parameters for 6 h after the infusion. Time course changes in all parameters essentially showed the same features as those of the control group (without infusion) and rHSA group (with administration of the same amount of rHSA). Blood biochemical tests of the withdrawn plasma at 6 h after the exchange transfusion have also been carried out. No significant difference was found between the rHSA-heme and rHSA groups, suggesting the initial clinical safety of this entirely synthetic O(2)-carrier as a red-cell substitute.

Albumins↗
PubMed2004

Physiological capacity of the reticuloendothelial system for the degradation of hemoglobin vesicles (artificial oxygen carriers) after massive intravenous doses by daily repeated infusions for 14 days.

A hemoglobin vesicle (HbV; diameter 252 +/- 53 nm) or liposome-encapsulated Hb is an artificial oxygen carrier developed for use as a transfusion alternative, and its oxygen-transporting capacity has been well characterized, although critical physiological compartments for the Hb degradation after a massive infusion of HbV and the safety outcome remain unknown. In this study, we aimed to examine the compartments for its degradation by daily repeated infusions (DRI) of HbV, focusing on its influence on the reticuloendothelial system (RES). Male Wistar rats intravenously received the HbV suspension at 10 ml/kg/day for 14 consecutive days. The cumulative infusion volume (140 ml/kg) was equal to 2.5 times the whole blood volume (56 ml/kg). The animals tolerated the DRI well and survived, and body weights continuously increased. One day after DRI, hepatosplenomegaly occurred significantly through the accumulation of large amounts of HbV. Plasma clinical chemistry was overall normal, except for a transient elevation of lipid components derived from HbV. These symptoms subsided 14 days after DRI. Hemosiderin deposition and up-regulation of heme oxygenase-1 coincided in the liver and spleen but were not evident in the parenchyma of these organs. Furthermore, the plasma iron and bilirubin levels remained unchanged, suggesting that the heme-degrading capacity of the RES did not surpass the ability to eliminate bilirubin. In conclusion, phospholipid vesicles for the encapsulation of Hb would be beneficial for heme detoxification through their preferential delivery to the RES, a physiological compartment for degradation of senescent RBCs, even at doses greater than putative clinical doses.

Animals↗
PubMed2004

Metabolism of hemoglobin-vesicles (artificial oxygen carriers) and their influence on organ functions in a rat model.

Phospholipid vesicles encapsulating Hb (Hb-vesicles: HbV) have been developed for use as artificial O(2) carriers (250 nm phi). As one of the safety evaluations, we analyzed the influence of HbV on the organ functions by laboratory tests of plasma on a total of 29 analytes. The HbV suspension ([Hb]=10 g/dl) was intravenously infused into male Wistar rats (20 ml/kg; whole blood = 56 ml/kg). The blood was withdrawn at 8h, and 1, 2, 3, and 7 days after infusion, and the plasma was ultracentrifuged to remove HbV in order to avoid its interference effect on the analytes. Enzyme concentrations, AST, ALT, ALP, and LAP showed significant, but minor changes, and did not show a sign of a deteriorative damage to the liver that was one of the main organs for the HbV entrapment and the succeeding metabolism. The amylase and lipase activities showed reversible changes, however, there was no morphological changes in pancreas. Plasma bilirubin and iron did not increase in spite of the fact that a large amount of Hb was metabolized in the macrophages. Cholesterols, phospholipids, and beta-lipoprotein transiently increased showing the maximum at 1 or 2 days, and returned to the control level at 7 days. They should be derived from the membrane components of HbV that are liberated from macrophages entrapping HbV. Together with the previous report of the prompt metabolism of HbV in the reticuloendothelial system by histopathological examination, it can be concluded that HbV infusion transiently modified the values of the analytes without any irreversible damage to the corresponding organs at the bolus infusion rate of 20 ml/kg.

Animals↗
PubMed2004

Hemoglobin-vesicles suspended in recombinant human serum albumin for resuscitation from hemorrhagic shock in anesthetized rats.

OBJECTIVE: Hemoglobin-vesicle (HbV) has been developed to provide oxygen-carrying ability to plasma expanders. Its ability to restore the systemic condition after hemorrhagic shock was evaluated in anesthetized Wistar rats for 6 hrs after resuscitation. The HbV was suspended in 5 g/dL recombinant human serum albumin (HbV/rHSA) at an Hb concentration of 8.6 g/dL. DESIGN: Prospective, randomized, controlled trial. SETTING: Department of Surgery, School of Medicine, Keio University. SUBJECTS: Forty male Wistar rats. INTERVENTIONS: The rats were anesthetized with 1.5% sevoflurane inhalation throughout the experiment. Polyethylene catheters were introduced through the right jugular vein into the right atrium for infusion and into the right common carotid artery for blood withdrawal and mean arterial pressure monitoring. MEASUREMENTS AND MAIN RESULTS: Shock was induced by 50% blood withdrawal. The rats showed hypotension (mean arterial pressure = 32 +/- 10 mm Hg) and significant metabolic acidosis and hyperventilation. After 15 mins, they received HbV/rHSA, shed autologous blood (SAB), washed homologous red blood cells (wRBC) suspended in rHSA (wRBC/rHSA, [Hb] = 8.6 g/dL), or rHSA alone. The HbV/rHSA group restored mean arterial pressure to 93 +/- 8 mm Hg at 1 hr, similar to the SAB group (92 +/- 9 mm Hg), which was significantly higher compared with the rHSA (74 +/- 9 mm Hg) and wRBC/rHSA (79 +/- 8 mm Hg) groups. There was no remarkable difference in the blood gas variables between the resuscitated groups; however, two of eight rats in the rHSA group died before 6 hrs. After 6 hrs, the rHSA group showed significant ischemic changes in the right cerebral hemisphere relating to the ligation of the right carotid artery followed by cannulation, whereas the HbV/rHSA, SAB, and wRBC/rHSA groups showed less changes. CONCLUSIONS: HbV suspended in recombinant human serum albumin provides restoration from hemorrhagic shock that is comparable with that using shed autologous blood.

Anesthesia↗
PubMed2003

Oxygenation of hypoxic region in solid tumor by administration of human serum albumin incorporating synthetic hemes.

Recombinant human serum albumin incorporating synthetic heme (rHSA-FeP) was tested for its ability to increase O(2) tension in the hypoxia of the solid tumor rat model. By the direct administration of the rHSA-FeP solution (10 mL/kg) via the aorta descendens to the ascites hepatoma LY80 tumor on the right femur, the O(2) tension of the hypoxic region immediately increased to 3.45 +/- 1.43 Torr, which corresponds to a 2.4-fold increase compared to that of the baseline value. These high O(2) levels continued for 300 s after the infusion. The rHSA-FeP solution can be utilized not only as a red blood cell substitute but also as an O(2)-carrying medicine for the effective reoxygenation of the hypoxia solid tumor.

Animals↗
PubMed2003

Phase II clinical study of photodynamic therapy using mono-L-aspartyl chlorin e6 and diode laser for early superficial squamous cell carcinoma of the lung.

Photofrin is the most commonly used photosensitizer for photodynamic therapy (PDT). The major side effect of Photofrin is cutaneous photosensitivity. A second generation photosensitizer, mono-L-aspartyl chlorin e6 (NPe6) has shown anti-tumor efficacy and rapid clearance from skin. Therefore, we conducted a phase II clinical study to investigate the anti-tumor effects and safety of NPe6 in patients with early superficial squamous cell carcinoma of the lung. Enrollment criteria consisted of endoscopically evaluated early stage lung cancer with normal chest X-ray and CT images, no lymph node or distant metastasis. Tumors were located no more peripherally than subsegmental bronchi, the peripheral margin had to visible, and the tumor size had to not more than 2 cm in diameter. The histologic type of the tumor had to squamous cell carcinoma. Laser irradiation (100 J/cm2) using a diode laser was performed at 4 h after administration of NPe6 (40 mg/m2). Among 41 patients with 46 lesions, 40 with 45 lesions were eligible for safety evaluation, and 35 patients with 39 lesions were judged as eligible for efficacy evaluation. No serious adverse drug reactions were observed. Disappearance of skin photosensitivity was recognized within 2 weeks in 28 of 33 patients (84.8%) and in all the other seven patients first tested at 15-18 days. Complete response (CR) was seen in 84.6% of lesions (82.9% of patients). This study demonstrated excellent anti-tumor effects and safety, especially low skin photosensitivity in patients with early stage lung cancer. PDT using the second generation photosensitizer NPe6 and a diode laser will likely become a standard modality of PDT for central type early superficial squamous cell carcinoma of the lung.

Aged↗
PubMed2003

Respiratory flow in a realistic tracheostenosis model.

The possible mechanism of wheeze generation in tracheostenosis was identified by measuring inspiratory and expiratory flow in a "morphological and distensible" realistic tracheostenosis model. The shape of the model was based on CT (Computed Tomography) images of a patient that had tracheostenosis. A trachea consists of tracheal cartilage rings and smooth muscle. Spatial variation of wall distensibility was achieved in the model by varying the wall thickness based on the elastic modulus measured in pig airways. The spatial variation influenced the flow in the airway and the turbulence production rate decreased faster at smooth muscles. Using the model, we investigated the mechanism of wheeze generation by focusing on the turbulence intensity. The turbulence intensity in expiratory flow was about twice that in inspiratory flow, and larger vortices existed in post-stenosis in expiratory flow, and thus might contribute to wheeze generation.

Animals↗
PubMed2003

Pretreatment of serum containing hemoglobin vesicles (oxygen carriers) to prevent their interference in laboratory tests.

Hemoglobin vesicles (HbV, diameter: 251 +/- 81 nm) are artificial oxygen (O2) carriers encapsulating concentrated hemoglobin (Hb) solution with phospholipid bilayer membrane, and their O2 transporting ability in vivo has been extensively studied. It is important to clarify the interference of the HbV suspension in clinical laboratory tests performed on serum and to establish a pretreatment method to avoid such an interference. The HbV suspension, acellular Hb solution ([Hb] = 10 g/dl) or saline, was mixed with a pooled human serum at various ratios up to 50 vol% ([Hb] = 5 g/dl), and the magnitude of the interference effect of HbV and Hb on 30 analytes was studied. The mixture of the HbV suspension and serum was ultracentrifuged (50,000 g, 20 min) to remove the HbV particles as precipitate, and the supernatant was analyzed and compared with the saline control group. The HbV particles were also removed by centrifugation (2,700 g, 30 min) in the presence of dextran (Mw 200 kDa). The HbV suspension showed considerable interference effects in most analytes. The majority of these effects was more serious than those of the acellular Hb solution. These findings are thought to be due to the light absorption of Hb in HbV and/or the light scattering generated in the suspension that interferes with the colorimetric and turbidimetric measurements. The components of HbV may also interfere with the chemical reactions of the studied assays. However, removal of the HbV from the supernatant diminished the interference in most of the assays: this is an advantage of HbV in comparison with acellular chemically modified Hb solutions.

Blood Substitutes↗