Intestinal Complication With Myxomatous Mitral Valve Diseases in Chihuahuas.

The effects of cardiac disease on the intestine have been reported in humans but not in dogs. We investigated the effects of myxomatous mitral valve disease (MMVD), which is capable of causing congestion and tissue hypoperfusion, on the intestine in Chihuahuas, a breed frequently encountered in clinical practice as the preferred breed for MMVD. In this study, 69 Chihuahuas were divided into four groups based on echocardiography and chest radiography: 19 healthy Chihuahuas (H) and 50 Chihuahuas with MMVD classified according to the ACVIM consensus (stage B1, B2, C/D). In all the cases, serum intestinal fatty acid-binding protein (I-FABP) and D/L-lactate concentrations, markers of intestinal mucosal injury, were measured. I-FABP was significantly higher in stage C/D Chihuahuas than in other groups (p < 0.05), and stage B2 was significantly higher than H (p < 0.05). D-lactate was significantly increased in stages B2 and C/D compared to H and stage B1 (p < 0.05). L-lactate was significantly higher in stage C/D Chihuahuas than in any other group (p < 0.05), and stage B2 was significantly higher than that in H and stage B1 (p < 0.05). Intestinal mucosal injury risk was significantly higher in Chihuahuas with heart failure due to MMVD, suggesting that the risk could increase with worsening heart disease. This is the first study to investigate the intestinal complications of MMVD, and further investigations a needed in the future.

Safety profile of vonoprazan compared with proton pump inhibitors: insight from a pharmacovigilance study.

Proton pump inhibitors (PPIs) are used to treat acid-related disorders such as peptic ulcer and gastroesophageal reflux disease. Recently, vonoprazan, a novel potassium-competitive acid blocker (P-CAB), has been introduced as more effective treatment option. The purpose of this study was to clarify the adverse events associated with vonoprazan compared to PPIs using a spontaneous reporting system database. We performed a retrospective pharmacovigilance disproportionality analysis using the Japanese Adverse Drug Event Report (JADER) database. Adverse event reports submitted to the Pharmaceuticals and Medical Devices Agency between 2004 and 2017 were analyzed, and the reporting odds ratio (ROR) and 95% confidence interval (CI) for each adverse event were calculated. The database comprised 11,433 reports associated with PPIs, and 636 reports with vonoprazan. Hepatic and skin disorders were commonly detected in both PPIs and vonoprazan. There was a significant association of interstitial lung disease with PPIs as a class (ROR: 1.61, 95%CI: 1.47-1.77), but not with vonoprazan. Vonoprazan was strongly associated with haemorrhagic enterocolitis (ROR, 86.5; 95%CI, 59.7125). Among the PPIs, the signal score of microscopic colitis was noteworthy in the case of lansoprazole (ROR, 405; 95%CI, 348-472). It is suggested that there is a diversity in the strength of the association between PPIs and vonoprazan with adverse events. Our results may provide useful information for the treatment of acid-related disorders, but further research with more data is needed to finally clarify this.

Evaluation of adverse events associated with filgrastim originator and biosimilar using a spontaneous reporting system database.

Biosimilar products of filgrastim have become available for improved sustainability of cancer care; however, the real-world safety profile remains unknown. The purpose of this study was to clarify the adverse events associated with filgrastim originator and its biosimilar using the Japanese Adverse Drug Event Report (JADER) database. Adverse event reports submitted to the Pharmaceuticals and Medical Devices Agency between 2014-2018 were extracted. We calculated the reporting odds ratio and 95% confidence interval for each adverse event. We obtained 584 reports of adverse events associated with filgrastim originator and 102 reports with its biosimilar. Signals were detected for bone marrow failure and febrile neutropenia with both filgrastim originator and its biosimilar; whereas those for drug resistance and hypoxia only involved filgrastim originator, and those for interstitial lung disease only involved its biosimilar. The safety profiles of filgrastim originator and its biosimilar were partly different. Further studies are needed to confirm these findings.

Surgical correction for sinus venosus atrial septal defect with partial anomalous pulmonary venous connection in a dog.

A 5-year-old male toy poodle was referred for corrective surgery of an atrial septal defect. A sinus venosus-type atrial septal defect (ASD) with partial anomalous venous connection, suspected pulmonary hypertension, and pulmonary edema was confirmed by radiography, echocardiography, and cardiac computed tomography. Thoracic radiographs showed right heart enlargement. Echocardiography revealed right atrial and ventricular dilatation with mild flattening of the interventricular septum. Left-to-right shunt flow through the ASD was observed on color Doppler examination. Surgical correction of the sinus venosus ASD with a partial anomalous pulmonary venous connection was performed under cardiopulmonary bypass. A follow-up evaluation at 1 year after surgery showed resolution of the right-sided volume overload and no evidence of recurrence of ASD. Complications were not observed. Our findings indicate that surgical correction under cardiopulmonary bypass is a valid treatment option for an ASD with a partial anomalous pulmonary venous connection.

Maxillary single-jaw surgery combining Le Fort I and modified horseshoe osteotomies for the correction of maxillary excess.

A modified technique of horseshoe osteotomy combined with Le Fort I osteotomy for superior and posterior repositioning of the maxilla is presented. Eight patients with maxillary excess associated with retrogenia or microgenia were treated with this technique in combination with genioplasty. The maxillary segment was repositioned a maximum of 5.0mm posteriorly and 7.0mm superiorly at point A. The mandible autorotated anterosuperiorly to achieve sound occlusion. Point B moved 2.0-10.0mm anteriorly and 5.0-10.0mm superiorly. The pogonion moved 7.0-17.0mm anteriorly in combination with genioplasty. All patients obtained sound occlusion and a good profile after the operation. Almost no skeletal relapse was observed during 1 year of postoperative follow-up. Patients with long faces with maxillary excess and retrogenia often have small, unstable condyles. In these cases, because surgical intervention to the ramus can result in postoperative progressive condylar resorption, maxillary single-jaw surgery with a horseshoe osteotomy, thereby avoiding ramus intervention, is a less invasive option.

Response to thyrotropin-releasing hormone stimulation tests in preterm infants with transient hypothyroxinemia of prematurity.

OBJECTIVE: Whether hormone supplementation is necessary for infants with transient hypothyroxinemia of prematurity (THOP) remains controversial, and further analysis of the hypothalamus-pituitary-thyroid axis of infants with THOP is necessary. STUDY DESIGN: Thyrotropin-releasing hormone (TRH) stimulation tests were performed at 2 weeks of age in 50 infants with a gestational age of 30 weeks or less, and the data were analyzed retrospectively. RESULT: Subjects were divided into three groups; group A consisted of euthyroid infants, group B consisted of infants with THOP and group C consisted of hypothyroid infants. The basal and peak thyroid-stimulating hormone level of group C in response to TRH stimulation tests was significantly higher than the others, but no differences were observed between groups A and B. CONCLUSION: The response of infants with THOP to the TRH stimulation test was not different from that of euthyroid infants, which suggested that their hypothalamic-pituitary-thyroid axis was appropriately regulated in infants with THOP.

Subcutaneous fat accumulation in early infancy is more strongly associated with motor development and delay than muscle growth.

AIM: Physical growth in neurologically healthy preterm infants affects motor development. This study investigated the separate relationships between muscle and fat in infancy and later motor development and physical growth. METHODS: Muscle thickness and subcutaneous fat thickness of the anterior thigh were measured using ultrasound images obtained from neurologically healthy preterm infants at birth, 3, 6, 12 and 18 months' corrected age. We also obtained the Pediatric Evaluation of Disability Inventory and Alberta Infant Motor Scale scores at 18 months' corrected age to assess motor ability and motor delay. RESULTS: Thirty preterm infants completed the study protocol. There was a significant positive correlation between motor ability and increments in subcutaneous fat thickness during the first 3 and 6 months' corrected age (r = 0.48 and 0.40, p < 0.05, respectively), but not between motor ability and muscle thickness growth in any of the periods. A secondary, logistic regression analysis showed that increments in subcutaneous fat thickness during the first 3 months were a protective factor for motor delay. CONCLUSION: Subcutaneous fat accumulation in early infancy is more strongly associated with motor development and delay than muscle growth.

PDGF and TGF-ß promote tenascin-C expression in subepithelial myofibroblasts and contribute to intestinal mucosal protection in mice.

BACKGROUND AND PURPOSE: Tenascin-C (TnC) is a multi-domain extracellular matrix glycoprotein that is expressed at a high level during embryogenesis but is almost absent during normal postnatal life. This multi-domain complex molecule is reported to associate with both pro-inflammatory and anti-inflammatory signalling cascades. In this study, we examined how TnC modulated intestinal inflammation. EXPERIMENTAL APPROACH: TnC pathophysiology was evaluated in cultures of rat intestinal subepithelial myofibroblasts (ISEMF) and intestinal epithelial cells. Wild-type and TnC(-/-) mice were treated with dextran sodium sulfate (DSS) to induce colitis. KEY RESULTS: DSS-induced colitis in mice markedly increased TnC in the damaged mucosal areas and up-regulated mRNA for TnC, pro-inflammatory cytokines and growth factors (PDGF-B and TGF-ß1). In addition, 2,4,6-trinitrobenzene sulfonic acid-induced colitis and SAMP1/Yit mice, a model of spontaneous Crohn's disease, also exhibited increased mucosal TnC in colon and ilea respectively. PDGF receptor-α (PDGFRα) positive ISEMF were the primary TnC-producing cells in colon tissues. Accordingly, ISEMF collected from the rat colon constitutively expressed both TnC and PDGFRα. PDGF-BB and TGF-ß1 up-regulated both TnC mRNA and protein levels in ISEMF. Knock-down of TnC gene increased susceptibility to DSS-induced colitis, compared with TnC(+/+) littermates. TnC(-/-) mice showed marked abrasion of intestinal mucosal barrier and increased inflammatory scores. Moreover, TnC accelerated both trans-well migration and wound healing in epithelial cells. CONCLUSIONS AND IMPLICATIONS: The pharmacological profiles of PDGF-BB and TGF-ß in colitis tissues and ISEMF suggest that increased TnC production during inflammation contributed to epithelial cell migration, remodelling and protection of intestinal barriers.

A novel modification of a bone repositioning device and a new technique for reestablishing facial contours after mandibular resection surgery.

A novel modification of a bone repositioning device previously published by the same authors is introduced. A flexible tube to define the intersegmental bony relationship is filled with light-cured resin. It solidifies following exposure to strong visible light for about 1 min. This technique can be used for bone positioning after mandibular resection surgery and during positioning of the proximal segment after sagittal split ramus osteotomy. The authors also propose a simple method for determining the contour of the reconstructed mandible to regain the original shape and form. The advantage of this technique is its simplicity and flexibility compared with other methods of bone positioning during mandibular segmental surgery.

Evaluation of plasma C-terminal atrial natriuretic peptide in healthy cats and cats with heart disease.

BACKGROUND: The clinical implications of evaluating C-terminal atrial natriuretic peptide (ANP) concentration in cats are still controversial. HYPOTHESIS: The objective of this study was to investigate the relationship between plasma C-terminal ANP concentration and left atrial pressure (LAP) in healthy cats with volume overload (study 1), and to compare plasma C-terminal ANP in normal cats and cats with cardiomyopathy (study 2). ANIMALS: Five healthy adult cats were used in study 1, and clinically healthy cats (n=8) and cats with cardiomyopathy (n=14) were used in study 2. METHODS: In study 1, cats were anesthetized and given acetated Ringer's solution (100 mL/kg/h for 60 minute) via the cephalic vein. Hemodynamic measurements and blood samples, collected from the jugular vein, were performed at 10-min intervals. In study 2, blood samples from normal cats and cats with cardiomyopathy were collected from the cephalic vein. The plasma C-terminal ANP concentration was determined by radioimmunoassay for human alpha-ANP. RESULTS: In study 1, volume overload significantly increased the C-terminal ANP concentration and LAP from baseline. The C-terminal ANP concentration was strongly correlated with the mean LAP. In study 2, age, E wave velocity, and the ratios of the left atrium to aorta were significantly higher in the cats with cardiomyopathy compared with the normal cats. The C-terminal ANP concentration was significantly higher in the cats with cardiomyopathy compared with the normal cats. CONCLUSIONS AND CLINICAL IMPORTANCE: Our results suggest that the measurement of plasma C-terminal ANP in cats may provide additional information for the diagnosis of heart disease.

Local delivery system of cytotoxic agents to tumors by focused sonoporation.

Recently, ultrasound-targeting microbubble destruction has been employed in molecular gene therapy, and a new potent nonviral gene transfer method known as 'sonoporation' has been developed. We investigated the efficiency of sonoporation toward growth inhibition of human gingival squamous carcinoma cell line, Ca9-22, in vitro and in vivo. The cytotoxicity of bleomycin (BLM) was investigated using flow-cytometric analysis and Hoechst's staining in vitro assay systems. We found that the delivery of BLM by sonoporation induced cytotoxic effect toward Ca9-22 cells in vitro. Our in vivo results showed that tumors nearly disappeared in Ca9-22 cell-implanted nude KSN/slc mice treated with a low dose of BLM followed by sonoporation during the 4-week experimental period. Histological analysis revealed that the cytotoxic effect was mainly apoptosis. We previously reported that the cytolethal distending toxin B (cdtB) from Actinobacillus actinomycetemcomitans, a periodontopathic bacterium, is responsible for cell cycle arrest and apoptosis in vitro. Thus, we used sonoporation to transfect a cdtB-expressing plasmid into Ca9-22 cells and examined cell viability in vitro and in vivo. We found that an administration of cdtB-expressing plasmid followed by sonoporation-induced marked growth inhibition of Ca9-22 cells and apoptotic cells were also observed in vitro and in vivo. These findings suggest that local administration of cytotoxic agents with sonoporation is a useful method for molecular cancer therapy.

c-Jun N-terminal kinase is activated in non-small-cell lung cancer and promotes neoplastic transformation in human bronchial epithelial cells.

c-Jun N-terminal kinase (JNK) has been reported to either potentiate or inhibit oncogenesis, depending upon the cellular context, but its role in lung neoplasia is unclear. Here we sought to define the role of JNK in lung neoplasia by examining evidence of JNK phosphorylation in non-small-cell lung cancer (NSCLC) biopsy samples and by using genetic and pharmacologic approaches to modulate JNK expression and activity in cultured cells. Immunohistochemical staining for JNK phosphorylation was detected in 114 (45%) of 252 NSCLC biopsy samples and was predominantly nuclear, providing evidence of JNK activation in a subset of NSCLC cases. Introduction of a doxycycline-inducible, constitutively active, mutant mitogen-activated protein kinase kinase 4 (MKK4) into the human bronchial epithelial cell lines BEAS-2B and HB56B increased the cells' proliferation, migration, invasion and clonogenicity. Depletion of JNK in MKK4 mutant-transformed BEAS-2B cells by introduction of JNK1/2 short hairpin RNA reversed the transformed phenotype, indicating that JNK activation is oncogenic and MKK4 confers neoplastic properties in these cells. The proliferation of NSCLC cell lines HCC827 and H2009, in which JNK and its substrate c-Jun are constitutively phosphorylated, was inhibited by SP600125, a JNK kinase inhibitor. We conclude that JNK is activated in a subset of NSCLC biopsy samples and promotes oncogenesis in the bronchial epithelium, suggesting that strategies to inhibit the JNK pathway should be considered for the prevention and treatment of NSCLC.

Effect of prior hyperglycemia on IL-6 responses to exercise in children with type 1 diabetes.

The proinflammatory cytokine interleukin-6 (IL-6) may modulate the onset and progression of complications of diabetes. As this cytokine increases after exercise, and many other exercise responses are altered by prior glycemic fluctuations, we hypothesized that prior hyperglycemia might exacerbate the IL-6 response to exercise. Twenty children with type 1 diabetes (12 boys/8 girls, age 12-15 yr) performed 29 exercise studies (30-min intermittent cycling at approximately 80% peak O2 uptake). Children were divided into four groups based on highest morning glycemic reading [blood glucose (BG) < 150, BG 151-200, BG 201-300, or BG > 300 mg/dl]. All exercise studies were performed in the late morning, after hyperglycemia had been corrected and steady-state conditions (plasma glucose < 120 mg/dl, basal insulin infusion) had been maintained for > or = 90 min. Blood samples for IL-6, growth factors, and counterregulatory hormones were drawn at pre-, end-, and 30 min postexercise time points. At all time points, circulating IL-6 was lowest in BG < 150 and progressively higher in the other three groups. The exercise-induced increment also followed a similar dose-response pattern (BG < 150, 0.6 +/- 0.2 ng/ml; BG 151-200, 1.2 +/- 0.8 ng/ml; BG 201-300, 2.1 +/- 1.1 ng/ml; BG > 300, 3.2 +/- 1.4 ng/ml). Other measured variables (growth hormone, IGF-I, glucagon, epinephrine, cortisol) were not influenced by prior hyperglycemia. Recent prior hyperglycemia markedly influenced baseline and exercise-induced levels of IL-6 in a group of peripubertal children with type 1 diabetes. While exercise is widely encouraged and indeed often considered part of diabetic management, our data underscore the necessity to completely understand all adaptive mechanisms associated with physical activity, particularly in the context of the developing diabetic child.

Structure and property of self-assemble valinyl bolaform amides having different chirality.

Bolaform amides were designed from N,N'-bis(carboethoxy-L-valinyl)-diaminoethane (1) by linking t-butyloxycarbonyl-valine through ethylenediamine (EDA) to enable spectroscopic and X-ray diffraction analyses. N,N'-Bis(Boc-L-valinyl)-diaminoethane (2) and N,N'-bis(Boc-D-valinyl)-diaminoethane (3) were composed of L-Val and D-Val, respectively. N-(Boc-L-valinyl)-N'-(Boc-D-valinyl)-diaminoethane (4) was composed of both L-Val and D-Val, and was achiral (meso-peptide). Peptide 5 was a 1:1 mixture of 2 and 3, and was also achiral (racemate). These peptides mediated gelation of corn oil at a concentration of approximately 1%. Within crystals, the peptides formed beta-sheet ribbons, but differences were observed in hydrogen-bonding patterns and side-chain arrangements. These differences were also deduced from temperature dependence of amide protons. Force-field calculations based on the crystal structures indicated that association of beta-sheet ribbons had energy benefits, and it was assumed that molecular aggregation progressed spontaneously. These structural studies indicated the chirality of amino acids affected for the properties of bolaform amides.

Sweating responses during activation of the muscle metaboreflex in humans is altered by time of day.

AIM: The aim of the present study was to test for a time-of-day effect on sweating responses to activation of the muscle metaboreflex. METHODS: Eight male subjects each participated in two exercise sessions, one in the morning and one in the evening. Within each session there were two 60-s bouts of isometric handgrip (IHG) exercise at 50% maximal voluntary contraction. Prior to IHG, whole body warming by a water-perfused suit initiated mild sweating. The first bout of IHG exercise began at 06.00 hours (am) and 18.00 hours (pm). Blood circulation to the forearm was occluded for 120 s, beginning 5 s before the end of the second bout of IHG to activate the muscle metaboreflex. RESULTS: During both bouts of exercise, sweating rate (SR) on both the chest and right forearm significantly increased from the pre-exercise period in both am and pm sessions. SR rapidly decreased during first minute of recovery after the first bout of IHG exercise. However, during post-exercise ischaemia (PEI) after the second bout of IHG exercise, SR was maintained significantly above the pre-exercise level only in the pm session. The increases in SR on the chest and right forearm during PEI were significantly greater in the pm, than in the am, session. However, SR of the palm was not maintained during PEI. CONCLUSIONS: We conclude that under mild hyperthermic conditions, the sweating response in non-glabrous skin to activation of the muscle metaboreflex exhibits a time-of-day effect.

Usefulness of microspheres composed of gelatin with various cross-linking density.

The release rate of insulin, as a model peptide, from gelatin microspheres (GM) prepared with gelatin having various cross-linking densities in vitro was examined. The release of insulin from GM showed the burst effect, followed by a slow release phase regardless of the cross-linking density of gelatin. The total amount of insulin released in 2 weeks decreased with increasing cross-linking density of gelatin. The release rate of insulin within 6 h was well correlated with the cross-linking density of gelatin. The remaining amounts of both insulin and GM after injection of insulin incorporated in GM to mice femoral muscle tissue were also examined in vivo. Both insulin and GM rapidly disappeared from the injection site within 1 day, and thereafter slowly disappeared over 14 days. The time courses of the remaining amounts were fairly similar to each other. Furthermore, the remaining amount of insulin 1 day after administration was well correlated with the cross-linking density of gelatin. These data suggest that insulin was released from GM with the degradation of GM in mice muscular tissue and that the release rate of insulin can be controlled by modifying the cross-linking density of gelatin. In conclusion, the control of the release rate of insulin from GM can be achieved under both in vitro and in vivo conditions by gelatin through the alteration of cross-linking conditions.

Effects of active recovery under a decreasing work load following intense muscular exercise on intramuscular energy metabolism.

The effect of active recovery at a decreasing % of MVC following intense muscular exercise on intramuscular pH was investigated in vivo using 31P-MRS. Seven healthy men participated, and their right wrist flexor muscle group was examined. The subjects were asked to flex their right wrist at 60 % of the maximum voluntary contraction (MVC) every 2 s until the intracellular pH in the wrist flexor muscle decreased to 6.4. After the exercise period, the subjects underwent active or passive recovery for 10 min. For the active recovery (AR), the subject was asked to continue exercising at a decreasing % of MVC, decreasing from 25 to 5 % MVC every two min during AR. 31P-MR-spectra were obtained throughout the experiments, and from the spectra the intracellular pH (pHi) was calculated as an indicator of intracellular events. AR data were compared to data collected during passive recovery (PR). During AR, the pHi increased immediately after the exercise period; whereas in that of PR, it did not recover within 5 minutes after exercise. The results suggested that mild exercise was an effective manoeuver to promote recovery from intramuscular metabolic acidosis.

Progesterone stimulates the expression of aminopeptidase A/angiotensinase in human choriocarcinoma cells.

In human placenta aminopeptidase A (APA), a principal enzyme that converts angiotensin II to angiotensin III, seems to be involved in angiotensin II metabolism during pregnancy. In this study, we investigated the possible effects of progesterone and estrogen on APA mRNA and protein levels in choriocarcinoma cells as a model for placenta. By RNase protection assay, progesterone induced higher APA mRNA levels than estrogen at the same concentration. Progesterone exhibited dose-dependent stimulation of APA mRNA, 1.8-fold increase at 10(-6) m for 24 h treatment. Progesterone at 10(-6) m increased APA mRNA levels within 12 h and in time-dependent fashion up to 24 h. Fluorescence-activated cell sorting analysis and measurements of APA activities revealed the induction of APA protein by progesterone. Expression of progesterone receptors (PR) and glucocorticoid receptors (GR) were determined in these cells by RT-PCR, which suggested that the progesterone's actions might be displayed through PR and/or GR. These findings may serve as a useful model to study the effects of progesterone on angiotensin II metabolism in placenta, although the physiological validity of these studies remains to be clarified.

Pharmacokinetic-pharmacodynamic modelling of human insulin: validity of pharmacological availability as a substitute for extent of bioavailability.

A method for assessing the extent of bioavailability (EBA) of human insulin from pharmacological data was determined. The time course governing increases in the plasma concentration of immuno-reactive insulin (IRI), as well as its pharmacological effects (glucodynamics), was determined after the intravascular administration of varying doses of human insulin. Pharmacokinetic (PK), pharmacodynamic (PD), and link models were constructed to elucidate the quantitative relationship between plasma IRI levels and pharmacological effects. After extravascular administration of the test formulation, only the time course governing the observed pharmacological effects was determined. The pharmacological data was translated into theoretical plasma concentration data, using the PK-PD model. Following this, the area under the theoretical plasma concentration-time curve (AUC) of the test formulation was calculated. The EBA was then estimated against a reference (intravascular) formulation, using a conventional equation. Since the pharmacological effects of insulin were observed to be highly dosing-rate-dependent, the PD model used in this study was modified to apply over a wide range of infusion rates. The results of the PK-PD analysis indicate that the doses administered can be accurately predicted from pharmacological data. To validate this method, the EBAs of controlled release formulations (the Osmotic Mini Pumps) of insulin, subcutaneously administered to the rat, were estimated. The EBA values obtained (92-96%) fell within a reasonable range. The area under the effect-time curves (AUE) obtained following subcutaneous applications of the Osmotic Mini Pump were calculated in a model-independent manner, in addition to pharmacological availabilities (PA), which were estimated against the reference (intravascular) formulations. The estimated PA values varied from 312% to 78%, in accordance with the intravascular input rates of the reference formulations. This indicates that PA should not be used as a substitute for EBA, unless data involving similar intravascular dosing rates to that of the reference formulations is available.

Effects of low-viscosity sodium hyaluronate preparation on the pulmonary absorption of rh-insulin in rats.

PURPOSE: A low-viscosity formulation for pulmonary delivery of rh-insulin as model peptide drugs was developed using a solution of sodium hyaluronate. METHOD: The effects of different concentrations and pH values of low-viscosity solutions of hyaluronate on the pulmonary absorption of rh-insulin were examined after intratracheal administration in rats. The permeation of fluorescein isothiocyanate (FITC)-dextran (molecular weight 4300; FD-4) and insulin through excised rat trachea in vitro were also examined. RESULTS: The hyaluronate (2140 kDa) solutions (0.1% and 0.2% w/v) at pH 7.0 significantly enhanced the pharmacological availability (PAB) of insulin compared to the aqueous solution of insulin at pH 7.0. The absorption-enhancing effect at a concentration of 0.1% w/v hyaluronate was greater than that at a concentration of 0.2% w/v hyaluronate. Furthermore, the greatest absorption-enhancing effect was obtained, regardless of the molecular weight of hyaluronate, when the concentration of hyaluronate was adjusted to 0.47 microM. Absorption-enhancing effects were consistent with the effect of a 0.1 w/v hyaluronate preparation at pH 4.0 and 7.0 on the permeation of FITC-dextran and insulin through excised rat trachea in vitro. CONCLUSION: Low-viscosity hyaluronate preparation was shown to be a useful vehicle for pulmonary delivery of peptide drugs.