Biomedical subjects

M Fukami

Publications and source records attributed to M Fukami.

At least 37 records · Page 2Linked to original sources

PubMed1996

The mechanism of comparable serum cholesterol lowering effects of pravastatin sodium, a 3-hydroxy-3-methylglutaryl coenzyme A inhibitor, between once- and twice-daily treatment regimens in beagle dogs and rabbits.

In dogs, no significant difference in the reduction of serum cholesterol was observed among three dosing regimens of pravastatin: once in the morning (3 mg/kg), once in the evening (3 mg/kg), and twice-daily (1.5 mg/kg x 2) for 21 days. In rabbits, pravastatin was administered at a dose of 50 mg/kg once-daily given in the evening or 25 mg/kg twice-daily for 14 days; the respective serum and liver cholesterol levels were decreased by 41% and 7% in the once-daily dosing and by 51% and 11% in the twice-daily dosing. The amount of low density lipoprotein (LDL) receptor protein was increased 1.2-1.3-fold (P < 0.05) by both treatments, and no significant difference was noted between these treatment regimens. In addition, there was no significant difference in the extent of up-regulated LDL receptor protein between once-daily dosing in the evening and once-daily dosing in the morning. In the experiments with rabbit hepatocytes, the up-regulated LDL receptor activity induced by preincubation with pravastatin was retained even 24 hr after the removal of pravastatin. These results suggest that the comparable efficacy of pravastatin between once- and twice-daily treatment could be explained by retention of up-regulated LDL receptor activity for more than 24 hr in vitro and in vivo.

Administration, Oral↗

PubMed1996

[Patency of the ostium of the frontal sinus after endoscopic endonasal surgery for chronic sinusitis].

We examined the patency of the ostium of the frontal sinus after endoscopic endonasal surgery for chronic sinusitis. This study involved one hundred and seventy-two nasal sides of ninety cases who underwent surgery in this unit in the preceding three-year period by the designated three surgeons. All patients were followed up for more than one year after surgery. We obtained a high postoperative patent rate of 90.1%. However, communication between the frontal and ethmoidal sinus could not be confirmed in 9.9% of the cases due to the presence of polyp or adhesion in the middle meatus. Cases with preoperative severe lesion of the frontal sinus showed significantly lower rates of patent than cases with preoperative mild and/or no lesion. In cases where the opening of the ostium could not be sufficiently widened during surgery because the size around the ostium was already small, lower patent rates resulted. However, even in such cases, scraping or curetting of the surrounding bone should be avoided, because it may cause postoperative narrowing of the ostium due to new bone formation. Cases with unsatisfactory results caused by pathological changes in the middle meatus showed significantly lower patent rates than cases with satisfactory postoperative results. It is recommended that accurate cleaning of the ethmoid sinus and adequate postoperative treatment be considered important. Endoscopic endonasal opening of the ostium of the frontal sinus is shown to be a safe and reliable procedure, which can be performed with clear visualization.

Adolescent↗

PubMed1996

[A case of localized amyloidosis of the ureter].

A case of localized amyloidosis of the ureter is reported. The patient was a 49-year-old female whose chief complaint was macrohematuria. Roentogenographic examination showed left hydronephrosis due to stenosis of left middle ureter. Left nephrouretectomy with cuff was performed with a diagnosis of the left ureteral tumor, and pathological examination revealed localized amyloidosis of the left ureter. Localized amyloidosis of the ureter is a rare lesion, and this is the twenty-first case reported in the Japanese literature. Review of the literature revealed that it is difficult to differentiate this lesion from other ureteral tumors by roentgenographic examination, and it is important to perform preoperative or intraoperative biopsy of ureteral tumors if benign diseases cannot be ruled out.

Amyloidosis↗

PubMed1995

The mechanism of lack of hypocholesterolemic effects of pravastatin sodium, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, in rats.

In order to clarify the reason why pravastatin, a 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitor, did not show hypocholesterolemic effects in rats, the changes of various parameters affecting the serum cholesterol levels by pravastatin were determined in rats and rabbits, as a comparison. In rabbits, pravastatin administration at 50 mg/kg for 14 days decreased serum and liver cholesterol by 40% and 8%, respectively. The hepatic LDL receptor activity was increased 1.7-fold, and VLDL cholesterol secretion was decreased. Cholesterol 7 alpha-hydroxylase activity was not changed. In contrast, in rats, serum cholesterol was increased by 14% at 50 mg/kg and 27% at 250 mg/kg for 7 days, respectively. At 250 mg/kg, liver cholesterol was significantly increased by 11%. Under these conditions, neither the hepatic LDL receptor activity nor cholesterol 7 alpha-hydroxylase was changed, and VLDL cholesterol secretion was increased. At 250 mg/kg, net cholesterol synthesis in rat liver was increased after 7 days of consecutive administration. These results imply that in rats, stimulated net cholesterol synthesis caused the increase of liver cholesterol followed by the increase of VLDL cholesterol secretion, and resulted in the raise of plasma cholesterol. Although hepatic HMG-CoA reductase was induced almost the same fold in both animals at 50 mg/kg, the induced HMG-CoA reductase activity in rats might overcome the inhibitory capability of pravastatin, resulting in an increase of net cholesterol synthesis, but not in rabbits. This over response to pravastatin in rats might cause the lack of hypocholesterolemic effects of this drug.

Animals↗

PubMed1995

Reduction of serum cholesterol levels alters lesional composition of atherosclerotic plaques. Effect of pravastatin sodium on atherosclerosis in mature WHHL rabbits.

We examined whether serum cholesterol reduction alters the lesional composition of atherosclerotic plaques. To reduce serum cholesterol levels, we gave pravastatin sodium, a 3-hydroxy-3-methylglutaryl Coenzyme A reductase inhibitor, to mature Watanabe heritable hyperlipidemic rabbits, an LDL receptor-deficient animal model, for 48 weeks. Atherosclerotic lesions were immunohistochemically and conventionally stained and each lesional component area was measured by a color image analyzer. Compared with those of a placebo group, serum LDL cholesterol levels were reduced by 22% (P<.05). Data for atherosclerosis indicated a significant decrease in percent of surface lesion area (26% reduction) and in intimal thickening (30% reduction) in the abdominal aorta, as well as in coronary stenosis (29% reduction). Data for lesional composition indicated a significant decrease in the percent area of macrophage plus extracellular lipid deposits in aortic lesions (32% reduction) and coronary lesions (45% reduction). A significant increase was observed in the percent area of collagen in aortic lesions and in the percent area of smooth muscle cells in coronary lesions. The plaques seemed to become stable lesions as a result of pravastatin treatment. In conclusion, a long-term reduction of serum LDL cholesterol reduced lipid-related lesional components, in addition to suppressing the progression of established atherosclerosis.

Animals↗

PubMed1995

Activity of smooth muscle phosphatases 1 and 2A in rabbit basilar artery in vasospasm.

BACKGROUND AND PURPOSE: Subarachnoid hemorrhage frequently leads to a long-term cerebral artery narrowing called vasospasm. Recently, the involvement of myosin light chain kinase has been found in experimental vasospasm in our laboratory. We therefore measured the activity of serine/threonine protein phosphatases 1 and 2A in the rabbit basilar artery in vasospasm and in vasocontraction to study their role, particularly in regard to vasospasm compared with vasocontraction. METHODS: Vasospasm was produced in the rabbit basilar artery by a two-hemorrhage method. Vasocontraction was induced by local application of KCl or serotonin to the rabbit basilar artery after a transclival exposure. The control animals were treated with saline instead of fresh blood. Serine/threonine protein phosphatase activity in the basilar artery was assayed with the use of [32P]phosphorylase-a as a substrate; protein phosphatase 1 activity was evaluated as protein phosphatase activity in the presence of 1 nmol/L okadaic acid, whereas protein phosphatase 2A activity was assessed as protein phosphatase activity inhibited by 1 nmol/L okadaic acid. RESULTS: Values of mean activity of protein phosphatase 1 in myofibrillar extract were 3.58 +/- 0.26 nmol/min per milligram in the control group, 3.22 +/- 0.12 nmol/min per milligram in the spastic group on day 2, and 3.01 +/- 0.16 nmol/min per milligram in the spastic group on day 4 (a significant decrease in protein phosphatase 1 activity in the spastic group on days 2 and 4). In contrast, these values did not show any significant changes in the KCl and serotonin groups. Values of mean activity of protein phosphatase 2A in cytosolic extract were 0.90 +/- 0.07 nmol/min per milligram in the control group, 0.75 +/- 0.10 nmol/min per milligram in the spastic group on day 2, and 0.62 +/- 0.17 nmol/min per milligram in the spastic group on day 4 (a significant reduction in protein phosphatase 2A in the spastic group on days 2 and 4). There was no evidence of significant changes of protein phosphatase 2A in cytosolic extract in the KCl and serotonin groups. CONCLUSIONS: Protein phosphatase 1 in myofibrillar extract is reported to catalyze the dephosphorylation of myosin light chain and calponin, whereas protein phosphatase 2A in cytosolic extract catalyzes the dephosphorylation of calponin and caldesmon. In addition, the phosphorylation of calponin and caldesmon results in the loss of their ability to inhibit smooth muscle contraction. Therefore, the significant decrease in activity of protein phosphatases 1 and 2A in vasospasm may result in uninterrupted vascular smooth muscle contraction by the preservation of phosphorylation of not only myosin light chain but also calponin and caldesmon.

Animals↗

PubMed1995

Endoscopic and Caldwell-Luc approaches in chronic maxillary sinusitis: a comparative histopathologic study on preoperative and postoperative mucosal morphology.

The aim of the present investigation was to study the histopathologic mucosal changes occurring in chronic maxillary sinusitis both preoperative and postoperative to functional endoscopic sinus (FES) surgery and the Caldwell-Luc (C-L) operation. Correlations were also sought between the histopathologic parameters and endoscopic findings, as well as patient symptoms. Sixty sinuses with the FES surgery and 55 sinuses with the C-L procedure were studied. The histologic parameters were graded semiquantitatively and compared preoperatively and postoperatively. The C-L operation reduced almost all parameters, whereas after the FES operation only edema and inflammatory cells were significantly reduced. Fibrosis increased postoperatively with both methods. The number of inflammatory cells was closely correlated to a thickened antral mucosa and to purulent secretion. No valid correlations were found when comparing histology with patient symptoms. All in all, histologic considerations suggest that asthmatic patients with severe sinonasal polyposis might benefit from the C-L procedure.

Asthma↗

PubMed1995

[Improvement of olfactory disturbance by endoscopic endonasal surgery for chronic sinusitis].

Olfactory disturbance is the one of the most important symptoms of chronic sinusitis. In the present study, we followed up the postoperative clinical course of olfactory disturbance in patients who underwent surgery for chronic sinusitis. Ninety patients with severe olfactory disturbance or anosmia who underwent endoscopic endonasal surgery for chronic sinusitis with severe olfactory disturbance or anosmia in the preceding three-year period were enrolled in this study. We obtained a high postoperative improvement rate of 78.8%. We compared and examined our cases' postoperative clinical course concerning their olfactory disturbance and various factors in other patients before and after surgery, and obtained the following results: a) Young patients, 30 years old or under at the time of surgery, showed significantly higher rates of improvement than patients who were 50 years old or more at the time of surgery. b) Even though revision surgery was performed, the improvement rates were almost the same as after the initial surgery. c) Although the Alinamin intravenous olfaction test is regarded as an olfaction threshold test, we have seen quite a few cases in which improvement was achieved despite the absence of a preoperative response to the Alinamin intravenous olfaction test. d) There was no clear correlation between the presence of preoperative lesions of the ethmoid sinus and the olfactory cleft and the improvement rates. e) The cases with unsatisfactory results concerning the paranasal sinuses and nasal cavity--those accompanied by postoperative adhesions of the olfactory cleft, recurrence of polyps, etc.,--showed significantly lower improvement rates than cases with satisfactory postoperative results. During surgery in patients with severe olfactory disturbance, we conclude that it is particularly important to adequately clean the lesions of the olfactory cleft and the anterior and posterior ethmoid sinus endoscopically. This ensures leaving clear the olfactory cleft.

Adult↗

PubMed1995

[Indications for endoscopic sinus surgery. A clinical study on patients with a poor post-operative course].

One hundred and fifty-three patients with chronic sinusitis underwent endoscopic endonasal sinus surgery. They were preoperatively evaluated on the basis of their complaints, the severity of nasal polyps, X-ray findings, and axial and/or coronal CT scans. Postoperative degree of improvement in their complaints and endoscopic findings in the nasal cavity and sinus cavities were assessed. Most patients, including those with severe maxillary sinusitis, had a good postoperative course. The percentage of improvement in their complaints was 99.3%. Even in the case of olfactory disturbance, which is the most difficult symptom to treat, the percentage of improvement was 81.0%. There were only 8 patients with complaints and pathological findings in their nose or sinuses after the operation, 4 with allergic rhinitis and/or asthma, 1 with severe inflammation of the olfactory cleft, 1 with thickening of the bone in the sinuses after a 25-year history of sinusitis without treatment, and 2 with narrowing of the antrostoma at the middle meatus after the operation.

Adolescent↗

PubMed1995

Evaluation of endoscopic sinus surgery for chronic sinusitis: post-operative erythromycin therapy.

We discuss the results of endoscopic endonasal sinus surgery for chronic pan-sinusitis characterized by nasal polyposis, especially the effects of post-operative long-term administration of low-dose erythromycin (EM) therapy. The subjects analysed in this retrospective study are surgical cases who had initially been operated for chronic pan-sinusitis. They are classified into one group who has received a post-operative long-term, low-dose EM regimen and into another group who has not received this treatment. The groups have been compared with respect to: (1) the degree of improvement in the post-operative subjective symptoms; (2) postoperative objective findings of the ethmoidal sinus and the ostium of the frontal sinus; and (3) the degree of improvement in the maxillary sinus lesion. Better improvement is achieved in subjective symptoms and objective findings in the EM group than in the non-EM group.

Adolescent↗

PubMed1993

Lysozyme and lactoferrin in human maxillary sinus mucosa during chronic sinusitis. An immunohistochemical study.

Immunohistochemistry was used to study the localization of lysozyme (LZ) and lactoferrin (LF) in the human sinus mucosa during recurrent and chronic sinusitis. Serous cells of submucosal mixed glands and polymorphonuclear leukocytes both displayed a strongly positive staining reaction to both LZ and LF in the normal mucosa. A positive though weak staining for LZ and LF could also be found occasionally within goblet cells. In the mucosa from patients with recurrent or chronic sinusitis, the staining reaction to LZ appeared to intensify in goblet cells. Furthermore, an increased immunoreactivity of glands vis-à-vis LZ and LF was also noted occasionally. Atypical glands were frequently found in mucosa from patients with chronic sinusitis. The epithelium of these latter glands often showed an intense staining reaction to LF, but a rather weak reaction to LZ. The results of the present study suggest that the observed increase in LZ and LF secreting activity of goblet cells, epithelial cells and newly formed atypical glands may play a part in the defense mechanism of the sinus mucosa during the course of chronic sinusitis.

Adult↗

PubMed1993

Effects of HMG-CoA reductase inhibitors on skeletal muscles of rabbits.

This study was undertaken to evaluate the potential of HMG-CoA reductase inhibitors, pravastatin sodium (hereafter abbreviated to pravastatin) and simvastatin, for induction of myopathy and influence on the ubiquinone content of skeletal and cardiac muscles and other tissues in the rabbit. Both drugs were administered orally to New Zealand White rabbits (n = 5) at the dose of 50 mg/kg per day for 14 days. Serum cholesterol levels in the pravastatin- and simvastatin-treated groups were reduced significantly by 47% an 58% on day 14 (P < 0.05), respectively, as compared with the control group, but the difference between the two treatment groups was not significant. In animals of the simvastatin-treated group, abnormal elevations of creatine kinase (CK) and lactate dehydrogenase (LDH) levels were observed, in association with severe lesions in skeletal muscles, but not cardiac muscle. The ubiquinone content in skeletal muscle in this treatment group was not affected, even in the muscles that had severe lesions, whereas that in liver and cardiac muscle was significantly reduced compared with the control group. The results suggest that there is no direct correlation between myopathy and the decrease of ubiquinone content in skeletal muscles. In contrast, the animals in the pravastatin-treated group did not show any changes in CK and LDH levels, ubiquinone content in liver and muscles, or in histopathological features of muscle fibers. The difference between the adverse effects seen with the two drugs could be attributed to physicochemical properties: simvastatin permeates the plasma membrane because of its hydrophobic nature, whereas pravastatin does not, because it is hydrophilic.

Administration, Oral↗

PubMed1993

Formation of mucosal polyps in the nasal and maxillary sinus cavities by infection.

Unilateral maxillary sinusitis was experimentally induced in New Zealand White rabbits with Streptococcus pneumoniae serotype 3, Bacteroides fragilis NCTC 9343, and Staphylococcus aureus V8. In another group of rabbits, sinusitis was induced by blocking of the sinus ostium only. Bacteriologic and light microscopic analysis was performed after 5 days to 1 month. Granulation-like polyps developed after deep mucosal inflammatory trauma initiating fibroblast proliferation, angiogenesis, and epithelial migration to cover the polyp. In regions of a more superficial trauma-characterized by epithelial desquamation and fibroblast growth-proliferation and differentiation of basal cells resulted in the formation of microcavities dissecting off edematous polyps. Polyps could be found in all sinusitis groups, irrespective of inducing agent. The cellular events of polyp formation appear to be the result of a continuous inflammatory reaction and are not directly related to the presence of a certain microorganism. Instead, the potential of any microorganism to induce a deep mucosal trauma or epithelial desquamation seems essential for its ability to initiate polyp formation.

Animals↗

PubMed1992

Tissue selectivity of pravastatin sodium, lovastatin and simvastatin. The relationship between inhibition of de novo sterol synthesis and active drug concentrations in the liver, spleen and testis in rat.

Tissue selectivity of pravastatin sodium (pravastatin), lovastatin and simvastatin, 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors was examined by measuring inhibition of de novo sterol synthesis and active drug concentrations in the liver, spleen and testis in rats after a single oral administration (25 mg/kg) of these drugs. Regarding tissue drug concentrations, all three drugs were liver selective: concentrations of drugs in the liver were about ten-times higher than those in the spleen and testis. On the other hand, pravastatin was far more liver selective in inhibiting sterol synthesis than two other inhibitors: pravastatin inhibited de novo sterol synthesis in the liver but minimally in the spleen and testis, whereas lovastatin and simvastatin inhibited in all three tissues. Microautoradiographic and in vitro cellular-uptake studies demonstrated that pravastatin remained in the extracellular space in the spleen, whereas the other drugs entered the cell. We conclude that pravastatin exhibits a liver-selective inhibition of sterol synthesis because the agent permeates the cell membrane in the liver, but not in non-hepatic tissues.

Animals↗

PubMed1992

Glycerophospholipid metabolism: back to the future.

It has become customary to regard the various glycerophospholipids as quite similar, and the acyl groups are considered to have little influence on the behaviour of the lipids in membranes or metabolism. Nevertheless, a number of recent observations by the authors and others indicate a high degree of metabolic compartmentation and substrate specificity with regard to the acyl substituents (acyl specificity) of glycerophospholipid metabolising enzymes in intact cells. 1. [32P]Orthophosphate and [3H]glycerol are incorporated into phosphatidylcholine (PC) and phosphatidylethanolamine (PE) of platelets and Swiss 3T3 fibroblasts with a [32P]/[3H]-ratio several fold lower than in glycerol-3-phosphate, phosphatidic acid (PA) and phosphatidylinositol (PI), suggesting distinct metabolic separation (probably by cellular compartmentation) of the glycerol and choline (or ethanolamine) branches of de novo phospholipid biosynthesis. 2. In fibroblasts the [32P]/[3H]-ratio varied 50-fold among the molecular species of PC, PE, PI and PA, which indicates that the enzymes involved in these conversions have some degree of acyl specificity. 3. In vitro assays for lipid-converting enzymes employ detergents, which affect acyl specificity of the enzymes (lipid kinases) both by their chemical nature and concentrations. 4. Thrombin stimulation of platelets causes formation of a multitude of diacylglycerol (DAG) molecular species, but only one major molecular species of PA is formed indicating that the DAG kinase may have distinct acyl specificity in the intact cell. 5. However, this specificity could also result from the net reactions of DAG kinase(s) and PA phosphohydrolase(s), which would constitute an ATP-utilising, paired regulation of the molecular species of PA and the inositol lipids on one hand, and PC, PE phosphatidylserine and triacylglycerol on the other. These findings indicate a high complexity of glycerophospholipid metabolism and a distinct acyl specificity in intact cells that are not apparent from studies in vitro. A major challenge for future research in this area is to bridge the apparent discrepancy between in vivo and in vitro observations regarding glycerophospholipid metabolism, an endeavour that will require more knowledge about the physical chemistry of naturally occurring molecular species than is available today. The most prevailing appreciation of glycerophospholipids among biological scientists to-day is that they can be distinguished functionally, topographically and metabolically only by their head groups and that they form the bilayer in biological membranes. Most of us know that the fatty acid in the sn-2 position is unsaturated and have been indoctrinated that the higher the degree of unsaturation, the greater the fluidity of the membrane.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1992

Effects of pravastatin sodium alone and in combination with cholestyramine on hepatic, intestinal and adrenal low density lipoprotein receptors in homozygous Watanabe heritable hyperlipidemic rabbits.

Pravastatin sodium (pravastatin), a tissue-selective inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, was administered alone (50 mg/kg) or in combination with cholestyramine, a bile acid sequestrant resin, at the level of 2% in the diet to homozygous Watanabe heritable hyperlipidemic (WHHL) rabbits for 4 weeks. The low density lipoprotein (LDL)-cholesterol levels were reduced by 29% and 56% with pravastatin alone and the combination treatment, respectively. Hepatic LDL receptor activity was increased by 11.2- and 13.9-fold with pravastatin alone and the combination treatment, respectively. The LDL receptor activity in the untreated homozygous WHHL rabbits was only 2.5% of that in the normal rabbits. mRNA for the LDL receptor in the liver was also increased by 2.1- and 3.4-fold with pravastatin alone and the combination treatment, respectively. On the other hand, mRNA for the LDL receptor in the adrenal gland was not affected by pravastatin and the combination treatment, whereas the mRNA in the intestine was increased in both groups. These results suggest the following: 1) the induction of hepatic LDL receptor activity by the treatment of pravastatin alone or in combination with cholestyramine is the main cause of the reduction of serum cholesterol levels by these treatments even in LDL receptor-deficient animals. 2) The induction of the mRNA for the LDL receptor in the liver and intestine, but not that in the adrenal gland, might be a reflection of the tissue-selective inhibition of cholesterol synthesis by pravastatin.

Adrenal Glands↗

PubMed1992

Effects of inhibitors of protein kinase C and calpain in experimental delayed cerebral vasospasm.

Vasospasm was produced in adult mongrel dogs by a two-hemorrhage method, and the spastic basilar arteries were exposed via the transclival route on Day 7. Tonic contraction was produced in the normal canine basilar arteries by a local application of KCl or serotonin after transclival exposure. The exposed spastic and tonic basilar arteries then received a topical application of the following: 1-(5-isoquinolinesulfonyl)-2-methyl-piperazine (H-7), a potent inhibitor of protein kinase C acting at the catalytic domain; calphostin C, a specific inhibitor of protein kinase C acting at the regulatory domain; or calpeptin, a selective inhibitor of calpain. Both spastic and tonic basilar arteries were effectively dilated by H-7. Calphostin C caused only slight dilation of spastic basilar arteries but moderate dilation of tonic basilar arteries. Dilation in response to calpeptin was remarkable in the spastic basilar arteries but slight in the tonic basilar arteries. The doses of calphostin C and calpeptin required to obtain maximum effect were markedly lower in the tonic model than in the spastic model. The spastic and tonic models had a similar dose-dependent response to H-7 but quite a different response to calphostin C or calpeptin, suggesting a difference in the function of protein kinase C and calpain in the two models. Furthermore, the effect of calphostin C on the reversal of vasospasm was increased significantly after topical treatment with calpeptin. It is suggested that the majority of the catalytic domain of protein kinase C is dissociated from the regulatory domain, probably by a limited proteolysis with calpain, and is markedly activated in vasospasm.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗

PubMed1991

Characterization of CS-045, a new oral antidiabetic agent, II. Effects on glycemic control and pancreatic islet structure at a late stage of the diabetic syndrome in C57BL/KsJ-db/db mice.

Antidiabetic effects of CS-045 were evaluated in 5-month-old C57BL/KsJ-db/db mice (db/db). CS-045 administered for 3 weeks to diabetic db/db mice as a 0.2% food admixture improved hyperglycemia (855 +/- 25 v 298 +/- 62 mg/dL, P less than .01) and glucose intolerance, and lowered plasma triglyceride (299.6 +/- 28.7 v 76.3 +/- 20.7 mg/dL, P less than .01) and free fatty acid (FFA) levels (1.16 +/- 0.14 v 0.57 +/- 0.07 mEq/L, P less than .01). Food intake was not changed, while a small but significant increase in body weight was observed in CS-045-treated mice. Plasma insulin levels gradually increased after 5 days of CS-045 treatment, and a nonsignificant increase was observed in plasma insulin levels after 3 weeks (1.85 +/- 0.50 v 4.54 +/- 1.47 mg/mL). In contrast, the plasma glucagon levels decreased after 3 weeks of CS-045 treatment. Histological examination by aldehyde-fucshin staining demonstrated that pancreatic beta cells in CS-045-treated db/db mice were heavily regranulated, whereas most of the beta cells were extensively degranulated in nontreated db/db mice. The heavily regranulated state of beta cells was also compatible with an increase in pancreatic insulin content in CS-045-treated db/db mice. Electron microscopic analysis showed a well-developed endoplasmic reticulum and the accumulation of much amorphous structural material in the intracisternal space of beta cells from CS-045-treated db/db mice, which were suggestive of an increase in insulin synthesis. Moreover, CS-045 treatment decreased exocrine-containing islets, which was associated with the islets' degeneration process. Immunohistochemical staining of islets showed that CS-045 treatment normalized the distribution pattern of endocrine cells in the islets of db/db mice, reflected by a predominantly peripheral location of alpha and delta cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗