Tumour enhancement with newly developed Mn-metalloporphyrin (HOP-9P) in magnetic resonance imaging of mice.

The purpose of the study is to evaluate the tumour enhancing characteristics and biodistribution of a newly developed metalloporphyrin derivative, HOP-9P (13, 17-bis (1-carboxypropionyl) carbamoylethyl-3, 8-bis (1-phenylpropyloxyethyl)-2,7,12,18-tetra- methyl-porphynato manganese (III)). Seven mice bearing SCC VII tumours were imaged using T1-weighted conventional spin echo magnetic resonance images before and 5 min, 2 h and 24 h after intravenous injection of 0.1 mmol/kg of HOP-9P. For the acquired images, signal intensities of the tumour, muscle and oil-phantom were measured. Then, tumor/oil and tumor/muscle signal intensity ratios were calculated. Nineteen mice were sacrificed before or after the administration of HOP-9P (at 5 min, 2 h and 24 h), and the biodistribution of manganese in the tumour, muscle, liver, blood and kidneys was measured using optical emission spectrometers and was expressed as micrograms of manganese per gram of tissue. The tumour/muscle signal intensity ratio at 24 h (3.18 +/- 0.34) was significantly higher than precontrast ratio (1.77 +/- 0.20) (P < 0.05). The biodistribution assessment of manganese demonstrated that HOP-9P gradually and consistently accumulated in the tumour to reach the highest concentration at 24 h (3.49 +/- 1.22 micro gMn/g). It is concluded that HOP-9P is a potential tumour-specific MR contrast agent.

Expertise and age-related changes in components of intelligence.

In a sample of 263 male GO players at 48 levels of expertise and ranging from 18 to 78 years of age, it was found that factors of expertise deductive reasoning (EDR) and expertise working memory (EWM) were independent of factors of fluid reasoning (Gf) and short-term working memory (STWM) that, along with cognitive speed (Gs), have been found to characterize decline of intelligence in adulthood. The main effects of analyses of cross-sectional age differences indicated age-related decline in EDR and EWM as well as in Gf, STWM, and Gs. However, interaction and partialing analyses indicated that decline in EDR and EWM decreased to no decline with increase in level of expertise. The results thus suggest that with increase in factors known to raise the level of expertise--particularly, intensive, well-designed practice--there may be no age-related decline in the intelligence that is measured in the abilities of expertise.

Assessment of gadolinium-enhanced time-resolved three-dimensional MR angiography for evaluating renal artery stenosis.

OBJECTIVE: The purpose of this study was to assess the image quality of gadolinium-enhanced time-resolved three-dimensional (3D) MR angiography and to evaluate its accuracy in revealing renal artery stenosis. SUBJECTS AND METHODS: Thirty-nine patients underwent MR angiography using an ultrafast 3D Fourier transform spoiled gradient-recalled acquisition in the steady state (TR/TE range, 2.6/0.7--0.8). Five seconds after administration of 15--20 mL gadodiamide hydrate, four or five consecutive data sets with imaging times of 7.0--7.6 sec were acquired during a single breath-hold. A timing examination was not performed. Image quality was assessed using quantitative analysis (signal-to-noise, contrast-to-noise, and venous-to-arterial enhancement ratios) and qualitative analysis (presence of venous overlap, presence of artifacts, and degree of renal arterial enhancement). MR angiography depiction of the renal artery stenosis was evaluated using conventional angiography as the standard of reference. RESULTS: On the best arterial phase, average aortic signal-to-noise ratio (+/-SD) was 74.5 +/- 24.4, aorta-to--inferior vena cava contrast-to-noise ratio was 70.8 +/- 23.4, and inferior vena cava--to-aorta venous-to-arterial enhancement ratio was 0.03 +/- 0.04. No venous overlap was seen in 38 of 39 patients. Substantial enhancement of renal arteries was seen in all patients without any noticeable artifacts. MR angiography correctly depicted the degree of stenosis in 44 of 47 normal arteries, 13 of 16 mildly stenotic arteries, five of five moderately stenotic arteries, three of four severely stenotic arteries, and one of one occluded artery. Sensitivity and specificity for revealing greater than 50% stenosis was 100%. CONCLUSION: Time-resolved 3D MR angiography can provide high-quality arteriograms. Its performance in revealing renal artery stenosis is comparable with that of conventional angiography.

Pretreatment with a deleted form of hepatocyte growth factor (dHGF) prevents the mortality of plasma-loss-induced hypovolemic shock in rats.

Severe trauma, infection, burn, pancreatitis and major surgery often induce circulatory collapse leading to multiple organ failure and death. It is hypothesized that therapy for the attenuation of circulatory collapse may improve the prognosis in these diseases. Previous work has documented that pretreatment with a deleted form of hepatocyte growth factor (dHGF) in normal rats increases the circulating plasma volume that reflects its accelerating action of hepatic protein synthesis. Therefore, the effects of pretreatment with dHGF on hypovolemic shock models were studied in rats. Rats were intravenously administered dHGF (1 mg/kg, twice daily for 5-6 days) or vehicle, and subjected to a 25% total body surface area full-thickness burn or a trypsin-induced acute pancreatitis. In rats that were receiving vehicle, survival rates on day 7 after injury induction were 12% in the burn model and 5% in the pancreatitis model, respectively. In both models, hematocrit values were apparently increased and circulating plasma volumes were decreased compared to sham-operated rats at 6 h after injury induction. The pretreatment of animals with dHGF increased the survival rates on day 7 to 40% in the burn model and 29% in the pancreatitis model. dHGF-treatment in normal rats decreased the hematocrit values and increased the circulating plasma volumes, and these changes of hematocrit value and circulating plasma volume were also maintained after injury induction. These findings suggest that dHGF pretreatment prevents the mortality in the severe burn and acute pancreatitis, and that its effect may contribute to ameliorating the progressing of plasma-loss-induced hypovolemia.

A deleted form of human hepatocyte growth factor stimulates hepatic lipogenesis and lipoprotein synthesis in rats.

Here we report the effect of the recombinant human deleted form of hepatocyte growth factor (dHGF) on lipid metabolism in rats. In primary cultured rat hepatocytes, dHGF accelerated incorporation of [(14)C]acetate into cellular lipids in a concentration-dependent manner. dHGF also increased the gene expression and enzyme activity of glucose-6-phosphate dehydrogenase, a rate-limiting enzyme of the pentose phosphate pathway, in hepatocytes. These results suggest that dHGF stimulates hepatocyte lipogenesis through upregulation of the pentose pathway and NADPH formation. Injection of dHGF into normal rats induced elevation of the serum triglyceride, phospholipid and cholesterol levels dose-dependently and in the same time course as the liver growth. dHGF injections stimulated the [(14)C]acetate incorporation into the liver lipids, but not into the adipose tissue nor the small intestine. Serum very low-density lipoprotein (VLDL) and low-density lipoprotein (LDL) levels were elevated by dHGF injections. [(14)C]Leucine incorporation into VLDL and LDL was also increased by dHGF injections. In rats with alcohol-induced fatty livers, dHGF treatment markedly diminished the accumulated liver triglyceride, while elevating serum lipid concentrations. The present results indicate that dHGF stimulates exclusively hepatic lipogenesis and increases serum lipoprotein levels in rats.

Dynamic MR dacryocystography: a new method for evaluating nasolacrimal duct obstructions.

OBJECTIVE: The purpose of this study was to evaluate the clinical performance of newly implemented dynamic MR dacryocystography. CONCLUSION: Dynamic MR dacryocystography, which requires neither ionizing radiation nor chemical contrast media with high viscosity, may be a useful tool for depicting nasolacrimal obstructions.

MRA of intracranial aneurysm models: a comparison of contrast-enhanced three-dimensional MRA with time-of-flight MRA.

PURPOSE: The purpose of our study was to compare contrast-enhanced 3D MR angiography (MRA) using ultrafast spoiled gradient-recalled acquisition in the steady state (SPGR) with 2D and 3D time-of-flight (TOF) MRA for visualization of intracranial lateral saccular aneurysm models. METHOD: We used lateral saccular aneurysm models with a height of 10 mm and neck sizes of 2.5 and 10 mm. Imaging was performed using a 1.5 T MR system with a head coil. Contrast-enhanced 3D MR angiograms were obtained using 3D ultrafast SPGR sequence with and without the MR Smartprep technique. Two-dimensional and 3D TOF MR angiograms were also obtained. RESULTS: Contrast-enhanced multiphase 3D MR angiograms taken every 5 s after injection of contrast medium proved superior to the other MRA techniques for delineating lateral saccular aneurysm models. Contrast-enhanced 3D MRA images taken with inadequate delay after MR Smartprep trigger showed poor visualization of the aneurysm model. CONCLUSION: Use of contrast-enhanced multiphase 3D MRA with ultrafast SPGR with shorter TR and TE resulted in clear images of the lateral saccular aneurysm model.

Deleted form of hepatocyte growth factor ameliorates the mortality rate of severe thermal injury in rats.

BACKGROUND: The modulating effects of the deleted form of hepatocyte growth factor (dHGF) on burn-induced mortality rates and hepatic protein synthesis were studied in rats. METHODS: Rats were anesthetized, subjected to a 40% full-thickness scald burn, and divided into 2 groups receiving dHGF and vehicle. RESULTS: In normal rats, dHGF-treatment (1 mg/kg intravenously, twice daily) for 5 days increased the circulating plasma volume. In burned rats that were receiving vehicle, the survival rate on day 23 after the burn was 27%. The serum albumin levels were decreased and did not reverse to the normal levels until day 23 after the burn. Serum alpha 2-concentration in the injured rats was increased, whereas serum levels of transferrin, total protein, and high-density lipoprotein-cholesterol were decreased. The treatment of animals with dHGF (1 mg/kg intravenously, 3 times daily) for 3 days increased the survival rate on day 23 by 64%. In the animals treated with dHGF for 3 or 6 days, serum alpha 1-, alpha 2-, and beta-globulin concentrations were increased by the dHGF treatment. The serum levels of albumin, transferrin, total protein, and high-density lipoprotein-cholesterol reversed to normal levels or higher. CONCLUSIONS: Our data show that dHGF treatment may attenuate the decrease of the circulating plasma volume after burn and reduce a high risk of burn shock. It is also indicated that dHGF accelerates synthesis of not only acute-phase reactants but also other hepatic proteins such as albumin and transferrin on severe burn injury. These findings suggest that the appropriate upregulation of hepatic protein synthesis induced by dHGF may accelerate the physiologic recovery process after thermal injury and contribute to ameliorating the burn-induced death.

[Kinematic MRI using short TR single shot fast spin echo (SSFSE) in evaluating swallowing].

PURPOSE: To determine the utility of short TR single shot fast spin echo (SSFSE) MR imaging for evaluating swallowing. MATERIALS AND METHODS: Five healthy volunteers underwent kinematic MR imaging of swallowing with a 1.5T MR scanner using the short TR (300 ms) SSFSE sequence. Twenty phases of sagittal sections were acquired within 6 sec, where the temporal resolution was 300 ms. For oral contrast medium, we used prune yogurt juice with Fe added. RESULTS: The image contrast of short TR SSFSE was found to be somewhere like that of T1-weighted images. In all cases, both the buccal and pharyngeal stages of swallowing were successfully depicted. The Fe-added prune yogurt juice performed as a positive contrast medium and helped determine anatomical structures in the buccal stage. CONCLUSION: Short TR (300 ms) SSFSE was useful in evaluating swallowing. The combined use of Fe-added prune yogurt juice was helpful in enhancing the surface of the oropharynx.

A mutant of deleted variant of hepatocyte growth factor (dHGF) with alanine substitution in the N-terminal basic region has higher activity in vivo.

In a previous study, we generated a mutant of dHGF (deleted variant of hepatocyte growth factor), termed #2, with higher specific activity than dHGF in assays of mitogenic activity on rat hepatocytes and America opossum kidney epithelial cells (OK). In the present study, we examine in vivo hepatotropic and renotropic activities of #2 and its distribution to target tissues, liver and kidney. Administration of #2 to normal rats significantly increased serum levels of total protein, albumin, free-cholesterol, and HDL-cholesterol and liver weight in a dose-dependent manner. Analysis of these parameters suggests that #2 is more potent than dHGF as a hepatotropic factor in vivo. In addition, #2 reduced mortality of mercuric chloride-administered mice and the effect was stronger than that of dHGF. When injected to mice, a larger amount of #2 than dHGF was rapidly distributed to the liver. Sixty minutes after injection, the concentrations of #2 in plasma, liver, and kidney were higher than those of dHGF. These distribution properties and the higher mitogenic activity in vitro may explain why #2 exerts more potent in vivo biological activity than dHGF.

Effective administration route for the deleted form of hepatocyte growth factor To exert its pharmacological effects.

The pharmacokinetics and the pharmacological effects of the deleted form of hepatocyte growth factor (dHGF) after intravenous (iv), subcutaneous (sc), or intramuscular (im) administration (0.25 and 2. 5 mg/kg) were studied in rats. After single iv administration (2.5 mg/kg), dHGF in serum rapidly decreased (alpha- and beta-phase half-life: 3.2 and 26.5 min, respectively). Two to four hours after single sc or im administration (2.5 mg/kg), the serum level of dHGF reached a maximum and then gradually declined (half-life: 2.7 h). The serum levels were not changed by repetitive iv administration, but were dramatically decreased by repetitive sc or im administration. Liver weight and serum levels of total protein, albumin, and HDL-cholesterol were significantly increased by iv administration of dHGF (twice daily for 4 days at 0.25 mg/kg). Sc or im administration of dHGF did not increase these parameters at the same dose, but did significantly at 2.5 mg/kg. These observations suggest that iv administration is the most effective in exerting the pharmacological effects of dHGF among three administration routes. dHGF after iv administration was distributed mainly and rapidly into liver (53.6% of the injected dHGF within 5 min) and was sustained at a higher level in the liver than in plasma. In infusion (0.5 mg/kg/3 h), dHGF level in plasma and liver reached a steady-state 15 and 60 min after starting the infusion, respectively. The steady-state level of dHGF was 7- to 9-fold higher in liver than in plasma, and the higher level in liver was sustained beyond the steady-state.

(+/-)-cis-2-methylspiro[1,3-oxathiolane-5,3'-quinuclidine] hydrochloride, hemihydrate (SNI-2011, cevimeline hydrochloride) induces saliva and tear secretions in rats and mice: the role of muscarinic acetylcholine receptors.

We investigated effects of (+/-)-cis-2-methylspiro[1,3-oxathiolane-5,3'-quinuclidine] hydrochloride, hemihydrate (SNI-2011, cevimeline hydrochloride), a rigid analogue of acetylcholine, on saliva and tear secretions in rats and mice to evaluate its therapeutical efficacy for xerostomia and xerophthalmia in patients with Sjogren's syndrome and X-ray exposure in the head and neck. Intraduodenal administrations of SNI-2011 increased saliva secretion in a dose-dependent manner at doses ranging from 3 to 30 mg/kg in normal rats and mice, two strains of autoimmune disease mice and X-irradiated saliva secretion defective rats. The salivation elicited by SNI-2011 was completely inhibited by atropine. A similar atropine-sensitive response was observed in tear secretion. In rat submandibular/sublingual gland membranes, [3H]quinuclidinyl benzilate (QNB) binding was saturable, and Scatchard plot analysis revealed a single population of binding sites with a Kd of 22 pM and a maximal binding capacity of 60 fmol/mg protein. The competitive inhibition curve of the [3H]QNB binding by SNI-2011 was obtained, and its dissociation constant value calculated from IC50 was 1-2 microM. These results suggest that SNI-2011 increases saliva and tear secretions through a direct stimulation to muscarinic receptors in salivary and lacrimal glands, and they suggest that SNI-2011 should be beneficial to patients with Sjögren's syndrome and X-ray exposure in the head and neck.

[Dynamic magnetic resonance dacryocystography using half Fourier single shot fast spin echo sequence].

Dynamic magnetic resonance dacryocystography (MRD) was implemented using 1.5T superconductive imager with a standard head coil. Prior to MRD, a pair of polyethylene microcatheters were inserted into the lower lacrimal canaliculi. Injecting a mixture of 6 ml of saline and 4 ml of xylocaine (0.5%) as a substitute for contrast medium, repeated measurement of thick section heavily T2 weighted image using half Fourier single shot fast spin echo (SSFSE) sequence was performed. MRD could well depict the pathologies of the lacrimal sac and the lacrimal duct in five cases of epiphora. It pinpointed the level of lacrimal duct obstruction, which was confirmed by both X-ray dacryocystography and intraoperative findings. Dynamic MRD is a reliable method of diagnosing nasolacrimal duct obstruction without using ionizing radiation or chemical contrast medium.

Effects of the deleted form of hepatocyte growth factor on serum hyaluronate levels in rats with liver cirrhosis.

Effects of the deleted form of hepatocyte growth factor (dHGF) on serum hyaluronate levels, an index for liver cirrhosis, were studied in rats. The levels of serum hyaluronate increased in rats with dimethylnitrosamine- or carbontetrachloride-induced cirrhotic liver with prolongation of prothrombin time, which indicates disorder of liver function. Daily intravenous injection of dHGF reduced the elevated serum hyaluronate levels with improvement of the prolonged prothrombin time. These results suggest that the amelioration of hepatic function disorder by dHGF leads to a reduction of the increased serum hyaluronate levels.

Preventive effects of the deleted form of hepatocyte growth factor against various liver injuries.

The effects of a naturally occurring deleted form of hepatocyte growth factor (HGF) on hepatic disorder were studied in various models of hepatic failure. The pretreatment of rats and mice with the deleted form of HGF prevented the liver injuries and coagulopathy induced by endotoxin, dimethylnitrosamine and acetaminophen and reduced the mortality due to hepatic dysfunction induced by these hepatotoxins. The concurrent administration of the deleted form of HGF also prevented the liver injury and hepatic fibrosis in mice treated with alpha-naphthylisothiocyanate and in rats treated with dimethylnitrosamine. Moreover, the deleted form of HGF normalized the results of the bromosulphalein-clearance test and ameliorated jaundice in rats with periportal cholangiolitic hepatopathy induced by alpha-naphthylisothiocyanate. The deleted form of HGF also reversed the coagulopathy in rats with hepatic disorder induced by dimethylnitrosamine or by 70% resection of cirrhotic liver (induced by carbon tetrachloride). In Long Evans cinnamon rats receiving vehicle, 20 out of 21 animals died within 4 days after the onset of jaundice. After infusion of the deleted form of HGF for 4 days, 7 out of 20 Long-Evans cinnamon rats survived. These results indicate that the deleted form of HGF could have therapeutic potency in patients with severe hepatic failure.

Deleted form of hepatocyte growth factor (dHGF) increases the number of platelets in rats with liver cirrhosis.

The effect of the deleted form of hepatocyte growth factor (dHGF) on thrombopoiesis was studied in rats. When normal rats were injected with dHGF (0.5 mg/kg i.v. twice a day), the number of platelets increased to about 1.5-fold the initial level. In addition, the treatment with dHGF (0.5 mg/kg i.v. twice daily) significantly increased the number of platelets in rats with liver cirrhosis induced by carbon tetrachloride and phenobarbital. When dHGF was given to rats at a dose of 0.05 or 0.5 mg/kg from the beginning of the induction of dimethylnitrosamine liver cirrhosis to day 28, dHGF dose-dependently ameliorated thrombocytopenia and completely prevented it at a dose of 0.5 mg/kg. These results indicate that dHGF may be applicable to the treatment of thrombocytopenia associated with liver cirrhosis.

Long-lasting salivation induced by a novel muscarinic receptor agonist SNI-2011 in rats and dogs.

The sialogogic effect of SNI-2011, a novel muscarinic receptor agonist, (+/-)-cis-2-methylspilo [1,3-oxathiolane-5,3'-quinuclidine] hydrochloride, hemihydrate, was compared with that of pilocarpine hydrochloride in a dose range in which the two muscarinic agonists exhibited approximately similar efficacy in eliciting salivation. Pilocarpine (0.66-2.0 mg/kg, i.d.) induced a marked but short-lasting salivation in rats, whereas the salivation induced by SNI-2011 (20-60 mg/kg, i.d.) lasted 1.4- to 1.8-fold longer. In dogs, the sialogogic effect of SNI-2011(1-3 mg/kg, i.v.) also lasted about 2-fold longer than that of pilocarpine (0.1-0.3 mg/kg, i.v.). The plasma SNI-2011 level that caused salivation at a rate of 0.4 ml/min was about 100 ng/ml and higher rates of salivation (over 0.4 ml/min) induced by 1 mg/kg SNI-2011 lasted for about 90 min in dogs. The plasma pilocarpine level that caused salivation at a rate of 0.4 ml/min was about 25 ng/ml and the higher rate of salivation (over 0.4 ml/min) induced by 0.1 mg/kg pilocarpine lasted only for 20 min in dogs. Effective plasma levels of SNI-2011 persisted longer than those of pilocarpine. These results indicate that SNI-2011 may be useful in the treatment of xerostomia because of its long-lasting sialogogic action.

Amelioration of disordered hepatic protein synthesis by the deleted form of hepatocyte growth factor in models of liver failure in rats.

Because the liver plays an important role in protein synthesis and cholesterol metabolism and reductions in these functions are observed in almost all hepatic disorders, the effects of the deleted form of hepatocyte growth factor (dHGF) on disordered hepatic protein synthesis were studied in various liver-injured rat models using Wistar male rats. In the 70% hepatectomized rats, plasma clotting time was prolonged and the serum level of total protein and the liver protein content were decreased. The treatment of the animals with dHGF (100-500 micrograms kg-1, i.v., twice daily) ameliorated these parameters at 48 or 72 h. The administration of carbon tetrachloride or D-galactosamine to hepatectomized rats induced a marked prolongation of plasma clotting time and hypoproteinaemia. In the animals treated with dHGF (500 micrograms kg-1, i.v., twice daily) these parameters were rapidly reversed compared with those of control groups. In a hepatocellular necrosis model induced by dimethylnitrosamine, the plasma clotting time was extremely prolonged, and liver protein content, serum total protein, albumin, HDL-cholesterol (as an index of lipoprotein) and plasma lecithin-cholesterol acyltransferase activity severely reduced. In this severely injured model, dHGF (5-500 micrograms kg-1, i.v., twice daily for 28 days) dose-dependently prevented the loss of liver protein content and improved the disordered plasma coagulability and serum protein levels. These results suggest that dHGF is useful for ameliorating the disorders in hepatic functions such as protein synthesis.

[Effects of partial nephrectomy on the pharmacokinetics and pharmacodynamics of recombinant human erythropoietin (SNB-5001) in rats].

The present study examined the pharmacokinetic and pharmacodynamic profiles of recombinant human erythropoietin (SNB-5001) in partially nephrectomized rats. The plasma level of SNB-5001 was measured by a 2-step enzyme immunoassay. The plasma disappearance curve after intravenous injection of SNB-5001 (50 U/kg) in these rats showed a biexponential pattern similar to that in non-treated rats, conforming to a two-compartment model. However, the total body clearance was reduced, the plasma half life was prolonged and the area under the concentration-time curve of SNB-5001 was increased by the partial nephrectomy. The distribution volumes of SNB-5001 were almost the same as those in non-treated rats. It is suggested that the kidney may contribute to the elimination of SNB-5001. Dose-dependent increases of reticulocytes, red blood cells, hemoglobin and hematocrits were observed after seven repetitive intravenous injections of SNB-5001 in both partially nephrectomized rats and non-treated rats. Hemopoietic responses were calculated by subtracting the initial values from the values after SNB-5001 injections of each hematological parameter (reticulocytes, red blood cells, hemoglobin and hematocrits). Hemopoietic responses in partially nephrectomized rats were apparently stronger than those in non-treated rats. These results suggest that the reduction of clearance by the partial nephrectomy may contribute to the hemopoietic responses, in addition to suggesting that the uremic conditions do not inhibit the effects of SNB-5001 in partially nephrectomized rats.

[Pharmacodynamics and therapeutic usage of recombinant human erythropoietin (SNB-5001) in animal models].

In mice, SNB-5001 released reticulocytes dose-dependently. In rats, rabbits and dogs given the same doses of SNB-5001, each dose-response curve of hemopoiesis almost showed parallelism. SNB-5001 induced nearly the same extent of hemopoiesis in these animals. After the hemopoiesis caused by SNB-5001, reticulocytes decreased within a week in both rats and dogs, but numbers of red blood cells (RBC) were higher than each control group for over 2 weeks in rats and for over 3 weeks in dogs. In polycythemic rats given excessive doses (200-5000 U/kg) of SNB-5001, blood volume increased, but blood pressure did not change. In the renal anemic rats produced by partial nephrectomy, dose-related and cumulative hemopoiesis were observed in both groups given SNB-5001 with different administration schedules (once a day for a week or once a week for 3 weeks). In the phrebotomized rats, SNB-5001 accelerated the recovery from the anemia induced by phrebotomy when given in a large quantity (6 ml/rat) and prevented the progressive anemia induced by intermittent phlebotomies when given in a small quantity (1 ml/rat x 3). SNB-5001 also improved the anemia caused by chronic inflammation in rats. However, increases of hemoglobin and hematocrit were smaller than that of RBC. Those results were caused by impaired release of iron from the reticuloendothelial system.