Noninvasive evaluation of the malignant potential of intracranial meningiomas performed using proton magnetic resonance spectroscopy.

OBJECT: Controversy exists about correlations between histological tumor grade and magnetic resonance (MR) spectroscopy data. The authors studied single-voxel proton MR spectroscopy as a noninvasive way to evaluate grade of malignancy in intracranial meningiomas. METHODS: The authors compared the results of MR spectroscopy with those derived by the MIB-1 staining index (SI) in 29 meningiomas. Proton MR spectroscopy was performed using stimulated echo acquisition and volume-localized solvent-attenuated proton nuclear MR sequences before surgery or other therapy. Twenty-four tumors were histologically benign (13 meningothelial, three fibrous, four transitional, three angiomatous, and one chordoid); four were atypical (Grade II), and one was papillary (Grade III). The mean MIB-1 SI in the benign group was significantly lower than those in the other groups (p = 0.0041). The mean choline-containing compound (Cho)/ creatine and phosphocreatine (Cr) ratios in the benign and nonbenign groups were 2.56+/-1.26 and 7.85+/-3.23, respectively (p = 0.0002). A significant linear correlation was observed between the Cho/Cr ratio and the MIB-1 SI (r0.05 = 0.74, p<0.001). Necrosis was present histologically in four of the five meningiomas classified either as atypical or papillary. Magnetic resonance spectroscopy revealed a methylene signal in these meningiomas that was not detected in benign meningiomas. Of the five meningiomas in which only a lactate signal was observed, two were benign and the MIB-1 SI in these two benign meningiomas was higher than the mean value for the benign group. Alanine, detected in 12 of 30 meningiomas, did not correlate with either tumor grade or Cho/Cr ratio. CONCLUSIONS: Proton MR spectroscopy is a useful diagnostic method for determining the proliferative or malignant potential of meningiomas according to the Cho/Cr ratio. A lactate and/or methylene signal suggests a high-grade tumor.

EM574, an erythromycin derivative, is a motilin receptor agonist in the rabbit.

This study was performed to examine whether an erythromycin derivative, de(N-methyl)-N-isopropyl-8,9-anhydroerythromycin A 6,9-hemiacetal (EM574) is a motilin receptor agonist in the rabbit gastrointestinal tract. EM574 and porcine motilin induced contractions in segments of isolated rabbit intestine with pEC50 values of 8.26 +/- 0.04 and 8.69 +/- 0.07, respectively, but not in rat or guinea pig preparations. The sensitivity and efficacy of the response to both compounds in rabbits decreased aborally and was insensitive to pretreatment with atropine or tetrodotoxin, but was markedly suppressed under Ca(2+)-free conditions. EM574 and porcine motilin specifically displaced [125I-Tyr23]canine motilin bound to gastric antral smooth muscle homogenates with plC50 values of 8.21 +/- 0.13 and 9.20 +/- 0.11, respectively. The pEC50 value for the contractile response and plC50 value for the receptor binding for motilin, EM574, erythromycin A and three other derivatives correlated well (r = 0.94, P < 0.01). Tissue section autoradiography in the antrum revealed that specific labeled motilin binding sites were localized in the circular muscle layer and myenteric plexus, and could be reduced in the presence of an excess of EM574. These results indicate that EM574 is a potent motilin receptor agonist in the rabbit gastrointestinal tract.

Prevention of gastric ulcer relapse induced by indomethacin in rats by a mutein of basic fibroblast growth factor.

We found indomethacin aggravates healed gastric ulcers (ulcer relapse) in rats. In the present study, we examined the effects of human basic fibroblast growth factor (bFGF) mutein CS23 (TGP-580) and histamine H2-receptor antagonists (H2-RAs) on ulcer relapse in this model. In male SD rats, gastric ulcers were induced in the antrum by injection of acetic acid. Indomethacin (1 mg/kg/day) given s.c. for 2 weeks starting 4 weeks after the operation aggravated the healed ulcer; the areas with and without indomethacin were 4.8 +/- 1.4 and 0.4 +/- 0.3 mm2, respectively. Drugs were given orally once daily for 4 weeks starting 2 days after the operation or for the 2-week indomethacin administration period. Treatment with ranitidine (100 mg/kg), cimetidine (100 mg/kg) and TGP-580 (0.1 mg/kg) for 4 weeks accelerated the healing. The aggravation by indomethacin was significantly inhibited by pretreatment with TGP-580 and mildly inhibited by cimetidine but not ranitidine. When the drugs were co-administered with indomethacin for 2 weeks, the aggravation was significantly prevented by ranitidine and mildly inhibited by cimetidine and TGP-580. Both TGP-580 and H2-RAs can prevent the ulcer relapse induced by indomethacin but via different modes of action: TGP-580 inhibits relapse mainly by acting on the process of healing, while H2-RAs act mainly on the process of aggravation.

Role of endogenous basic fibroblast growth factor in the healing of gastric ulcers in rats.

Recently, it has been pointed out that growth factors play an important role in the healing of gastrointestinal ulcers. In the present study, we examined the role of endogenous basic fibroblast growth factor (bFGF) in the healing of gastric ulcers in the rat. In male SD rats, gastric ulcers were induced in the antrum by injection of acetic acid. Time-dependent changes in the area and bFGF content in the ulcerated area and distribution of bFGF in the ulcerated mucosa were examined. Effects of bFGF mutein CS23 (TGP-580) and a monoclonal antibody for bFGF (MAb 3H3) on the healing of the gastric ulcers and angiogenesis in the ulcer bed were also examined. The content of bFGF in the ulcerated area increased with time as the ulcer healed and reached a maximum 7 days after ulcer formation. In the gastric ulcer bed, many cells such as fibroblasts and macrophages were positively stained immunohistochemically by anti-bFGF antiserum. MAb 3H3 (0.1 mg/rat/day, i.v.) inhibited angiogenesis in the ulcer bed and significantly delayed ulcer healing, while TGP-580 (0.001-0.1 mg/kg x 2/day, p.o.) increased the number of microvessels in the ulcer bed and accelerated the healing. These results suggest that endogenous bFGF may play an important role in the healing of gastric ulcers in the rat and that the angiogenic properties of bFGF (TGP-580) may be involved in its effect on ulcer healing.

Acinic cell tumour of the maxillary sinus: an unusual case initially diagnosed as parotid cancer.

An unusual case of acinic cell tumour of the maxillary sinus is presented. The patient, a 41-year-old male who had undergone incomplete excision of the tumour in the left parotid region previously, was referred to our department for further treatment. The initial pathological diagnosis was adenocarcinoma of the parotid gland. CT-scan not only revealed tumours in the left pre-auricular and upper neck region, but also an enhanced mass in the left maxillary sinus. Although there were neither nasal symptoms nor destruction of the maxillary bone, aspiration biopsy of the maxillary sinus revealed class V. Total maxillectomy, radiotherapy and systemic chemotherapy were performed just after total parotidectomy and radical neck dissection at the left side. The clinical and histopathological findings are discussed.

A human monoclonal antibody to a human self-antigen, CD2 derived from human peripheral blood lymphocytes engrafted in SCID mice.

To establish human hybridoma lines, production of human immunoglobulin (Ig) and behavior of the implanted human peripheral blood lymphocytes (PBL) were characterized in severe combined immunodeficiency (SCID) mice. Human PBL from healthy donors were injected into the peritoneal cavity of SCID mice, and they were immunized with self-antigen, CD2. CD45+ cells (human PBL) migrated to lymphoid tissues in the mice as early as 4 days, accounting for more than half the lymph node cells and thymocytes. The number of cells releasing human IgG specific to the antigen increased 3.5 weeks after immunization without the usual constraint that production of the IgG, an autoantibody, is prohibited by immunological tolerance in humans. Therefore, we established several human hybridomas secreting human IgG to CD2, since splenocytes and lymph node cells from the implanted SCID mice at 3.5 weeks were fused with a human B lymphoblastoid cell line. A human anti-CD2 monoclonal antibody (MAb) was confirmed to bind to natural CD2 on human T cells by flow cytometric analysis. The epitope for the MAb was identical with a portion that the ligand LFA-3 binded, so that the MAb might reduce the inflammatory reaction caused by preventing activation of human T cells. Here, we report that the human immune system could be reconstituted in SCID mice to develop human hybridomas producing human MAb to a human self-antigen.

Targeted disruption of the neurotrophin-3 gene with lacZ induces loss of trkC-positive neurons in sensory ganglia but not in spinal cords.

We have replaced the NT-3 gene with Escherichia coli-derived lacZ gene by means of homologous recombination in embryonic stem cells and thus produced null mutant mice. Mice homozygous for this mutation developed to birth, but most of them could not suck well and died within 2 days after birth. The surviving homozygous mutant mice displayed movement disorder similar to ataxia. The expression of lacZ was widely distributed in the target tissues of peripheral nerves, spinal motor neurons, lumbar dorsal root ganglia and trigeminal ganglia during the prenatal periods. A neuroanatomical examination revealed that there was marked cell reduction present in trigeminal and lumbar dorsal root ganglia in the developing homozygous mutant mice. In these tissues, the expression of trkC, a high-affinity receptor for NT-3, was markedly reduced. In contrast, we did not find any morphological abnormalities, significant cell loss or decreased levels of trkC expression in the motor neurons present in the ventral horn of the spinal cord. These results indicate that the absence of the NT-3 gene leads to a defect in the sensory nervous system, but it may be complemented by other neurotrophins in the motor nervous system during the development.

Effects of delapril on stroke, kidney dysfunction and cardiac hypertrophy in stroke-prone spontaneously hypertensive rats.

This study was performed to investigate the beneficial effects of prolonged treatment with an angiotensin converting enzyme (ACE) inhibitor, delapril, on the appearance of symptoms of hypertensive cardiovascular disease in stroke-prone spontaneously hypertensive rats (SHRSP). Cardiovascular disease symptoms: stroke, kidney dysfunction and cardiac hypertrophy, were evaluated by monitoring the incidence of stroke signs, urinary excretion of protein and the heart weight, respectively. The SHRSP that were kept under salt-loaded conditions (1% NaCl drinking solution) from six weeks of age developed severe hypertension, showed an increased incidence of stroke signs and increased urinary excretion of protein. Long-term treatment with delapril (10mg/kg/day, p.o. for four weeks) decreased the blood pressure and completely inhibited the incidence of stroke signs and the increase in urinary excretion of protein. In SHRSP that were kept under normal conditions (without 1% NaCl drinking solution), long term treatment with delapril at the same dose decreased the heart weight and, after five weeks of treatment, left ventricular weight was decreased significantly and the wall/lumen ratio of small coronary arterioles and the thickness of the left ventricular wall were decreased slightly. These results indicate that delapril can prevent the development of symptoms of hypertensive cardiovascular diseases: stroke, kidney dysfunction and cardiac hypertrophy, with antihypertensive activity in SHRSP.

Stimulation of thrombopoiesis in mice by fibroblast growth factor 9.

Fibroblast growth factor 9 (FGF-9), a novel member of the FGF family, was found to have thrombopoietic activity in vitro and in vivo. In an in vitro megakaryocyte colony-stimulating factor assay, anti-mouse interleukin-6 (IL-6) monoclonal antibody neutralized FGF-9 activity. This suggests that the activity may be exerted via IL-6 induction. BALB/c mice that received subcutaneous FGF-9 injections of 4 to 100 micrograms/day for 2 weeks showed a dose-dependent transient increase in peripheral platelet counts 10 to 12 days after the first treatment. Histologic studies showed a marked increase in megakaryocytes in bone marrow and extramedullary hematopoiesis in the spleen and the liver. Examination of changes in the DNA content of bone marrow megakaryocytes revealed that the ploidy distribution underwent a marked shift 3 days after FGF-9 injection, with a large increase in the 2N megakaryocyte population. The major modal ploidy shifted from the normal 16N to 2N. The number of megakaryocyte progenitor cells in FGF-9-treated mice increased up to 1.5-fold in the bone marrow and 10-fold in the spleen on day 6. These results indicate that FGF-9 acts on the in vivo proliferation of megakaryocytes.

Ultrastructural and immunohistochemical study of salivary duct carcinoma of the parotid gland.

A case of salivary duct carcinoma of the parotid gland found in an 81-year-old man was studied by light microscopy, immunohistochemistry, and electron microscopy. Histologically, the tumor was composed of elongated cords of cells and ductal structure with desmoplastic stromal reaction. Tumor cell nests sometimes showed central comedonecrosis. Immunohistochemically, the tumor cells were positive for cytokeratin and epithelial membrane antigen, and they were negative for S-100 protein and muscle-specific actin. Electromicroscopically, two cell types were identified. The first cell type showed electron-lucent cytoplasm with scant organelles. The second type cell contained numerous mitochondria. Neither acinar nor myoepithelial cell differentiation was observed. These findings suggest that salivary duct carcinoma originates from the interlobular or excretory ducts.

Enterococcus faecalis aggravates pyelonephritis caused by Pseudomonas aeruginosa in experimental ascending mixed urinary tract infection in mice.

Mixed urinary tract infection was caused by simultaneous inoculation of 10(4) CFU each of Enterococcus faecalis TN2005 and Pseudomonas aeruginosa P9 into the bladders of CBA/J mice. Both organisms proliferated in the kidneys, and viable cell counts of E. faecalis TN2005 reached a peak level of 4.1 x 10(5) CFU per pair of kidneys within the first 24 h, while P. aeruginosa P9 counts increased more slowly. The number of P. aeruginosa P9 cells peaked at 8.3 x 10(6) CFU per pair of kidneys 5 days after infection. Five days after mixed infection, infiltration of neutrophils into the renal pelvis and renal medulla was observed. Immunohistochemical staining revealed the presence of E. faecalis antigen in the renal medulla. P. aeruginosa antigen was detected mainly in the renal pelvis 5 days after infection and in the renal medulla as well as the renal pelvis 14 days after infection. Mixed infection induced pyelonephritis within 5 days after mixed infection, while it was not observed until 14 days after infection with P. aeruginosa P9 alone. P. aeruginosa P9 inoculated together with E. faecalis TN2005 was more resistant to eradication from the kidneys by beta-lactam antibiotics than P. aeruginosa P9 inoculated alone. These results suggest that E. faecalis TN2005 invades the renal medulla first in mixed urinary tract infection and induces histological changes which lead to aggravation of the pyelonephritis caused by P. aeruginosa P9.

TCV-116, a novel angiotensin II receptor antagonist, prevents intimal thickening and impairment of vascular function after carotid injury in rats.

Inhibitory effects of TCV-116 [(+-)-1-(cyclohexyloxycarbonyloxy)ethyl2-ethoxy-1-[[2'-(1H- tetrazol-5- yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylate], a novel angiotensin II AT1 subtype receptor antagonist, on the proliferation of vascular smooth muscle cells and the impairment of endothelium-dependent vascular relaxation were examined in the rat carotid balloon injury model. DNA content in the carotid artery was increased 3 days after carotid balloon injury and reached a plateau 14 days after the injury. Beneficial effects of TCV-116 in this model were examined 14 days after the injury. Oral administration of TCV-116 at 1 and 10 mg/kg/day significantly inhibited the increase in DNA content by 69 and 85%, respectively. Histological examination demonstrated that TCV-116 at 1 and 10 mg/kg significantly inhibited intimal thickening by 43 and 58%, respectively. Cilazapril (10 mg/kg/day p.o.) also inhibited intimal thickening by 48%. Contracting or relaxing vascular responses to phenylephrine or sodium nitroprusside did not differ between uninjured and injured arteries. However, acetylcholine-induced endothelium-dependent relaxation was greatly reduced in injured arteries; maximal relaxation was 6 +/- 2% (n = 17). TCV-116 at 1 and 10 mg/kg significantly ameliorated the impairment of vascular relaxation; maximal relaxation was 25 +/- 8 (n = 7) and 51 +/- 12% (n = 5), respectively. In uninjured arteries, L-NG-monomethyl arginine (300 microM), an inhibitor of endothelium-derived relaxing factor synthesis, inhibited acetylcholine (10 microM)-induced relaxation by 58 +/- 4% (n = 5). Scanning electron micrographs demonstrated that TCV-116 (10 mg/kg/day) enhanced restoration of endothelial cells in the carotid artery 14 days after injury.(ABSTRACT TRUNCATED AT 250 WORDS)

Inhibitory effect of TCV-309, a novel platelet activating factor (PAF) antagonist, on endotoxin-induced disseminated intravascular coagulation in rats: possible role of PAF in tissue factor generation.

The possible involvement of platelet activating factor (PAF) in the pathogenesis of endotoxin-induced disseminated intravascular coagulation (DIC) was investigated in rats using a novel potent PAF antagonist, TCV-309. TCV-309 (> 1 mg/kg, i.v.) showed beneficial effects in rats with experimental DIC induced by a 4-hour sustained infusion of endotoxin (1 mg/kg) in a dose-dependent manner. TCV-309 (1 mg/kg) significantly ameliorated the decrease in platelet count and plasma fibrinogen, the prolongation of prothrombin time (PT) and activated partial thromboplastin time (APTT) and the increase in fibrin and fibrinogen degradation products (FDP) and inhibited glomerular fibrin deposition. Furthermore, plasma tissue factor (TF) activity was greatly increased in the DIC rats, and this was also significantly decreased by TCV-309 (1 mg/kg). TCV-309 (1 mg/kg) did not affect these parameters in normal rats. A 4-hour sustained infusion of PAF (60 micrograms/kg) caused mild but significant changes in some DIC parameters such as PT, fibrinogen and FDP concentration and increased the plasma TF activity. TCV-309 (1 mg/kg) inhibited all these PAF-induced changes. TCV-309 (0.1 mM) itself had no direct in vitro effects on the blood coagulation system including TF activity. These results strongly suggest that PAF plays a role in the pathogenesis of endotoxin-induced DIC via the generation of TF. Prophylactic use of PAF antagonists may therefore be useful for the treatment of DIC with sepsis.

Upregulation of fibroblast growth factor-receptor messenger RNA expression in rat brain following transient forebrain ischemia.

Recently, we demonstrated that transient forebrain ischemia in rats leads to an early and strong induction of basic fibroblast growth factor (bFGF) synthesis in astrocytes in the injured brain regions. In this study, in order to clarify the targets of such raised endogenous bFGF levels, the messenger RNA (mRNA) expression of its receptors (flg and bek) in the hippocampus following transient forebrain ischemia induced by four-vessel occlusion for 20 min was investigated using an in situ hybridization technique. Transient forebrain ischemia induced an increase in the number of flg mRNA-positive cells from an early stage (24 h after ischemia) in the hippocampal CA1 subfield where delayed neuronal death occurred later (48-72 h after ischemia). This increase became more marked with the progression of neuronal death and was still evident in the same area 30 days later. The time course of the appearance and distribution pattern of flg mRNA-positive cells in the CA1 subfield were quite similar to those of bFGF mRNA-positive cells. On the other hand, in situ hybridization for bek mRNA showed only slight and transient (observed 72 h and 5 days after ischemia) increases in the number of mRNA-positive cells in the CA1 subfield following ischemia. The use of in situ hybridization and glial fibrillary acidic protein immunohistochemistry in combination demonstrated that the cells in the CA1 subfield that exhibited ischemia-induced flg or bek mRNA expression were astrocytes. These data indicate that transient forebrain ischemia induces upregulation of fibroblast growth factor-receptor expression, accompanied by increased bFGF expression in astrocytes, and suggest that the increased astrocytic bFGF levels in injured brain regions act on the astrocytes via autocrine systems and are involved in the development and maintenance of astrocytosis.

Antiobesity and antidiabetic actions of a new potent disaccharidase inhibitor in genetically obese-diabetic mice, KKA(y).

AO-128 is a potent and structurally novel inhibitor of the intestinal disaccharidases, such as maltase and sucrase. Genetically obese-diabetic mice, KKA(y), were used to examine the acute or long-term effectiveness of this compound. AO-128 decreased a postprandial rise in blood glucose after sucrose solution loading dose-dependently; the ED50 to reduce a delta increment of blood glucose by 50% was 0.22 mg/kg. The intestinal sucrase and maltase activities were suppressed to 7 and 48% of the control levels, respectively, at a dose of 0.21 mg/kg. Four-week-old female KKA(y) mice were kept on a laboratory diet containing 10 or 50 ppm of AO-128 for 12 weeks. The high dose of AO-128 reduced food intake and body weight gain throughout the experimental period. On the other hand, the low dose reduced body weight gain for the first 4 weeks without any effect on food intake. Development of the hyperglycemia and hyperinsulinemia characteristic of KKA(y) mice was moderately prevented by the low dose, and completely by the high dose. Hypertriglyceridemia tended to be suppressed by the AO-128 treatment. The high dose decreased the hemoglobin A1 level and parametrial adipose tissue weight. Hepatomegaly and fatty liver were ameliorated by AO-128 dose-dependently. Nephropathy was ameliorated by the high dose. These findings indicate that AO-128 may be useful for treating human obesity and diabetes.

Effect of thyrotropin-releasing hormone (TRH) in experimental spinal cord injury: a quantitative histopathologic study.

Spinal cord injuries in rats were experimentally produced by compressing the cord (T11 vertebra level) for 60 min with stainless steel screws. Morphometric analysis of the injured cord revealed that at 14 days post-injury, there were significant correlations between the neurologic score (NS) and all morphometric parameters, including total cross-sectional area (rs = 0.438), lesioned area (rs = -0.421) and area of the gray (rs = 0.377) and white matter (rs = 0.704). Although rats treated with thyrotropin-releasing hormone (TRH; 22.5 mg/kg, s.c., twice daily for 7 days starting 24 hr post-injury) showed significant improvement in NS 14 days post-injury, there were no significant differences in morphometric parameters between saline- and TRH-treated rats. In addition, no significant correlation was observed between NS and any of the morphometric parameters in TRH-treated rats, even though there was a significant correlation between the area of white matter and NS in saline-treated rats. These results suggest that neurologic recovery closely reflects the histopathological changes evident at the injury site in the present model, and that the improvement of neurologic status seen in rats with cord injury given TRH starting 24 hr post-injury is not due to protection against progression of neural damage at the injury site.

Antitumor effect of recombinant human interleukin-2 on the growth of murine hemangioendothelioma D14 in nude mice: occurrence of large granular cells in the tumor.

The antitumor effect of recombinant human interleukin-2 (rIL-2) on murine hemangioendothelioma D14 (D14) in female BALB/c-nu/nu mice was examined histologically. D14 cells which had been maintained in vitro were transplanted subcutaneously into nude mice on day 0 (1 x 10(7) cells/mouse). The mice with established tumor on day 28 received rIL-2 subcutaneously at a dose of 20 micrograms/mouse/day for 35 days. On day 63, the mice were killed, and the tumor, spleen and bone marrow were examined histologically. In the mice that had received rIL-2, tumor growth was significantly suppressed. Histologically, there was marked infiltration of large granular cells (about 15-30 microns in diameter) in the tumors. In the adjacent areas, there was a significant increase in the number of tumor cells showing karyorrhexis. The large granular cells (LGC) contained periodic acid Schiff-positive round granules in the cytoplasm and were stained positively for Thy-1.2 surface antigen. The LGC were also positive for asialo GM1 surface antigen but not for Lyt-1, Lyt-2 or IgG surface antigens. This evidence suggests that the LGC are lymphokine-activated killer-like cells which were derived from a natural killer cell lineage. The concomitant increases in the number of LGC and the number of cells showing karyorrhexis in the tumors of the mice treated with rIL-2 suggest that LGC play an important role in the destruction of tumor cells.

Involvement of thromboxane A2, leukotrienes and free radicals in puromycin nephrosis in rats.

Thromboxane A2 (TXA2), leukotrienes (LTs) and free radicals are considered to be possible mediators in the induction of glomerular injury and proteinuria. In this study, we examined the involvement of these three mediators and the protective effect of simultaneous inhibition of all three in puromycin aminonucleoside (PAN) nephrosis in rats. A single intraperitoneal injection of PAN (100 mg/kg) induced massive proteinuria and enhanced production of TXA2 and LTs from arachidonic acid in renal cortical slices and renal glomeruli, and increased malondialdehyde levels in plasma, urine and renal cortex. Oral administration of CV-6504(HCl) (3 to 20 mg/kg/day, for 1 to 2 weeks), a novel treble inhibitor of TXA2 synthetase, 5-lipoxygenase and lipid peroxidation, dose-dependently attenuated PAN-induced proteinuria and the increases in these three mediators. Any single specific inhibitor (CV-4151, a TXA2 synthetase inhibitor; AA-861, a 5-lipoxygenase inhibitor; or CV-3611, a radical scavenger) or a combination of two inhibitors showed no or only a slight antiproteinuric effect, but the combination of all three inhibitors significantly reduced PAN-induced proteinuria. These results suggest that, these three mediators may be involved in the pathogenesis of PAN nephrosis and that CV-6504(HCl), which can simultaneously inhibit all three, may be a useful therapeutic agent for nephrosis.

Effects of a proton pump inhibitor, AG-1749 (lansoprazole), on reflux esophagitis and experimental ulcers in rats.

The effects of (+/-)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy-2- pyridyl]methyl]sulfinyl]-1H-benzimidazole (lansoprazole, AG-1749) and famotidine on various experimental ulcers in rats were compared. AG-1749 inhibited reflux esophagitis; gastric lesions induced by water-immersion stress, aspirin or ethanol; and duodenal ulcers induced by cysteamine or mepirizole in a dose-dependent manner: the ID50 values were 0.7, 2.4, 0.7, 8.5, 1.1 and 0.3 mg/kg, p.o. or i.d., respectively. Famotidine inhibited reflux esophagitis with an ID50 value of 12.9 mg/kg, but did not cause 50% inhibition of ethanol-induced gastric lesions even at 100 mg/kg, although it showed almost the same or a little stronger potency on other experimental ulcers: ID50 values were 0.3-1.4 mg/kg. Significant aggravation of ethanol- or water-immersion stress-induced lesions was observed in rats given famotidine at 30 mg/kg twice daily for 4 days, but not in rats given AG-1749 at 10 mg/kg twice daily. Administration of AG-1749 for 14 consecutive days markedly accelerated the healing of acetic acid-induced gastric and duodenal ulcers, and the healing effect was significant at 10 and 30 mg/kg/day, p.o. Famotidine also accelerated the healing of ulcers, but its potency was less than that of AG-1749. The results of this study indicate that although AG-1749 is slightly less potent than famotidine in inhibiting acutely induced gastroduodenal lesions, this agent is superior to famotidine in promoting the healing of ulcers and in inhibiting reflux esophagitis and ethanol-induced gastric lesions.

Increase in basic fibroblast growth factor-like immunoreactivity in rat brain after forebrain ischemia.

Using immunohistochemical techniques, a study was conducted to determine whether basic fibroblast growth factor (bFGF) is generated as one of the 'self-repair' responses in rat brain following transient forebrain ischemia. In normal brain, slight bFGF-like immunoreactivity was observed. However, in rats exposed to 20 min of forebrain ischemia, intense bFGF-like immunoreactivity was observed in the CA1 subfield of the hippocampus and the caudate putamen, and marked activity was evident in the temporal cortex, corpus callosum and the CA4 subfield of the hippocampus. Marked neuronal degeneration was also observed in these brain regions following forebrain ischemia. These results suggest that induction of bFGF-like immunoreactivity may be related to the healing which follows brain ischemia.