Ecabet sodium prevents esophageal lesions induced by the reflux of gastric juice in rats.

We investigated the effect of ecabet sodium (ecabet) on rat acute esophageal lesions induced by reflux of gastric juice. Ligation of both pylorus and fore-stomach induced the reflux of gastric juice, decreased the amount of mucus and formed hemorrhagic lesions in the esophageal mucosa. Intragastric injection of ecabet reduced the pepsin activity and prevented both the decrease of mucus amount and formation of lesions. Ecabet enhanced the reduction in lesion formation induced by omeprazole and ranitidine without a change in decreased acid concentration and pepsin activity. Digestion of mucosa and the reduction in mucus were prevented by ecabet in the everted HCl and pepsin treated esophageal sac. These results indicate that ecabet prevents esophageal lesions by inhibiting pepsin activity as well as by protecting mucus from degradation. These further implicate the therapeutic potential of ecabet for prevention/treatment of GERD, especially in combination with a proton pump inhibitor or H(2)-antagonist.

Expression profiles of cytokines and chemokines in murine MDR1a-/- colitis.

OBJECTIVE: MDR1a-/- mice spontaneously develop colitis as the result of imperfect epithelial barrier derived from MDR1a deficiency in the large intestine; however, the pathogenesis is not well understood. This study investigated the expression profiles of cytokines and chemokines in murine MDR1a-/- colitis. METHODS: MDR1a-/- and wild-type FVB mice were monitored from the 6th to the 16th week of age. Production of various cytokines and chemokines in the large intestine and mesenteric lymph node (MLN) cells was examined. RESULTS: Inflammatory cell infiltration, IL-1beta production, and MPO activity were aberrantly enhanced in the tissue of MDR1a-/- mice. Under various stimuli, MLN cells produced higher levels of Th1-type (IFN-gamma, IL-2, and IL-12) and proinflammatory (IL-1beta and TNF-alpha) cytokines. Inflammatory chemokines MIP-2/CXCL2, KC/CXCL1, MIP-1alpha/CCL3, MCP-1/CCL2, and RANTES/CCL5 were also markedly upregulated in the tissue. CONCLUSION: Since the expression profiles of cytokines and chemokines correspond well with those in human IBD, MDR1a-/- mouse is a useful model for the analysis of IBD pathophysiology.

Therapeutic plasma exchange in recurrent focal segmental glomerulosclerosis following transplantation.

Focal segmental glomerulosclerosis (FSGS) recurs in 30% of renal allograft transplants with graft loss in half of the cases. A humoral factor may be implicated. We report on the use of therapeutic plasma exchange (TPE) in 11 patients with recurrent FSGS post transplantation. Medical records from 1989-2000 were reviewed for 11 adults transplanted for biopsy proven FSGS. Ten patients developed proteinuria (x: 6.1 g; range: 3-40 g/24 h) within 2 months of transplantation. In 1 patient, proteinuria (4 g) occurred 2 years post transplantation. Biopsy in six patients revealed early recurrent FSGS, while in five, suspected recurrence was based on clinical findings. Each patient received 5-11 TPEs (x: 6) with the COBE Spectra, daily or on alternate days with 2.5-3.5 L 5% albumin as the replacement fluid. In four, FFP was included because of coagulopathy. All received immunosuppression (IS) during and after TPE. A persistent drop in 24 h urine protein (U.P.) was observed in 10/11 patients. Seven had >70% drop in 24 h U.P. following the course of TPE, while three had a reduction of 45-50%. No change occurred in 1 patient. Follow-up (9 months-5 years) of seven patients has shown a persistent U.P. of <1 g with successful allograft survival. In these patients, TPE appeared effective in early recurrent FSGS. The decrease in U.P. may result from combined TPE and IS. Although the disease is designated in category III by the ASFA, TPE should be considered early when FSGS recurrence is established.

Role of adenosine and P2 receptors in the penile tumescence in anesthetized dogs.

We studied the role of adenosine and P2 receptors in the pelvic nerve stimulation-induced penile tumescence in anesthetized dogs. A local intracavernous injection of adenosine induced the tumescence, which was abolished by intracavernous 8-(p-sulfophenyl)theophylline (8-SPT), an unspecific adenosine receptor antagonist, and by 4-(2-[7-amino-2-(2-furyl)[1,2,4]triazolo[2,3-a][1,3,5]triazin-5-yl amino]ethyl)phenol (ZM241385), an adenosine A(2A) receptor antagonist. ATP also induced the tumescence, which was diminished by 8-SPT, but not by reactive blue-2, a P2 receptor antagonist. Neither intracavernous beta, gamma-meATP nor ADP(beta)S, P2X and P2Y receptor agonists, induced tumescence. N(G)-nitro-L-arginine (L-NAME), a nitric oxide synthase inhibitor, and T-1032, a phosphodiesterase type V inhibitor, had no effects on the tumescence induced by adenosine. 8-SPT and reactive blue-2 had no effects on the tumescence induced by pelvic nerve stimulation. These results show that although exogenous adenosine and ATP induce tumescence, neither the adenosine nor the P2 receptor is involved in the tumescence induced by pelvic nerve stimulation in anesthetized dogs.

T-1032, a novel specific phosphodiesterase type 5 inhibitor, increases venous compliance in anesthetized rats.

Nitric oxide (NO) donors including organic nitrates dilate capacitance vessels. As inhibition of phosphodiesterase type 5 results in the accumulation of guanosine 3'5'-cyclic monophosphate (cGMP), specific phosphodiesterase type 5 inhibitors are expected to have a vasodilator property similar to that of NO donors. To test this hypothesis, we examined the effect of methyl2-(4-aminophenyl)-1,2-dihydro-1-oxo-7-(2-pyridinylmethoxy)-4-(3,4,5-trimethoxyphenyl)-3-isoquinoline carboxylate sulfate (T-1032), a novel specific phosphodiesterase type 5 inhibitor, on mean arterial pressure and mean circulatory filling pressure (an index of venodilation) compared with that of nitroglycerin and diltiazem in mecamylamine- and noradrenaline-treated anesthetized rats. Intravenous infusion of T-1032 (0.1, 1, 10 microg/kg/min) dose-dependently decreased mean arterial pressure (-3.8+/-0.3%, -9.1+/-0.8%, -16.8+/-1.5% at doses of 0.1, 1 and 10 microg/kg/min, respectively) and mean circulatory filling pressure (-6.1+/-0.9%, -12.5+/-0.7%, -18.6+/-3.0% at doses of 0.1, 1 and 10 microg/kg/min, respectively). The mean circulatory filling pressure-mean arterial pressure relationship revealed that T-1032 had a selective action on the mean circulatory filling pressure compared with diltiazem (10, 100 microg/kg/min) and a similar or more selective effect than nitroglycerin (0.3, 3 and 30 microg/kg/min). In the next study, we calculated venous compliance and unstressed volume from the mean circulatory filling pressure-volume relationship. Intravenous infusion of T-1032 (3 microg/kg/min) increased venous compliance (3.35+/-0.40 in T-1032 vs. 2.31+/-0.15 ml/kg/mm Hg in vehicle, P<0.05) without changing the unstressed volume (37.2+/-2.80 in T-1032 vs. 42.6+/-2.37 ml/kg in vehicle, P>0.05). It was concluded that T-1032 increased venous capacitance by increasing venous compliance, and that this selective phosphodiesterase type 5 inhibitor appeared to have a different vasodilator action from that of an NO donor and a Ca(2+) channel antagonist in that it had a selective action on the mean circulatory filling pressure.

Plasma exchange in stiff-man syndrome.

Stiff-man syndrome (STS) is a rare neurological disorder characterized by involuntary axial and proximal limb rigidity and continuous motor unit activity on electromyography (EMG). Autoantibodies to glutamic acid decarboxylase (GAD) present in 60% of the patients are implicated. We report on the use of plasma exchange (PE) in 2 patients with STS whose serum and cerebrospinal fluid were negative for GAD autoantibodies. One patient showed minimal clinical improvement following PE while the second reported subjective improvement, but not any different from that with medications. Based on the results of PE in our patients, it seems that those who are autoantibody negative are less likely to respond. Whether a more aggressive approach to PE will be beneficial remains speculative.

Pharmacological profile of T-1032, a novel specific phosphodiesterase type 5 inhibitor, in isolated rat aorta and rabbit corpus cavernosum.

This study was designed to examine the pharmacological properties of T-1032 (methyl-2-(4-aminophenyl)-1,2-dihydro-1-oxo-7-(2-pyridinylmethoxy)-4-(3,4,5-trimethoxyphenyl)-3-isoquinoline carboxylate sulfate), a novel phosphodiesterase type 5 inhibitor, in isolated rat aorta and rabbit corpus cavernosum. T-1032 (3x10(-11) to 3x10(-7) M) caused an endothelium-dependent relaxation in the isolated rat aorta precontracted with phenylephrine, and the relaxation was accompanied by an increase in cGMP but not cAMP levels. The T-1032-induced relaxation was attenuated by N(G)-nitro-L-arginine methyl ester (L-NAME) (10(-3) M), a nitric oxide (NO) synthase inhibitor, or 1H-[1,2,4]oxadiazolo[4,3-alpha]quinoxalin-1-one (ODQ) (10(-5) M), a guanylyl cyclase inhibitor. T-1032 (10(-9), 10(-8) M) produced a potentiation of the relaxation induced by sodium nitroprusside, but not of the relaxation induced by isoproterenol. In the isolated rabbit corpus cavernosum precontracted with phenylephrine, the electrical field stimulation-induced relaxation was attenuated by treatment with tetrodotoxin (10(-6) M) as well as L-NAME (10(-4) M). The L-NAME-inhibited relaxation was restored by treatment with L-arginine (5x10(-4) M). T-1032 (10(-9) to 10(-6) M) and sildenafil (10(-9) to 10(-6) M) produced a potentiation of the electrical field stimulation-induced relaxation as well as a decrease in basal tension in a concentration-dependent manner. It was concluded that T-1032 had potentiating effects on the NO/cGMP signaling pathway in isolated tissues, probably through specific blockade of phosphodiesterase type 5. T-1032 would be a useful compound to examine the physiologic functions of phosphodiesterase type 5 in mammalian tissues.

Potentiation of penile tumescence by T-1032, a new potent and specific phosphodiesterase type V inhibitor, in dogs.

We examined the mechanism underlying the potentiation of penile tumescence by methyl 2-(4-aminophenyl)-1, 2dihydro-1-oxo-7-(2-pyridinylmethoxy)-4-(3,4, 5-trimethoxyphenyl)3-isoquinoline carboxylate sulfate (T-1032), a new potent and selective phosphodiesterase type V inhibitor. In vivo, pelvic nerve stimulation induced a penile tumescence together with increase of total nitric oxide metabolite levels within the corpus cavernosa of anesthetized dogs. Intravenous (1-100 microg/kg) and intraduodenal (3, 30, 300 microg/kg) treatment with T-1032 dose dependently potentiated the tumescence. The potency of T-1032 was equivalent to that of sildenafil. T-1032 did not influence the intracavernous pressure when the pelvic nerve stimulation was absent. The potentiation of tumescence was more pronounced by intracavernous than i.v. injection. Intracavernous N(G)-nitro-L-arginine, a nitric-oxide synthase inhibitor, but not N(G)-nitro-D-arginine diminished the effects of T-1032 on the tumescence. Furthermore, i.v. T-1032 augmented the tumescence induced by sodium nitroprusside (SNP) but not by vasoactive intestinal polypeptide (VIP). In vitro, in isolated preparations of canine corpus cavernosum precontracted with phenylephrine, SNP (0. 01-100 microM) and VIP (0.01-1 microM) produced a dose-dependent relaxation accompanied by an increase in cGMP and cAMP levels, respectively. T-1032 augmented the relaxation induced by SNP but not by VIP. These data suggest that oral treatment with T-1032 has potential to improve erectile dysfunction through the inhibition of phosphodiesterase type V in the smooth muscles of corpus cavernosa.

Collaborative work to evaluate toxicity on male reproductive organs by repeated dose studies in rats 7). Effects of reserpine in 2- and 4-weeks studies.

To assess the efficacy of different period of treatment for evaluating male reproductive toxicity in rats, reserpine was subcutaneously administered on a daily basis to male Sprague-Dawley rats at dosages of 0.05, 0.1 or 0.2 mg/kg for 2 weeks or at dosages of 0.05 or 0.1 mg/kg for 4 weeks. At the end of the administration period the animals were sacrificed and sperm counts, organ weights and histopathological changes in the reproductive organs were examined. The sperm number in the caudal epididymis and genital organ weights were not affected by reserpine with either 2- or 4-weeks treatment. In the 4-weeks study, histopathological examination of the testes revealed retention of step 19 spermatids in the seminiferous tubules of stages IX to XII and decreased secretory content of the prostate in the 0.05 and 0.1 mg/kg groups. In the 2-weeks study, although no distinct histopathological changes were observed in the 0.05 mg/kg group, decreased secretory content of the prostate, apoptosis of spermatocytes in the seminiferous tubules of stage VII and cell debris of the epididymis were observed in the 0.1 and 0.2 mg/kg groups. These results suggested that 2-weeks treatment with reserpine is sufficient for detection of testicular toxicity, although higher dosage levels are appropriate than for 4-weeks treatment.

Lessons learned from the review of cardiac catheterization laboratories: a report from the Laboratory Survey Committee of the Society for Cardiac Angiography and Interventions.

The Laboratory Survey Committee of the Society for Cardiac Angiography and Interventions was created as a resource for physicians and administrators to provide comprehensive independent outside review services for cardiac catheterization laboratories. Since 1989, when the committee began its work, surveys of 23 catheterization laboratories have been completed. Our review of this experience identified several recurring problems among the laboratories. The purpose of this paper is to summarize our experience and highlight the lessons we learned in the hope that this information will benefit many other laboratories.

Femoral vascular access for large-volume collection of peripheral blood progenitor cells.

Central venous catheters are used frequently in large-volume leukapheresis to provide high flow rates for peripheral blood progenitor cell (PBPC) collection. In a retrospective study, we evaluated the safety and efficacy of short-term use of large-bore femoral venous catheters for the collection of PBPCs in 63 patients with hematologic and solid organ malignancies. All catheters were placed in an outpatient setting on the day of apheresis and remained in site if subsequent collections became necessary. A total of 101 procedures were performed. Thirty-five patients (56%) reached target levels after 1 collection. Twenty-four patients (38%) had 2 consecutive day collections while 4 patients (6%) required more than 2 collections. In this latter group, 2 patients did not have consecutive day collections. One had 2 consecutive day collections followed by a third collection 48 hours later. In the other, leukapheresis was performed for 2 consecutive days and then resumed 3 days later with 2 subsequent collections. The longest duration the catheter remained in site was 6 days. Catheter care was provided by the apheresis staff. All patients who had more than 1 collection were given instructions on how to care for their catheters at home. Only 1 patient had oozing at the catheter site during the collection. Thrombosis, mechanical, and infectious complications were not encountered. The short-term use of femoral venous catheters appears safe and effective for the collection of PBPCs.

Gastric mucosal function following withdrawal of omeprazole in rats.

In the following study the function of gastric mucosa after withdrawal of 4-week suppression of acid secretion was examined. Rats were treated orally for 4 weeks with omeprazole (CAS 73590-58-6, 150 mg/kg/day). While elevated plasma gastrin levels during the treatment returned to normal 4 days after the last dosing, exogenously applied pentagastrin induced higher acid secretion compared with the vehicle-treated controls. Acetylsalicylic acid induced mucosal lesion 3.6-fold over the control as well. In contrast, the HCl-induced lesion was inhibited by 24.4%. These results indicate that not only the acid secretion but also the mucosal protection is enhanced after 4-week treatment with omeprazole in rats.

Congenital intrahepatic arteriovenous fistulae in a young beagle dog.

Congenital intrahepatic arteriovenous fistulae, a rare hepatic vascular anomaly, in an 8-mo-old female beagle dog was investigated. The animal showed anorexia, repeated vomiting, hemorrhagic diarrhea, and jaundice for approximately 2 wk. There was mild to severe increase of serum alkaline phosphatase, glutamic-oxalacetic transaminase, glutamic pyruvic transaminase, total cholesterol, total bilirubin, and gamma-glutamyl transpeptidase. Macroscopically, the main abdominal organs showed hemorrhagic edema together with bloody ascites. Other characteristic findings were severe hepatic atrophy (right medial, quadrate, left medial, and lateral lobes) with multiple vascular cysts and compensatory hypertrophy of the other lobes. The cystic vessels seemed to extend from the proper hepatic arteries and their branches but were indistinguishable from the portal vein. Histopathologically, the atrophied hepatic lobes were characterized by wide, fibrous septa containing severe hyperplasia and anastomosis of the arteriolae and venulae and proliferation of bile ducts.

Donor peripheral blood stem cell infusions in recipients of living-related liver allografts.

BACKGROUND: In this pilot study, donor peripheral blood stem cell (DPBSC) infusions were performed in three recipients of living-related liver transplants (LRLT). METHODS: DPBSCs were obtained by leukapheresis after mobilization with granulocyte-colony-stimulating factor (Filgrastim). Donor leukapheresis was performed on the 5th postoperative day, and half of the DPBSCs were infused into the recipient on the day of collection. The second half of the pheresed product was cryopreserved for delayed administration. RESULTS: Results from preliminary studies of chimerism in LRLT recipients, at 20 weeks posttransplant, suggested that the levels of donor cells detected in LRLT recipients treated with DPBSC infusions may be higher than those observed for recipients of cadaver donor liver allografts and vertebral body marrow infusions. CONCLUSIONS: The results of this pilot study indicate that administration of mobilized DPBSC to recipients of LRLT is a feasible procedure for both donor and recipient.

Role of vagus nerves and gastrin in the gastric phase of acid secretion in male anesthetized rats.

We used the pylorus ligation model to determine the role of vagus nerves and gastrin in acid secretion induced by mechanical and chemical stimulation of the gastric lumen in anesthetized male rats. Gastric distension induced by intragastric instillation of saline resulted in a 17-fold increase in acid secretion over the basal level without an alteration in serum gastrin levels. Distension-stimulated acid secretion was inhibited by bilateral subdiaphragmatic vagotomy but not by CI-988, a gastrin receptor antagonist. Intragastric peptone produced a 71-fold increase in acid secretion over the basal level that was accompanied by a significant increase in serum gastrin levels. Whereas vagotomy almost abolished peptone-stimulated acid secretion, CI-988 inhibited peptone-stimulated acid secretion by only 50%. We conclude that the vagus nerves mediate acid secretion by mechanical and chemical stimulation and that gastrin mediates acid secretion partly by chemical stimulation but not by mechanical stimulation in anesthetized male rats.

Safety of large-volume leukapheresis for collection of peripheral blood progenitor cells.

Large volume leukapheresis (LVL) reduces the number of procedures required to obtain adequate peripheral blood progenitor cells (PBPCs) for autologous hematopoietic reconstitution. LVL involves the processing of > 15 L or 5 patient blood volumes using high flow rates. We report our experience with LVL evaluating its efficiency and adverse effects in 71 adult patients with hematologic or solid organ malignancies. All were mobilized with chemotherapy and granulocyte colony-stimulating factor (G-CSF). All collections used a double lumen apheresis catheter. Mean values per LVL were as follows: blood processed, 24.6 L; patient blood volumes processed, 5.9; ACD-A used, 1,048 ml; heparin used, 6,148 units; collect time, 290 min; blood flow rate, 89 ml/min. Eighty percent of the collections were completed in one or two procedures to obtain > or = 6.0 x 10(8) MNCs/kg body weight. The most frequent side effect (39%) was parasthesia due to citrate-related hypocalcemia. This was managed with oral calcium supplements and/or slower flow rates. Post-LVL electrolyte changes were generally asymptomatic. Prophylactic oral potassium supplements were administered in 57% of cases. Other reactions included hypotension (4%), prolonged parasthesia (1.4%), and headache (1.4%). Catheter problems in 9 (13%) of the procedures were attributed to clot formation (37%) or positional effects (63%). No bleeding occurred. Post-LVL decreases in hematocrit and platelet count averaged 3.5% and 46%, respectively. Six (4%) of the procedures required red blood cell transfusions. Platelet transfusions were given in 19 (13%) of the procedures. We conclude that adverse reactions with LVL are similar to those reported for conventional PBPC collections, making it safe and efficacious as an outpatient procedure.

Efficient synthesis and gastric (H+/K+)-ATPase-inhibitory activity of 2-aryl-4,5-dihydro-1H-thieno[3,2-e]benzimidazoles.

A series of 2-aryl-4,5-dihydro-1H-thieno[3,2-e]benzimidazoles (1, 2) was prepared by condensation of 5-acylamino-4,5,6,7-tetrahydrobenzo[b]thiophen-4-ones (9, 10) with ammonium acetate under azeotropic reaction conditions. Various congeners, N-methyl and N-phenyl analogues (3-5), 4,5-dihydro-1H-thieno[2,3-e]benzimidazoles (6), 4,5-dihydro-1H-thieno[2,3-g]benzoxazoles (7), and 4,5-dihydro-1H-thieno[2,3-g]benzothiazoles (8), were also prepared. Several compounds in this series were shown to be K(+)-competitive inhibitors of the gastric (H+/K+)-ATPase and more potent inhibitors than SK&F-96067, 3-butyryl-8-methoxy-4-(2-tolylamino)quinoline, on pentagastrin-stimulated acid secretion in chronic gastric fistula rats after intraduodenal administration.

[Cross sectional study of the relationship between bone density to diet and life style using ultrasound bone densitometry].

The relationship between bone density to diet and life style was investigated in pre- and postmenopausal women in Kyoto Prefecture in 1994 by a cross-sectional study. Bone densities of 453 women aged 30-86 years were measured by ultrasound bone densitometry. History of pregnancy and delivery, menstruation, medical history, bone and arthral symptoms, life style, food intake frequency, current and past intake of dairy products, and physical activity were examined by self-administered questionnaire. Analysis of covariance and multiple-regression analysis were performed to determine the relation between bone density and life style adjusted for age and obesity index among 151 premenopausal women (PRE), 244 postmenopausal but not sedentary (under 65 years of age) women (POST), and 58 sedentary (older than 65 years of age) women (SED). The results were as follows; 1) A marked age-related decline in bone density was observed at 45-55 years of age. The correlation coefficient between age and bone density was significant at -0.65 (p < 0.01). 2) Obesity index and bone density were positively correlated in each group. 3) Among the PRE group women, there was no relation between life style and bone density. Those who experienced bone fractures tended toward low bone density. Among the POST group, time since menopause, exercise, and current milk intake were significantly correlated with bone density. In the SED group, women with arthralgia showed significantly lower densities. 4) From multiple-regression analysis, age, obesity index, and milk intake during childhood were shown to be related to bone density in each group.

Five year trends in cardiac catheterization: a report from the Registry of the Society for Cardiac Angiography and Interventions.

The Society for Cardiac Angiography and Interventions has maintained a registry of cardiac catheterizations since 1979 and of percutaneous cardiac interventions since 1990. Data from 392,923 procedures (317,592 diagnostic catheterizations, 74,963 coronary interventions, and 368 valvuloplasties) for the years 1990-1994 inclusive are presented. Over the 5 year period there was a trend toward same day and 23 hr discharges (19% in 1990 to 29% in 1994), and a decrease in combined right and left heart procedures from 38% to 26%. For cardiac catheterizations ionic contrast use declined from 26% of procedures to 13% in 1994. The use of ionic contrast was even lower in interventional procedures, with laboratories reporting use in 21% of procedures in 1990 dropping to 9% in 1994. Balloons were the first choice device in 92.5% of native arteries and 82.7% of grafts in 1994. For the first time in 1994 more mitral than aortic valvuloplasties were reported.