Early and late post-ischaemic recovery of contractile function is affected to different degrees by isoflurane and halothane in the anaesthetized rabbit model

We took advantage of the partial protection exerted by suitable dosages of nicotinamide against the beta-cytotoxic effect of streptozotocin (STZ) to create a new experimental diabetic syndrome in adult rats that appears closer to NIDDM than other available animal models with regard to insulin responsiveness to glucose and sulfonylureas. Among the various dosages of nicotinamide tested in 3-month-old Wistar rats (100-350 mg/kg body wt), the dosage of 230 mg/kg, given intraperitoneally 15 min before STZ administration (65 mg/kg i.v.) yielded a maximum of animals with moderate and stable nonfasting hyperglycemia (155 +/- 3 vs. 121 +/- 3 mg/dl in controls; P < 0.05) and 40% preservation of pancreatic insulin stores. We also evaluated beta-cell function both in vitro and in vivo 4-9 weeks after inducing diabetes. In the isolated perfused pancreas, insulin response to glucose elevation (5-11 mmol/l) was clearly present, although significantly reduced with respect to controls (P < 0.01). Moreover, the insulin response to tolbutamide (0.19 mmol/l) was similar to that observed in normal pancreases. Perfused pancreases from diabetic animals also exhibited a striking hypersensitivity to arginine infusion (7 mmol/l). In rats administered STZ plus nicotinamide, intravenous glucose tolerance tests revealed clear abnormalities in glucose tolerance and insulin responsiveness, which were interestingly reversed by tolbutamide administration (40 mg/kg i.v.). In conclusion, this novel NIDDM syndrome with reduced pancreatic insulin stores, which is similar to human NIDDM in that it has a significant response to glucose (although abnormal in kinetics) and preserved sensitivity to tolbutamide, may provide a particularly advantageous tool for pharmacological investigations of new insulinotropic agents.     

Myocardial glucose uptake in patients with NIDDM and stable coronary artery disease

Whole body insulin resistance characterizes patients with NIDDM, but it is not known whether insulin also has impaired ability to stimulate myocardial glucose uptake (MGU) in these patients. This study was designed to evaluate MGU as measured by 2-[18F]fluoro-2-deoxy-D-glucose ([18F]FDG) and positron emission tomography (PET) in patients with NIDDM and stable coronary artery disease (CAD) under standardized metabolic conditions. Eight patients with NIDDM, 11 nondiabetic patients with CAD, and 9 healthy control subjects were enrolled in the study. MGU was quantitated in the normal myocardial regions with [18F]FDG and PET and the whole body glucose disposal by glucose-insulin clamp technique (serum insulin, -430 pmol/l). Plasma glucose and serum insulin concentrations were comparable in all groups during PET studies. The whole body glucose uptake was 45% lower in NIDDM patients (22 +/- 9 micromol x min(-1) X kg(-1) body wt [mean +/- SD]), compared with healthy control subjects (40 +/- 17 micromol x min(-1) x kg(-1) body wt, P < 0.05). In CAD patients, whole body glucose uptake was 30 +/- 9 micromol x min(-1) x kg(-1) body wt (NS between the other groups). MGU was similar in the normal segments in all three groups (69 +/- 28 micromol x min(-1) x 100 g(-1) in NIDDM patients, 72 +/- 17 micromol x min(-1) x 100 g(-1) in CAD patients, and 76 +/- 10 micromol x min(-1) x 100 g(-1) in healthy control subjects, NS). No correlation was found between whole body glucose uptake and MGU. As studied by [18F]FDG PET under stable normoglycemic hyperinsulinemic conditions, MGU is not reduced in patients with NIDDM and CAD in spite of peripheral insulin resistance. These findings suggest that there is no significant defect in MGU in patients with NIDDM.     

Steep central islands after myopic photorefractive keratectomy

The nitric oxide synthase inhibitor 7-nitroindazole (7-NI) dose-dependently (3.0-30.0 mg/kg) displayed anxiolytic activity, as measured by an increase in open arm exploration time in the elevated plus-maze (EPM), following intraperitoneal (i.p.) administration in rats. Acute administration of 7-NI at 30.0 mg/kg significantly (P < 0.05) increased open arm exploration time by 176% compared to vehicle control, similar to the benzodiazepine diazepam at 1.0 and 3.0 mg/kg (+ 191 and + 200%, respectively). However, 39 h following subchronic 5-day administration of diazepam twice daily (bid) at 3.0 mg/kg, diazepam was devoid of anxiolytic activity at 1.0 mg/kg, as measured by no difference in open arm exploration time compared to vehicle control, while the 3.0 mg/kg dose still produced a significant (P < 0.05) 175% increase in open arm exploration time. In contrast, following subchronic administration of 7-NI (30.0 mg/kg, bid), a significant (P < 0.01) enhancement in open arm exploration time was observed at 30.0 mg/kg (+ 665% compared to control). Therefore, inhibition of nitric oxide synthase by 7-NI resulted in anxiolysis similar to diazepam following acute administration in the EPM. However, following subchronic administration, unlike diazepam which showed an attenuation of anxiolytic activity, 7-NI displayed enhanced anxiolytic efficacy and was devoid of tolerance.     

KB-R7785, a novel matrix metalloproteinase inhibitor, exerts its antidiabetic effect by inhibiting tumor necrosis factor-alpha production

It has been suggested that tumor necrosis factor-alpha (TNF-alpha) is a key mediator of insulin resistance in non-insulin-dependent diabetes mellitus (NIDDM). TNF-alpha is synthesized as a membrane-bound precursor; this is proteolytically processed to an active form by a matrix metalloproteinase (MMP)-like enzyme. In this study, we have used KKAy mice which show insulin resistance like NIDDM to investigate the effects of KB-R7785, a novel MMP inhibitor, on blood glucose and insulin levels. Subcutaneous administration of KB-R7785 at 100 mg/kg twice daily (i.e., 200 mg/kg/day) for 4 weeks resulted in a significant decrease in plasma glucose levels which was observed after 3 weeks. Oral administration of pioglitazone (20 mg/kg twice daily or 40 mg/kg/day for 4 weeks), an agent known to ameliorate insulin sensitivity, significantly decreased plasma glucose levels during the treatment period. KB-R7785, but not pioglitazone, also significantly decreased plasma insulin levels. Lipopolysaccharide (LPS) increased plasma TNF-alpha levels to a significantly greater degree in KKAy mice than in normal C57BL mice; this was inhibitable in KKAy mice by KB-R7785. In contrast, pioglitazone did not affect the LPS-induced increase in plasma TNF-alpha levels in KKAy mice. These results suggest that KB-R7785 exerts its antidiabetic effect by ameliorating insulin sensitivity through the inhibition of TNF-alpha production.     

NIDDM in the elderly

OBJECTIVE: We conducted this study to assess the metabolic alterations in elderly patients with NIDDM. RESEARCH DESIGN AND METHODS: Healthy, lean (n = 15; age, 73 +/- 1 years; BMI, 23.8 +/- 0.5 kg/m2), and obese (n = 10; age, 71 +/- 1 years; BMI, 28.9 +/- 1.2 kg/m2) control subjects and lean (n = 10; age, 75 +/- 2 years; BMI, 24.0 +/- 0.5 kg/m2) and obese (n = 23; age, 73 +/- 1 years; BMI, 29.9 +/- 0.7 kg/m2) NIDDM patients underwent a 3-h glucose tolerance test, a 2-h hyperglycemic glucose clamp study, and a 3-h euglycemic glucose clamp study with tritiated glucose methodology to measure glucose production and disposal rates. RESULTS: Waist-to-hip ratio (WHR) was greater in both lean and obese NIDDM patients than in control subjects. Insulin responses during the oral glucose tolerance test were similar in obese subjects (control subjects: 417 +/- 64 pmol/l; NIDDM patients: 392 +/- 47 pmol/l) but were reduced in lean NIDDM patients (control subjects: 374 +/- 34 pmol/l; NIDDM patients: 217 +/- 20 pmol/l, P < 0.01). Lean and obese NIDDM patients had absent first-phase insulin responses during the hyperglycemic clamp. Second-phase insulin responses were reduced in lean (P < 0.01 vs. control subjects by analysis of variance) but not obese NIDDM patients. Hepatic glucose output was not increased in lean or obese NIDDM patients. Steady-state (150-180 min) glucose disposal rates were 16% less in lean NIDDM patients (control subjects: 8.93 +/- 0.37 mg.kg LBM (lean body mass)-1.min-1; NIDDM patients: 7.50 +/- 0.28 mg.kg LBM-1.min-1, P < 0.05) and 37% less in obese NIDDM patients (control subjects: 8.17 +/- 0.38 mg.kg LBM-1.min-1; NIDDM patients: 5.03 +/- 0.36 mg.kg LBM-1.min-1, P < 0.001). CONCLUSIONS: Lean elderly NIDDM patients have a profound impairment in glucose-induced insulin release but mild resistance to insulin-mediated glucose disposal. Obese elderly NIDDM patients have adequate circulating insulin, but marked resistance to insulin-mediated glucose disposal. Hepatic glucose output is not increased in elderly NIDDM patients.     

Different change in lipoprotein(a) levels from lipid levels of other lipoproteins with improved glycemic control in patients with NIDDM

OBJECTIVE: To evaluate change both in lipoprotein(a) [Lp(a)] and lipid levels in other lipoproteins in non-insulin-dependent diabetes mellitus (NIDDM) after short-term improvement of glycemic control. RESEARCH DESIGN AND METHODS: We compared Lp(a) levels in 210 NIDDM patients with those in 46 control subjects and evaluated the relationship between glycemic control and Lp(a) levels in diabetic patients. In addition, changes in Lp(a) levels and lipid levels were assessed after the improvement of glycemic control in 54 poorly controlled NIDDM patients. RESULTS: In NIDDM, Lp(a) levels in all patients, 62 patients with HbA1c < 6.0%, and 75 patients with HbA1c between 6.0 and 8.0%, were significantly higher than those in control subjects (19.1 [1.7-106.6], 19.2 [6.0-106.6], and 20.3 [2.7-75.3] vs. 15.4 [2.0-61.7] mg/dl, median [range], P < 0.05). Lp(a) levels in 73 patients with HbA1c of > or = 8.0% (18.7 [1.7-58.8] mg/dl) were not significantly different from those in control subjects. After glycemic control, lipid levels in plasma and in other lipoproteins fell significantly, but Lp(a) did not change (from 18.3 [1.7-58.8] to 18.4 [6.6-95.3] mg/dl). Changes in lipid levels, including Lp(a), did not correlate with those in fasting plasma glucose or HbA1c. CONCLUSIONS: These results suggest that elevated Lp(a) levels do not reflect poor glycemic control and that Lp(a) levels are independent of lipid levels in other lipoproteins after improved glycemic control in NIDDM.     

In vitro and in vivo reversal of multidrug resistance by GF120918, an acridonecarboxamide derivative

N-(4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)ethyl]- phenyl)-9,10-dihydro-5-methoxy-9-oxo-4-acridine carboxamide (GF120918) has been selected from a chemical program aimed at identifying an optimized inhibitor of multidrug resistance (MDR). The potency of GF120918 is assessed by dose-dependent sensitization of CHRC5, OV1/DXR and MCF7/ADR cells to the cytotoxicity of doxorubicin and vincristine respectively: GF120918 fully reverses multidrug resistance at 0.05 to 0.1 microM and is half maximally active at 0.02 microM. The spectrum of drugs sensitized by GF120918 coincides with those having the classical MDR phenotype. In CHRC5 cells, 0.01-0.1 microM GF120918 enhances the uptake of [3H]daunorubicin and blocks the efflux from preloaded cells. It is also shown that GF120918 is still active several hours after being taken away from the culture medium showing that it is not, like verapamil, effluxed rapidly by P-glycoprotein. GF120918 effectively competes with [3H]azidopine for binding P-glycoprotein, pointing to this transport membrane protein as its likely site of action. After i.v. administration to mice, GF120918 penetrates thoroughly various organs that have a tissue level/blood level ratio above 10. It is eliminated from organs and blood with a half-time of approximately 2.7 h. It is well absorbed after p.o. administration. In mice implanted i.p. with the MDR P388/Dox tumor, a single i.v. or p.o. dose of GF120918 restores sensitivity of the tumor to a single i.p. dose (5 mg/kg) of doxorubicin administered 1 h later. A statistically significant effect is observed at 1 mg/kg GF120918 i.v. and maximal effect is reached at 5 mg/kg. Similarly, whereas neither drug alone is effective, GF120918 (10 mg/kg i.p.) associated with doxorubicin (5 mg/kg i.p.) inhibits the growth of the moderately MDR C26 tumor implanted s.c. as assessed by tumor size at day 19. GF120918 does not modify significantly the distribution or the elimination of doxorubicin in mice ruling out the possibility that the antitumor effects seen might be explained by pharmacokinetic interactions.     

Assessment of insulin sensitivity and secretion with the labelled intravenous glucose tolerance test: improved modelling analysis

A new modelling analysis was developed to assess insulin sensitivity with a tracer-modified intravenous glucose tolerance test (IVGTT). IVGTTs were performed in 5 normal (NGT) and 7 non-insulin-dependent diabetic (NIDDM) subjects. A 300 mg/kg glucose bolus containing [6,6-(2)H2]glucose was given at time 0. After 20 min, insulin was infused for 5 min (NGT, 0.03; NIDDM, 0.05 U/kg). Concentrations of tracer, glucose, insulin and C-peptide were measured for 240 min. A circulatory model for glucose kinetics was used. Glucose clearance was assumed to depend linearly on plasma insulin concentration delayed. Model parameters were: basal glucose clearance (Cl(b)), glucose clearance at 600 pmol/l insulin concentration (Cl600), basal glucose production (Pb), basal insulin sensitivity index (BSI = Cl(b)/basal insulin concentration); incremental insulin sensitivity index (ISI = slope of the relationship between insulin concentration and glucose clearance). Insulin secretion was calculated by deconvolution of C-peptide data. Indices of basal pancreatic sensitivity (PSIb) and first (PSI1) and second-phase (PSI2) sensitivity were calculated by normalizing insulin secretion to the prevailing glucose levels. Diabetic subjects were found to be insulin resistant (BSI: 2.3 +/- 0.6 vs 0.76 +/- 0.18 ml x min(-1) x m(-2) x pmol/l(-1), p < 0.02; ISI: 0.40 +/- 0.06 vs 0.13 +/- 0.05 ml x min(-1) x m(-2) x pmol/l(-1), p < 0.02; Cl600: 333 +/- 47 vs 137 +/- 26 ml x min(-1) x m(-2), p < 0.01; NGT vs NIDDM). Pb was not elevated in NIDDM (588 +/- 169 vs 606 +/- 123 micromol x min(-1) x m(-2), NGT vs NIDDM). Hepatic insulin resistance was however present as basal glucose and insulin were higher. PSI1 was impaired in NIDDM (67 +/- 15 vs 12 +/- 7 pmol x min x m(-2) x mmol/l(-1), p < 0.02; NGT vs NIDDM). In NGT and in a subset of NIDDM subjects (n = 4), PSIb was inversely correlated with BSI (r = 0.95, p < 0.0001, log transformation). This suggests the existence of a compensatory mechanism that increases pancreatic sensitivity in the presence of insulin resistance, which is normal in some NIDDM subjects and impaired in others. In conclusion, using a simple test the present analysis provides a rich set of parameters characterizing glucose metabolism and insulin secretion, agrees with the literature, and provides some new information on the relationship between insulin sensitivity and secretion.     

Oxindole, a sedative tryptophan metabolite, accumulates in blood and brain of rats with acute hepatic failure

Rats treated with oxindole (10-100 mg/kg i.p.), a putative tryptophan metabolite, showed decreased spontaneous locomotor activity, loss of the righting reflex, hypotension, and reversible coma. Brain oxindole levels were 0.05 +/- 0.01 nmol/g in controls and increased to 8.1 +/- 1.7 or 103 +/- 15 nmol/g after its administration at doses of 10 or 100 mg/kg i.p., respectively. To study the role that oxindole plays in the neurological symptoms associated with acute liver failure, we measured the changes of its concentration in the brain after massive liver damage, and we investigated the possible metabolic pathways leading to its synthesis. Rats treated with either thioacetamide (0.2 and 0.4 g/kg i.p., twice) or galactosamine (1 and 2 g/kg i.p.) showed acute liver failure and a large increase in blood or brain oxindole concentrations (from 0.05 +/- 0.01 nmol/g in brains of controls to 1.8 +/- 0.3 nmol/g in brains of thioacetamide-treated animals). Administration of tryptophan (300-1,000 mg/kg p.o.) caused a twofold increase, whereas administration of indole (10-100 mg/kg p.o.) caused a 200-fold increase, of oxindole content in liver, blood, and brain, thus suggesting that indole formation from tryptophan is a limiting step in oxindole synthesis. Oral administration of neomycin, a broad-spectrum, locally acting antibiotic agent able to reduce intestinal flora, significantly decreased brain oxindole content. Taken together, our data show that oxindole is a neurodepressant tryptophan metabolite and suggest that it may play a significant role in the neurological symptoms associated with acute liver impairment.     

Tumor implantation along abdominal trocar site after pelviscopic removal of malignant ovarian tumor--a case report

The hypoglycemic effect of the rhizomes of Polygala senega L. var. latifolia Torrey et Gray (Polygalaceae) was investigated in normal and KK-Ay mice, one of the model animals of non-insulin dependent diabetes mellitus (NIDDM). The n-butanol extract of senega rhizomes (SN) (5 mg/kg) reduced the blood glucose of normal mice from 191 +/- 3 to 120 +/- 3 mg/dl 4 hours after intraperitoneal administration (P < 0.001), and also showed a significant decrease in the glucose level of KK-Ay mice from 469 +/- 38 to 244 +/- 14 mg/dl under similar conditions (P < 0.001). But streptozotocin-induced diabetic mice did not experience a change in the blood glucose after administration of SN. We propose that the hypoglycemic effect of SN occurs without altering the insulin concentration. Moreover, SN needs the presence of insulin in order to act. In addition, one of the active components of the hypoglycemic effect was identified as a triterpenoid glycoside, senegin-II.     

Evaluation of BTS 67 582, a novel antidiabetic agent, in normal and diabetic rats

1. The effect of BTS 67 582, a novel antidiabetic agent, has been evaluated on plasma glucose and plasma insulin in normal and streptozotocin-induced diabetic rats. 2. BTS 67 582 (3 to 300 mg kg-1, p.o.) caused a dose- and time-dependent reduction in plasma glucose and an increase in plasma insulin in both fasted and glucose-loaded normal rats. The ED50 for the glucose lowering effect of BTS 67 582 in fasted rats was 37.6, 18.4 and 18.5 mg kg-1 at 1, 2 and 4 h after administration respectively. 3. In streptozotocin-induced (50 mg kg-1, i.v.) diabetic rats, BTS 67 582 (37-147 mg kg-1, p.o.) caused significant reductions of plasma glucose following a glucose load, whereas glibenclamide (100 mg kg-1, p.o.) was ineffective. BTS 67 582 significantly increased plasma insulin compared to controls whereas glibenclamide did not. 4. BTS 67 582 did not displace [3H]-glibenclamide from its binding sites in rat brain, guinea-pig ventricle or the HIT-T15 insulinoma beta-cell line. BTS 67 582 does not therefore appear to modulate its action via an effect on the 'sulphonylurea' receptor. 5. In fasted rats, the glucose lowering effect of BTS 67 582 (100 mg kg-1 p.o.) and glibenclamide (1 mg kg-1, p.o.) were antagonized by diazoxide (30 mg kg-1, i.p.). In addition BTS 67 582, like glibenclamide, caused a dose-dependent rightward shift of cromakalim-induced relaxation of noradrenaline precontracted rat aortic strips, suggesting the involvement of KATP channels. 6. In summary, BTS 67 582 produces a blood glucose-lowering effect in normal and streptozotocin-induced diabetic rats associated with increased insulin concentrations. This effect appears to be due to a blockade of ATP-sensitive potassium channel activity via a different binding site to that of glibenclamide.     

The science and art of radiation oncology after a century

Troglitazone is a new oral hypoglycemic agent that reduces insulin resistance in non-insulin-dependent diabetes mellitus (NIDDM). However, this agent increases serum lipoprotein(a) [Lp(a)], which is known as an atherogenic lipoprotein. The relationships between the response of Lp(a) to troglitazone and the apolipoprotein(a) [apo(a)] phenotype were investigated in this study. Nineteen NIDDM patients were treated with troglitazone for 4 weeks. Lp(a) increased significantly from 20.1+/-16.5 mg/dL to 44.1+/-31.9 mg/dL (P<.001) in all study patients. Lp(a) increased from 25.7+/-34.2 mg/dL to 50.1+/-38.7 mg/dL (P = .03) in patients with smaller apo(a) phenotypes (S1S4 to S2S4). Lp(a) also increased from 17.5+/-12.0 mg/dL to 41.3+/-29.6 mg/dL (P<.01) in patients with larger apo(a) phenotypes (S3 to S4). Therefore, the increase of Lp(a) by troglitazone may be independent of the apo(a) phenotype.     

Neural network subtyping of depression

OBJECTIVE: To examine the mechanisms by which weight loss improves glycemic control in overweight subjects with NIDDM, particularly the relationships between energy restriction, improvement in insulin sensitivity, and regional and overall adipose tissue loss. RESEARCH DESIGN AND METHODS: Hyperinsulinemic glucose clamps were performed in 20 subjects (BMI = 32.0 +/- 0.5 [SEM] kg/m2, age = 48.4 +/- 2.7 years) with normal glucose tolerance (NGT) (n = 10) or mild NIDDM (n = 10) before and on the 4th (d4) and 28th (d28) days of a reduced-energy (1,100 +/- 250 [SD] kcal/day) formula diet. Body composition changes were assessed by dual energy x-ray absorptiometry and insulin secretory changes were measured by insulin response to intravenous glucose before and after weight loss. RESULTS: In both groups, energy restriction (d4) reduced fasting plasma glucose (FPG) (delta FPG: NGT = -0.4 +/- 0.2 mmol/l and NIDDM = -1.1 +/- 0.03 mmol/l, P = 0.002), which was independently related to reduced carbohydrate intake (partial r = 0.64, P = 0.003). There was a marked d4 increase in percent of insulin suppression of hepatic glucose output (HGO) in both groups (delta HGO suppression: NGT = 28 +/- 15% and NIDDM = 32 +/- 8%, P = 0.002). By d28, with 6.3 +/- 0.4 kg weight loss, FPG was further reduced (d4 vs. d28) in NIDDM only (P = 0.05), and insulin sensitivity increased in both groups (P = 0.02). Only loss of abdominal fat related to improvements in FPG (r = 0.51, P = 0.03) and insulin sensitivity after weight loss (r = 0.48, P = 0.05). In contrast to insulin action, there were only small changes in insulin secretion. CONCLUSIONS: Both energy restriction and weight loss have beneficial effects on insulin action and glycemic control in obesity and mild NIDDM. The effect of energy restriction is related to changes in individual macronutrients, whereas weight loss effects relate to changes in abdominal fat.     

Biotransformation of monoterpenes, bile acids, and other isoprenoids in anaerobic ecosystems

RGH-2716 is a novel 1-oxa-3,8-diazaspiro[4.5] decan 2-one, which was published to have potent inhibitory effect on neuronal Na and Ca movement and stimulatory action on nerve growth factor (NGF)-production, as well as to show significant antiamnesic activity in experimental amnesia models. The aim of the present experiments was to study the effect of the compound on the learning process and on the different stages of memory using water-labyrinth in normal and memory impaired young animals, as well as to study cognitive effect of RGH-2716 on aged animals. At the doses of 0.5 mg/kg i.p. or 3 mg/kg p.o. given before daily swimming, this compound improved the learning process of young animals impaired by either diazepam (DIA) or scopolamine (SCOP). In retrograde amnesia model RGH-2716 (3 mg/kg p.o.) significantly ameliorated consolidation process and retrieval of information impaired by SCOP or DIA. Nimodipine and vinpocetine (10 mg/kg p.o.) showed moderate effect compared to RGH-2716. Aged rats pretreated with daily i.p. RGH-2716 performed the tasks with significantly fewer errors and shorter swimming time than untreated aged rats. When aged animals had to solve a new labyrinth problem, treated aged rats showed significantly better learning ability than aged controls. One month of oral treatment of aged rats with 3 mg/kg dose of RGH-2716 two times daily resulted in a "tendency-like" improvement in learning of aged Fischer 344 and spontaneously hypertensive (SH) rats. The present results make RGH-2716 an interesting compound for the treatment of cognitive disorders.     

In vivo functional interaction between phencyclidine binding sites and sigma receptors to produce head-weaving behavior in rats

To investigate the in vivo functional interaction between phencyclidine (1-(1-phenylcyclohexyl)piperidine; PCP) binding sites and sigma receptors, we examined the effects of sigma receptor ligands on stereotyped head-weaving behavior induced by PCP, a putative PCP/sigma receptor ligand, and (+)-5-methyl-10,11-dihydroxy-5H-dibenzo(a,d)cyclo-hepten-5,10-imin e ((+)-MK-801; dizocilpine), a selective PCP binding site ligand, in rats. PCP (7.5 mg/kg, i.p.)-induced head-weaving behavior was inhibited by both N,N-dipropyl-2-[4-methoxy-3-(2-phenylethoxy)-phenyl]-ethylamine (NE-100; 0.03-1.0 mg/kg, p.o.), a selective sigma1 receptor ligand, and alpha-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperidine butanol (BMY-14802; 3 and 10 mg/kg, p.o.), a prototype sigma receptor ligand, in a dose-dependent manner, whereas NE-100 (0.1-1.0 mg/kg, p.o.) and BMY-14802 (3 and 10 mg/kg, p.o.) did not inhibit dizocilpine (0.25 mg/kg, s.c.)-induced head-weaving behavior. These results suggest that NE-100 and BMY-14802 act via sigma receptors. Dizocilpine-induced head-weaving behavior was potentiated by 1,3-di-o-tolyl-guanidine (DTG; 0.03-0.3 microg/kg, i.v.) and (+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine ((+)-3-PPP; 3 and 6 mg/kg, i.p.), sigma1/sigma2 receptor ligands, as well as by (+)-N-allyl-normetazocine ((+)-SKF-10,047: 8 mg/kg, i.p.), a sigma1 receptor ligand, while DTG (0.3 microg/kg, i.v.), (+)-3-PPP (6 mg/kg, i.p.) and (+)-SKF-10,047 (8 mg/kg, i.p.) did not induce this behavior. Potentiation of dizocilpine-induced head-weaving behavior by DTG (0.3 microg/kg, i.v.), (+)-3-PPP (6 mg/kg, i.p.) and (+)-SKF-10,047 (8 mg/kg, i.p.) was completely blocked by NE-100 (0.1 mg/kg, p.o.) and BMY-14802 (10 mg/kg, p.o.). These results suggest that PCP binding sites and sigma receptors are involved in PCP-induced head weaving behavior, and that sigma1 receptors play an important role in modulation of the head-weaving behavior.     

Selective cyclo-oxygenase-2 inhibitors and their influence on the protective effect of a mild irritant in the rat stomach

1. The effects of the non-selective cyclo-oxygenase (COX) inhibitor indomethacin and the selective COX-2 inhibitors, N-[2-(cyclohexyloxy)-4-nitrophenyl] methanesulphonamide (NS-398), 5-methanesulphonamido-6-(2,4-difluorothio-phenyl)-1-indan one (L-745,337) and 5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulphonyl) phenyl-2(5H)-furanone (DFU), on the protection induced by the mild irritant 20% ethanol were investigated in the rat stomach. 2. Instillation of 20% ethanol (1 ml, p.o.) effectively protected against gastric mucosal injury induced by subsequent instillation of 70% or 96% ethanol (1 ml, p.o.). 3. Oral administration of indomethacin (1.25-20 mg kg[-1]) dose-dependently counteracted the protective effect of 20% ethanol (ID50: 3.5 mg kg[-1]). 4. Likewise, NS-398 (0.1-1 mg kg[-1]), L-745,337 (0.2-2 mg kg[-1]) and DFU (0.02-0.2 mg kg[-1]) inhibited the protective effect of 20% ethanol in a dose-dependent manner with ID50 values of 0.3 mg kg(-1), 0.4 mg kg(-1) and 0.06 mg kg(-1), respectively. 5. Inhibition of mild irritant-induced protection was also found when NS-398 (1 mg kg[-1]) was administered s.c. or when 96% ethanol was used to damage the mucosa. 6. Pretreatment with 16,16-dimethyl-prostaglandin (PG)E2 at 4 ng kg(-1), a dose that did not protect against ethanol (70%)-induced mucosal damage when given alone, completely reversed the effect of the selective COX-2 inhibitors on the mild irritant-induced protection. 7. Pretreatment with dexamethasone (3 mg kg(-1), 24 and 2 h before instillation of 20% ethanol) did not affect the protective activity of the mild irritant, indicating that enzyme induction is not involved. 8. Indomethacin (20 mg kg(-1), p.o.) did not prevent the protection conferred by sodium salicylate (100 mg kg[-1]), dimercaprol (30 microg kg[-1]), iodoacetamide (50 mg kg[-1]) and lithium (20 mg kg[-1]). Likewise, the protective effect of these agents was not counteracted by NS-398 (1 mg kg(-1), p.o.). 9. Whereas indomethacin (20 mg kg(-1), p.o.) near-maximally inhibited gastric mucosal formation of PGE2, 6-keto-PGF1alpha and thromboxane (TX) B2 as well as platelet TXB2 release, the selective COX-2 inhibitors were ineffective. 10. The findings show that selective COX-2 inhibitors, although lacking in ulcerogenic activity, prevent the protection conferred by a mild irritant. Prostaglandis generated by a constitutive COX-2 could thus contribute to physiological functions involved in gastric homeostasis, although at present a non-COX-2-related mechanism underlying the effect of the selective COX-2 inhibitors tested on mild irritant-induced protection cannot be completely excluded.     

Transcutaneous electrical nerve stimulation: effect on peripheral nerve conduction, mechanical pain threshold, and tactile threshold in humans

The effects of FR139317((R)2-[(R)-2-[(S)-2-[[1-(hexahydro-1H-azepinyl)]carb onyl] amino-4-methyl-pentanoyl] amino-3-[3-(1-methyl-1H-indoyl)]propionyl]-amino-3-(2-pyridyl)prop ionic acid), an endothelin ET(A) receptor antagonist, on systemic and renal haemodynamic responses and excretory responses to chronic or acute nitric oxide (NO) synthase inhibition with NG-nitro-L-arginine (NOARG) have been examined. An intravenous bolus injection of FR139317 (10 mg kg(-1)) to chronic NO-deficient hypertensive rats (2.74 mM NOARG in drinking water for 4 weeks) elicited only a slight decrease in mean arterial pressure (MAP), to the same extent as seen in normotensive control rats. Injection of this drug induced no alteration of the renal haemodynamics of this chronic hypertensive model. Urine formation in control rats was significantly reduced by administration of FR139317. No significant decrease in urine formation was observed in the chronic NO-deficient rats. Acute intravenous injection of NOARG (5 mg kg(-1)) induced a gradual and significant increase in MAP, with a significant decrease in renal blood flow. A slight but insignificant diuretic effect was observed. In animals pretreated with FR139317 (10 mg kg(-1) i.v.) NOARG induced a significantly less potent increase in MAP, whereas similar renal haemodynamic responses to NOARG were observed. In contrast to the FR139317-untreated group, urine formation tended to decrease after administration of NOARG. These results suggest that endothelin, via the ET(A) receptor, contributes to the systemic pressor response to acute NO synthase inhibition, although renal vasoconstriction and functional changes induced by acute NO synthase inhibition are independent of ET(A) receptor-related effects. These results imply that action of endothelin via the ET(A) receptor is not involved in the maintenance of sustained hypertension induced by chronic NO synthase inhibition.     

Anti-Sa antibody is an accurate diagnostic and prognostic marker in adult rheumatoid arthritis

The aporphine alkaloids boldine and glaucine have been reported to show "neuroleptic-like" actions in mice, suggesting that they may act as dopamine antagonists. We have found that in vitro boldine displaces specific striatal [3H]-SCH 23390 binding with IC50 = 0.4 microM and [3H]-raclopride binding with IC50 = 0.5 microM, while the affinities of glaucine at the same sites are an order of magnitude lower. In vivo, however, 40 mg/kg boldine (i.p.) did not modify specific striatal [3H]-raclopride binding and only decreased [3H]-SCH 23390 binding by 25%. On the other hand, 40 mg/kg glaucine (i.p.) displaced both radioligands by about 50%. Behaviors (climbing, sniffing, grooming) elicited in mice by apomorphine (0.75 mg/kg s.c.) were not modified by boldine at doses up to 40 mg/kg (i.p.) but were almost completely abolished by 40 mg/kg glaucine (i.p.). In the apomorphine-induced (0.1 mg/kg s.c.) rat yawning and penile erection model, boldine and glaucine appeared to be similarly effective, inhibiting both behaviors by more than 50% at 40 mg/kg (i.p.). Boldine and glaucine, injected i.p. at doses up to 40 mg/kg, were poor modifiers of dopamine metabolism in mouse and rat striatum. These data suggest that boldine does not display effective central dopaminergic antagonist activities in vivo in spite of its good binding affinity at D1- and D2-like receptors, and that glaucine, although less effective in vitro, does appear to exhibit some antidopaminergic properties in vivo.     

ML 3000 reduces gastric prostaglandin synthesis without causing mucosal injury

In this study we characterized the effects of a novel anti-inflammatory drug, ML 3000 ([2,2-dimethyl-6-(4-chlorophenyl)-7-phenyl-2,3-dihydro-1H-pyrrolizine- 5-yl]-acetic acid), on the gastric mucosa and attempted to determine the mechanism responsible for its apparent stomach-sparing properties. Acute gastric damaging properties of ML 3000 versus indomethacin were examined in the rat, while chronic-type gastric ulcer was examined in the rabbit. At doses of up to 100 mg/kg p.o., ML 3000 did not produce significant acute gastric injury, while indomethacin at 5-20 mg/kg p.o. caused mucosal necrosis and bleeding. ML 3000 significantly inhibited gastric and blood prostaglandin E2 synthesis, with the higher doses tested (30 and 100 mg/kg) producing comparable effects to that seen with indomethacin at 10 or 20 mg/kg. Gastric and blood leukotriene B4 synthesis were not significantly affected by either drug. While indomethacin caused a significant increase in leukocyte adherence to mesenteric venules, ML 3000 did not. When administered repeatedly to rabbits, diclofenac caused penetrating ulcer formation in the gastric antrum of the majority of the animals. ML 3000 did not produce any detectable damage at doses of 10 or 30 mg/kg, but an ulcer was observed in one of five rabbits given the 100 mg/kg dose. Prior administration of ML 3000 (10-100 mg/kg) did not significantly affect the extent of gastric damage induced by subsequent oral administration of ethanol. These studies demonstrate that ML 3000 spares the gastric mucosa despite significantly suppressing gastric prostaglandin synthesis.(ABSTRACT TRUNCATED AT 250 WORDS)     

Neurochemical and behavioral characterization of potential antidepressant properties of indeloxazine hydrochloride

The potential antidepressant properties of indeloxazine hydrochloride were examined in vitro and in vivo. Indeloxazine showed preferential affinity for both [3H] citalopram (Ki: 22.1 nM) and [3H]nisoxetine binding sites (Ki: 18.9 nM) in membranes of the rat cerebral cortex. In microdialysis studies, intraperitoneal injection of indeloxazine (3 and 10 mg/kg) dose-dependently increased the extracellular level of both serotonin and norepinephrine in rat frontal cortex of freely moving rats. Amitriptyline was almost equivalent to indeloxazine in these two assays with the exception of a much weaker effect on extracellular serotonin levels. Spontaneous [3H]serotonin release from rat cortical synaptosomes was significantly enhanced by indeloxazine (10-1000 nM). In behavioral studies, indeloxazine increased the number of wheel rotations in forced swimming tests in both ICR mice (50 mg/kg, p.o.) and SAMP8//YAN, a substrain of senescence-accelerated mouse (20 and 30 mg/kg, p.o.). Indeloxazine (3-10 mg/kg p.o.) also inhibited the incidence of muricide in raphe-lesioned rats. These results suggest that indeloxazine is an inhibitor of serotonin and norepinephrine uptake and has potential antidepressant properties. In addition, the drug-induced enhancement of serotonin release may contribute to its potent effects on the serotonergic system in vivo.