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PubMed1999

Optic nerve oxygen tension in pigs and the effect of carbonic anhydrase inhibitors.

PURPOSE: To evaluate how the oxygen tension of the optic nerve (ONP(O)2) is affected by the administration of the carbonic anhydrase inhibitors dorzolamide and acetazolamide and by alterations in oxygen and carbon dioxide in the breathing mixture. METHODS: Polarographic oxygen electrodes were placed in the vitreous humor immediately over the optic disc in 20 anesthetized pigs. Blood gasses and cardiovascular physiology were monitored. ONP(O)2 was recorded continuously with breathing gasses of 21% O2-79% N2, 100% O2, 20% O2-80% N2, and 5.19% CO2-19.9%, O2-74.9% N2. Acetazolamide (15-1000 mg) and dorzolamide (6-1000 mg) were administered intravenously. RESULTS: The mean (+/- SD) ONP(O)2 was found to be 24.1+/-11.6 mm Hg when the pigs were breathing room air and 50.7+/-29.3 mm Hg when they were breathing 100% O2 (n = 15; P < 0.001). In response to breathing 5.19% CO2, ONP(O)2 changed from 20.8+/-5.6 mm Hg (with 20.0% O2) to 28.9+/-3.6 mm Hg (n = 4; P < 0.001). Intravenous injections of 500 mg dorzolamide increased ONP(O)2 from 16.4+/-6.1 mm Hg to 26.9+/-12.2 mm Hg, or 52.5%+/-21.2% (n = 5; P = 0.017). A dose-dependent effect on ONP(O)2 was seen with intravenous dorzolamide doses of 1000, 500, 250, 125, 63, 27, 15, and 6 mg. Intravenous injections of 500 mg acetazolamide increased ONP(O)2 from 23.6+/-9.5 mm Hg to 30.9+/-10.0 mm Hg (n = 6; P < 0.001), and a dose-dependent effect was seen with doses of 1000, 500, 250, 125, 31, and 15 mg. CONCLUSIONS: ONP(O)2 is significantly increased by the carbonic anhydrase inhibition of dorzolamide and acetazolamide, and the effect is dose dependent. These data demonstrate for the first time a direct effect of carbonic anhydrase inhibitors on ONP(O)2.

Acetazolamide↗

PubMed1998

Effect of a specific synthetic inhibitor of neutrophil elastase (ONO-5046) on the course of acute hemorrhagic pancreatitis in dogs.

In acute pancreatitis, particularly in severe cases, polymorphonuclear neutrophil (PMN) elastase induces tissue damage in remote organs such as the lung, as well in the pancreas itself. Therefore, we examined the therapeutic effect of a specific synthetic inhibitor of PMN elastase (ONO-5046: Ono Pharmaceuticals, Osaka, Japan) on the lung, liver, and kidney, as well as pancreas, in severe hemorrhagic pancreatitis in dogs. Acute hemorrhagic pancreatitis was induced by the injection of a mixture of autologous bile and porcine trypsin into the main pancreatic duct. Lipopolysaccharide (LPS) was administered intravenously as a septic challenge. Two animal groups were used. In one group, continuous infusion of ONO-5046 was started prior to the injection of LPS (ONO group). In the other group (control), saline was infused instead. At the end of the experiment (330 min after the injection of bile and trypsin), the pancreas revealed severe hemorrhagic pancreatitis, and a large amount of bloody ascites had accumulated in the peritoneal cavity. The white blood cell count was markedly reduced in response to the induction of pancreatitis, and was decreased further by the septic attack, irrespective of the administration of ONO-5046, although the count increased again in the ONO group. Serum levels of amylase and alpha2-macroglobulin-trypsin complex increased similarly in both groups following administration of bile and trypsin. Serum Ca levels decreased in both groups. At the end of the experiment, the wet weight of the lung was slightly higher in the control group (without ONO-5046). Microscopically, the pancreas showed severe hemorrhage accompanied by extensive interstitial edema in both groups. The lung and liver demonstrated mild infiltration of inflammatory cells in the interstitium in both groups, although the inflammatory change in the liver was slightly milder in the ONO group. These findings indicate that severe hemorrhagic pancreatitis cannot be alleviated by the administration of a specific inhibitor of PMN elastase alone, although this may lessen damage to remote organs such as the liver and lung. The white blood cell count decreased markedly after the induction of acute pancreatitis, and much more after a septic challenge. This seems to be closely related to the accumulation of bloody ascites in the peritoneal cavity.

Amylases↗

PubMed2004

Comparative pharmacology of guinea pig cardiac myocyte and cloned hERG (I(Kr)) channel.

INTRODUCTION: This study used whole-cell, patch clamp techniques on isolated guinea pig ventricular myocytes and HEK293 cells expressing cloned human ether-a-go-go-related gene (hERG) to examine the action of drugs causing QT interval prolongation and torsades de pointes (TdP) in man. Similarities and important differences in drug actions on cardiac myocytes and cloned hERG I(Kr) channels were established. Qualitative actions of the drugs on cardiac myocytes corresponded with results obtained from Purkinje fibers and measurement of QT interval prolongation in animal and human telemetry studies. METHODS AND RESULTS: Adult guinea pig ventricular myocytes were isolated by enzymatic digestion. Cells were continuously perfused with Tyrode's solution at 33-35 degrees C. Recordings were made using the whole-cell, patch clamp technique. Action potentials (APs) were elicited under current clamp. Voltage clamp was used to study the effect of drugs on I(Kr) (rapidly activating delayed rectifier potassium current), I(Na) (sodium current), and I(Ca) (L-type calcium current). Dofetilide increased the myocyte action potential duration (APD) in a concentration-dependent manner, with a pIC50 of 7.3. Dofetilide 1 microM elicited early afterdepolarizations (EADs) but had little affect on I(Ca) or I(Na). E-4031 increased APD in a concentration-dependent manner, with a pIC50 of 7.2. In contrast, 10 microM loratadine, desloratadine, and cetirizine had little effect on APD or I(Kr). Interestingly, cisapride displayed a biphasic effect on myocyte APD and inhibited I(Ca) at 1 microM. Even at this high concentration, cisapride did not elicit EADs. A number of AstraZeneca compounds were tested on cardiac myocytes, revealing a mixture of drug actions that were not observed in hERG currents in HEK293 cells. One compound, particularly AR-C0X, was a potent blocker of myocyte AP (pIC50 of 8.4). AR-C0X also elicited EADs in cardiac myocytes. The potencies of the same set of drugs on the cloned hERG channel also were assessed. The pIC50 values for dofetilide, E-4031, terfenadine, loratadine, desloratadine, and cetirizine were 6.8, 7.1, 7.3, 5.1, 5.2, and <4, respectively. Elevation of temperature from 22 to 35 degrees C significantly enhanced the current kinetics and amplitudes of hERG currents and resulted in approximately fivefold increase in E-4031 potency. CONCLUSION: Our study demonstrates the advantages of cardiac myocytes over heterologously expressed hERG channels in predicting QT interval prolongation and TdP in man. The potencies of some drugs in cardiac myocytes were similar to hERG, but only myocytes were able to detect important changes in APD characteristics and display EADs predictive of arrhythmia development. We observed similar qualitative drug profiles in cardiac myocytes, dog Purkinje fibers, and animal and human telemetry studies. Therefore, isolated native cardiac myocytes are a better predictor of drug-induced QT prolongation and TdP than heterologously expressed hERG channels. Isolated cardiac myocytes, when used with high-throughput patch clamp instruments, may have an important role in screening potential cardiotoxic compounds in the early phase of drug discovery. This would significantly reduce the attrition rate of drugs entering preclinical and/or clinical development. The current kinetics and amplitudes of the cloned hERG channel were profoundly affected by temperature, significantly altering the potency of one drug (E-4031). This finding cautions against routine drug testing at room temperature compared to physiologic temperature when using the cloned hERG channel.

Animals↗

PubMed2005

SKI306X, an oriental herbal mixture, suppresses gastric leukotriene B4 synthesis without causing mucosal injury and the diclofenac-induced gastric lesions.

SKI306X compound is a herbal mixture. This plant was in oriental medicine and was clinically approved for the treatment of osteoarthritis (OA) in Korea. SKI306X was previously found to have anti-inflammatory, analgesic and cartilage protective effects in several experimental models. In this study, SKI306X was investigated for its gastro-sparing effects on the gastric mucosa comparing with those of diclofenac, a conventional NSAID, and celecoxib, a cyclooxygenase-2 (COX-2) specific inhibitor. To investigate acute gastric damaging properties of SKI306X, the stomach of the animals was histologically and immuno-histochemically examined after single or repeated administration, and SKI306X demonstrated excellent gastric tolerability. SKI306X did not cause significant gastric irritation, erosion, or ulceration up to the orally administered dose of 2 g/kg and the intraperitoneal (i.p.) dose of 125 mg/kg. In contrast, diclofenac caused mucosal erosion, ulceration and bleeding at clinically effective doses. To determine the mode of gastro-sparing action, eicosanoid synthesis was examined in gastric mucosa and blood. SKI306X significantly decreased gastric and blood leukotriene B(4) (LTB(4)) production. However, SKI306X showed either no effect or a slight increase in levels of prostaglandin E(2) (PGE(2)). In addition, gastro-protective effects of SKI306X were exhibited by suppressing diclofenac-induced erosion and ulceration of gastric mucosa in a rat model and the possible mechanism of these effects were investigated. These studies demonstrated that SKI306X did not produce any significant damage up to dose of 2 g/kg and was effective in significantly protecting the damage associated to diclofenac-induced gastric ulcerations. SKI306X could spare the gastric mucosa through significantly suppressing gastric leukotriene (LT) synthesis.

Animals↗

PubMed1999

The action of flufenamic acid and other nonsteroidal anti-inflammatories on sulfate transport in the isolated perfused rat liver.

The influence of flufenamic acid and other nonsteroidal anti-inflammatories on sulfate transport in the liver was investigated. The experimental system was the isolated perfused rat liver. Perfusion was accomplished in an open, nonrecirculating system. The perfusion fluid was Krebs/Henseleit-bicarbonate buffer (pH 7.4), saturated with a mixture of oxygen and carbon dioxide (95:5) by means of a membrane oxygenator and heated to 37 degrees C. Sulfate transport (equilibrium exchange) was measured by employing the multiple-indicator dilution technique with simultaneous injection (impulse input) of [35S]sulfate. [3H]sucrose (indicator for the distribution of the sinusoidal transit times), and [3H]water (indicator for the total aqueous space). Analysis was accomplished by means of a space-distributed variable transit time model. Flufenamic acid and other anti-inflammatories inhibited sulfate transport in the liver. For a concentration of 100 microM, the following decreasing series of potency could be established: flufenamic acid (53.4 +/- 2.9%) > niflumic acid (41.1 +/- 1.4%) > mefenamic acid (35.6 +/- 3.3%) > piroxicam (16.6 +/- 1.9%) > naproxen (13.5 +/- 8.4)%) nimesulide (11.6 +/- 5.8%). Inhibition of sulfate transport by flufenamic acid was clearly concentration dependent; 250 microM flufenamic acid produced more than 95% inhibition. Flufenamic acid in the range between 50 and 250 microM did not affect the mean transit times of tritiated water (t water) and [3H]sucrose (t suc), the same applying to all other anti-inflammatory agents (100 microM) tested in this work. This means that these agents do not affect vascular and cellular spaces, even when present at high concentrations. The ratio of the intra- to extracellular sulfate concentrations ([C]i/[C]e), generally between 0.4 and 0.5 under control conditions, was affected only by 250 microM flufenamic acid and 100 microM niflumic acid. In the first case, this phenomenon is possibly due to the high degree of transport inhibition (more than 95%), which does not allow a uniform tracer distribution over the whole cellular space during a single passage through the liver. The degree of inhibition of sulfate transport by 100 microM flufenamic acid was a function of the concentration of nontracer sulfate. With sulfate in the range between 1.2 and 25 mM, the inhibition degree increased linearly with the concentration. In the presence of flufenamic acid, the saturation curve of equilibrium exchange showed a substrate inhibition-like phenomenon, which was absent in the control curve. As inhibitors of sulfate transport in hepatocytes, flufenamic and niflumic acids are less active than in erythrocytes by a factor of 10(2). This observation is most probably indicative of structural differences between the hepatic sulfate carrier and the anion carrier of erythrocytes. It is unlikely that the action of flufenamic acid and its analogs on sulfate transport is a consequence of energy metabolism inhibition. Nimesulide is as active as flufenamic or niflumic acid in inhibiting energy metabolism but considerably less efficient as an inhibitor of sulfate transport. Our results as well as literature data reveal that the interactions of the nonsteroidal anti-inflammatories with the liver membranes and intracellular structures are ample and complex. Even at high concentrations, however, these interactions are not so intense as to change the vascular and cellular spaces.

Animals↗