Non-lethal hyperoxic potentiation of lung disease in the rat following subcutaneous administration of bleomycin

Rats were treated with subcutaneous injections of either saline or 1, 3, or 5 units of bleomycin (BLM) each day for 5 days (5, 15, or 25 units total dose). One half of each group of animals was exposed to 80% oxygen for 4 days during BLM dosings. Rats treated with both 25 units BLM and hyperoxia died after being returned to room air. All remaining rats were sacrificed 6 weeks following the end of treatment. Of the BLM rats in room air, only the lungs of the 15-unit group exhibited histological change, a mild diffuse interstitial disease. Both lower dose groups demonstrated slight increases in hydroxy-proline (OHP) content, a marker of collagen deposition or lung injury. The lungs of BLM rats exposed to hyperoxia demonstrated greater increases in total lung OHP levels. The lungs of the 15-unit group demonstrated lesions consistent with diffuse interstitial pulmonary fibrosis. Short-term, sublethal hyperoxia clearly potentiated injury in the rat following subcutaneous BLM treatment as assessed by either lethality or markers of pulmonary pathology.     

Pharmacokinetics of GM1 ganglioside following parenteral administration

The pharmacokinetic parameters of monosialotetrahexosylganglioside (GM1) have been determined in healthy volunteers at 3 dose levels: 100, 200, 300 mg. Each dose was administered to separate groups of 12 volunteers. GM1 levels were determined in plasma, urine, and faeces by a method based on the property of the cholera toxin beta subunit to react specifically with GM1 ganglioside. A non-compartmental model was applied to determine standard pharmacokinetic parameters. The average AUC increased with dose (1002 +/- 121.2, 1306 +/- 146.1, 3155 +/- 121.6 micrograms mL-1 h after 100, 200, 300 mg, respectively). Plasma clearance was less than 3 mL min-1 and the distribution volume was close to the plasma volume (on average between 4.3 and 7.2 L). Mean residence time was about 43 h for all doses. GM1 was not detected in urine, while in faeces the amount of GM1 determined was similar to the baseline values obtained before dosing.     

Gastric ulcer formation and cyclo-oxygenase inhibition in cat antrum follows parenteral administration of aspirin but not salicylate

The ulcerogenic actions of aspirin and sodium salicylate in cat gastric antrum following intravenous injection, and their effects on the synthesis of two major cyclo-oxygenase products by antral mucosa have been determined. Near-maximal rates of gastric acid secretion were stimulated by histamine, infused i.v. for 1 h prior to bolus injection of aspirin or salicylate and throughout the subsequent 4 h. The area of lesions in the cat gastric antrum were then assessed macroscopically and the generation of both 6-oxo-PGF1 alpha and PGE2 from strips of antral mucosal tissue following 1 min vortex-incubation was determined by radioimmunoassay. The plasma and mucosal-tissue levels of both aspirin and salicylate were determined using HPLC techniques. Aspirin (0.2 mmol. kg-1 i.v.) induced substantial deep antral ulceration during the 4 h histamine infusion, whereas sodium salicylate (0.2 mmol. kg-1 i.v.) caused no significant macroscopic damage. Sodium salicylate likewise caused no significant inhibition in the ex vivo generation of either 6-oxo-PGF1 alpha or PGE2, whereas aspirin induced 92 +/- 3 and 97 +/- 1% inhibition of generation of these prostanoids respectively. The levels of total salicylate in plasma and mucosal tissue were comparable following bolus i.v. injection of aspirin or sodium salicylate. These observations support the concept that cyclo-oxygenase inhibition is an important mechanism underlying deep gastric ulceration induced by aspirin, when administered parenterally in the cat.     

Methylnaltrexone bromide: research update of pharmacokinetics following parenteral administration

INTRODUCTION: Opioid-induced constipation is a major side effect of the use of opioid pain medications in a palliative care population. At present, the only approved treatment for opioid-induced constipation is methylnaltrexone bromide subcutaneous injection. Methylnaltrexone is a peripherally restricted opioid antagonist with μ-opioid receptor selectivity that can reduce opioid activity in peripheral organs such as the gastrointestinal tract while sparing the pain relief afforded by the pain medications. AREAS COVERED: This article addresses the pharmacokinetics of parenterally administered methylnaltrexone, including the studies in humans that form the basis for our understanding, and information on the disposition, metabolism and elimination of the drug. From this review, the reader will gain an understanding of the body's handling of methylnaltrexone following intravenous or subcutaneous administration. EXPERT OPINION: Studies conducted to date indicate that methylnaltrexone has high bioavailability after subcutaneous administration at therapeutic dose levels, a terminal half-life of ～ 8 - 9 h, minimal metabolism, elimination involving renal and non-renal routes, and a limited potential for drug-drug interactions. Combined with high efficacy and good tolerability, the predictable pharmacokinetic behavior of methylnaltrexone facilitates its successful utilization in clinical practice for the treatment of opioid-induced constipation in patients with advanced medical illness.     

Absorption of diazepam in man following rectal and parenteral administration.

Serum concentrations of diazepam and N-desmethyldiazepam were measured in six adult patients following administration of 10 mg diazepam in solution by the rectal, intravenous, and intramuscular routes. Maximum serum concentrations of 121--200 ng/ml were recorded from 10 to 20 min. after the rectal instillation, whereas following intramuscular injection the levels rose slowly and irregularly, reaching a maximum (62--186 ng/ml) in 1 to 24 hours. The bioavailability of diazepam given by rectal instillation was found to be 50 +/- 17 per cent (mean +/- S. D.) as compared with the intravenous administration. The possible reasons for the low bioavailability are discussed. It is concluded that administration by rectal tube provides a useful alternative to the tablets (and intramuscular injections) when a rapid onset of effect of the drug is wanted, and when intravenous administration is not applicable or practical.     

The potential application of cyclo-oxygenase type 2 inhibitors to Alzheimer's disease

In recent years, dramatic progress has been made in the understanding of the neurogenetics and neurobiology of Alzheimer's disease (AD). A great deal of experimental evidence has accumulated to support the hypothesis that inflammatory mechanisms are involved in the pathophysiology of AD. In addition, epidemiological studies have revealed that anti-inflammatory medications reduce the risk of developing AD. However, long-term use of conventional anti-inflammatory drugs is associated with significant toxicity which limits their potential application to the treatment or prevention of AD. It is believed that the inhibition of cyclo-oxygenase type-1 (COX-1) causes much of this toxicity, while inhibition of COX type-2 (COX-2), which is induced by inflammatory stimuli, may confer the anti-inflammatory effect. COX-2 is also constitutively expressed in brain regions preferentially affected in Alzheimer's disease and may be directly involved in neuronal cell death. Therefore, selective COX-2 inhibitors represent a promising class of drugs for the treatment of AD.     

The phosphorylation of rat liver ribosomes following administration of dimethylnitrosamine

Following a single dose of dimethylnitrosamine (DMNA) the phosphorylation of rat liver ribosomes was strongly enhanced. The incorporation of [³²P]phosphate into the 40 S subunit was stimulated 5- and 9-fold 2 and 5 hr, respectively, after administration of the drug. The phosphorylation of the large ribosomal subunit was not affected. The enhanced phosphorylation of the small subunit was due to a 20-fold stimulated incorporation of phosphate into ribosomal protein S6, the only one affected by DMNA.     

Enhancement of opioid inhibition of GABAergic synaptic transmission by cyclo-oxygenase inhibitors in rat periaqueductal grey neurones

Cyclo-oxygenase (COX) inhibitors potentiate opioid inhibition of GABAergic synaptic transmission in rat periaqueductal grey (PAG) (Vaughan et al., 1997). In the present study, the relative contribution of cyclo-oxygenase-1 (COX-1) and COX-2 inhibition to this phenomenon was examined by use of whole-cell patch clamp recordings in brain slices. The μ-receptor partial agonist morphine (10 μM) had little effect on GABAergic synaptic transmission. Morphine reduced the frequency of spontaneous miniature inhibitory postsynaptic currents (m.i.p.s.cs) by 13%. The nonselective COX inhibitor, indomethacin, produced a dose-dependent potentiation of the morpine inhibition of m.i.p.s.c. frequency (maximum inhibition 42%, IC₅₀=6 nM). More selective COX-2 inhibitors produced a similar potentiation of the morphine inhibition of m.i.p.s.c. frequency; however, at greater concentrations (IC₅₀=57 nM piroxicam, 1.7 μM DFU). Maintaining slices in the protein synthesis inhibitor cycloheximide (1 μM), to prevent COX-2 induction, had no effect on the potentiation action of DFU (10 μM). These results demonstrate that the potentiation of opioid inhibition of GABAergic synaptic transmission in PAG is largely a result of inhibition of COX-1 activity. These findings suggest that COX-1, rather than COX-2 inhibition, mediates the synergistic analgesic actions of opioids and non-steroidal anti-inflammatory drugs (NSAIDs) in the midbrain PAG.     

Effects of somatostatin on ethanol-induced gastric erosions in the rat: role of mast cells

Somatostatin (S) inhibits hemorrhagic gastric erosions produced by ethanol. In this study we compared the dose-dependent effects of linear (reduced) and cyclic (oxidized) S with respect to mast cell degranulation. The gastric mucosal injuries were more inhibited by linear S than by cyclic S. But linear S aggravated injury at a certain dose (10(-7) mol/rat). Mucosal mast cell degranulation correlated significantly with the area of hemorrhagic mucosal lesions (r = 0.91). Both cytoprotection as well as aggravation potency of S may be connected to gastric mucosal mast cell activity in the rat.     

Enhancement of long-term potentiation in the rat hippocampus following cocaine exposure

The neural adaptations involved in initiating and maintaining the long-term consequences of utilizing drugs of abuse are the subject of intense investigation. It is commonly suggested that the neural plasticity mechanisms underlying physiological phenomena such as learning and memory may also be engaged when drug addiction occurs. The effect of cocaine on one prominent cellular mechanism for learning/memory, long-term potentiation (LTP), was assessed in the CA1 region of the rat hippocampus. Hippocampal slices obtained from animals treated in vivo for five days with cocaine (15 mg/kg i.p., daily) exhibited enhanced LTP vs saline treated controls. We suggest that this example of cocaine-induced enhancement of LTP provides an example of how synaptic plasticity mechanisms may be altered in a manner that contributes to the behavioral outcomes expressed, following exposure to psychostimulants.     

Penetration of antibiotic into interstitial tissue fluid following parenteral administration of lysine cephalexin

Serum and interstitial fluid levels of antibiotic have been measured at various times following i.m. administration of equivalent doses of lysine cephalexin and sodium ampicillin, in a cross-over design, to dogs fitted with s.c. implanted silastic "tissue cages" and the results subjected to pharmacokinetic analysis. Serum concentrations of cephalexin were consistently higher than those of ampicillin and elimination half-lives were calculated as 1.73 h and 0.87 h, respectively. The rate of appearance of cephalexin in the interstitial fluid (Ka 1.741 h-1 was faster than that for ampicillin (Ka 0.946 h-1) and the maximum concentration obtained also proved to be higher. The half-life of cephalexin in the interstitial fluid (6.79 h) was almost four times longer than that in serum whereas that of ampicillin (2.03 h) was only a little more than twice as long. As a consequence a greater concentration and retention in interstitial fluid was obtained with cephalexin at all times tested. Since the interstitial fluid levels of cephalexin were still relatively high 8-12 h after the administration of a single dose repeated administration of lysine cephalexin 2 or 3 times daily is expected to result in a beneficial accumulation of cephalexin in the interstitial fluid.     

Additional inhibitors of rat serum acute phase alpha 2-macroglobulin levels. Effect of 6-mercaptopurine and some lipoxygenase and cyclo-oxygenase inhibitors

With the use of a previously described electroimmunoassay, 4 more compounds were found to depress acute phase alpha 2-macroglobulin levels in rat serum following the injection of turpentine. The compounds, meclofenamic acid, dextropropoxyphene, 5,8,11,14-eicosatetraynoic acid and 6-mercaptopurine are thus grouped with a variety of anti-inflammatory agents, cyclo-oxygenase inhibitors, hypolipidaemics and colchicine, all of which share the property of reducing the concentration of alpha 2-macroglobulin in rat serum. Compounds with immunosuppressant properties, namely amethopterin, azathioprine, cyclophosphamide and 5-fluorouracil, the steroids, betamethasone and dexamethasone, the lipoxygenase inhibitor, nordihydroguaiaretic acid, and MK477, a compound said to stimulate prostaglandin synthesis, did not reduce serum levels of the acute phase protein. 6-Mercaptopurine, a compound known to show anti-inflammatory properties in some systems, proved to be the strongest inhibitor found so far. The rat acute phase protein electroimmunoassay may thus be an effective screen for detecting a new class of anti-inflammatory agents. Knowledge of the mechanisms of action of drugs that depress rat serum alpha 2-macroglobulin concentrations may promote understanding of the control of acute phase protein production by the liver.     

Species variation in gastric toxicity following chronic administration of ciprofibrate to rat, mouse, and marmoset

Comparative oral toxicity studies with ciprofibrate have been undertaken in the mouse, rat, and marmoset for up to 26 weeks. Chronic administration of ciprofibrate (20 mg/kg/day) produced a prolonged, modest, but statistically significant hypergastrinemia in the rat. Morphological changes in the rat stomach included increased eosinophilia and hypertrophy of oxyntic cells after 2 or more weeks treatment and hyperplasia of the neuroendocrine (NE) cells after 8 weeks treatment. In contrast, only a transient hypergastrinemia was induced, but not sustained in the mouse at the same dose level over an 8-week time period. No morphological changes were detected in the stomach of this species. In the marmoset treatment, up to 80 mg/kg/day for 26 weeks failed to induce hypergastrinemia and no significant alterations in gastric NE cells were detected.     

Relationship between the prevention of rat gastric erosions and the inhibition of acid secretion by prostaglandins

The formation of gastric mucosal erosions induced by indomethacin in the rat was inhibited in a time- and dose-dependent manner by antisecretory prostaglandins, the methyl analogues of PGE₂ being 400 times as active as the parent prostaglandin. PGA₂, a methyl analogue of PGF₂, and the H₂-receptor antagonist metiamide, also inhibited erosiol formation. There was a variable relationship between the doses required to inhibit erosions and to inhibit gastric acid secretion. In the anaesthetised rat, the low incidence of erosions with indomethacin was markedly increased by concurrent gastric perfusion with acid saline and taurocholate. This mucosal damage was inhibited by the methyl analogues of PGE₂, suggesting protective actions on the mucosa other than inhibition of acid secretion.     

Endogenous opioids mediate the hypoalgesia induced by selective inhibitors of cyclo-oxygenase 2 in rat paws treated with carrageenan

Mechanical hyperalgesia induced in rat paws by carrageenan (250microg) was modified by pre-treatment with three selective inhibitors of cyclo-oxygenase-2 (COX-2); celecoxib, rofecoxib and SC236. These inhibitors raised the nociceptive threshold above the normal, non-inflamed, level, inducing a state of hypoalgesia. Such hypoalgesia was observed in different strains of rat (Holtzman, Wistar and Sprague-Dawley) and after different modes of administration of the COX-2 inhibitor (locally, in the paw, or systemically). A selective inhibitor of COX-1 (SC 560; 1-10mg kg(-1)) decreased hyperalgesia but did not induce hypoalgesia. Pre-treatment with naltrexone (3mg kg(-1)), an opioid receptor antagonist, did not affect carrageenan-induced hyperalgesia but abolished the hypoalgesic effects of COX-2 inhibitors, without diminishing the anti-hyperalgesic effect of indomethacin. In rats made tolerant to the anti-nociceptive effects of morphine, all anti-nociceptive effects of SC236 were abolished but the anti-hyperalgesic effects of indomethacin or SC 560 were unaffected. We conclude that, in our model of inflammatory hyperalgesia, the anti-nociceptive effect of selective COX-2 inhibitors involved the participation of endogenous opioids.     

Comparative study of anti-inflammatory and ulcerogenic activities of different cyclo-oxygenase inhibitors

The aim of the present work was to study the in vivo anti-inflammatory activity of six NSAIDs, ibuprofen, diclofenac, nimesulide, meloxicam, celecoxib and rofecoxib, using the rat air-pouch model of inflammation to characterize the ability of these drugs to induce gastric damage and PGE₂ inhibition. Selective compounds were observed to have no ulcerogenic properties at anti-inflammatory doses; however, these drugs were weaker inhibitors of several inflammatory aspects such as cell influx and exudate formation. In contrast, the non-selective and preferential compounds present anti-inflammatory properties at lower doses than presented by selective drugs. At anti-inflammatory doses, only meloxicam and ibuprofen produced gastric damage and inhibition of PGE₂ synthesis, suggesting that ulcerogenic properties of NSAIDs cannot be predicted by their selectivity index, since meloxicam demonstrates ulcerogenic properties despite its preferential profile.