Inadequate treatment of ventilator-associated pneumonia: risk factors and impact on outcomes.

Initial antibiotic therapy is an important determinant of clinical outcomes in ventilator-associated pneumonia (VAP). Several studies have investigated this issue, with conflicting results. This study investigated risk factors of inadequate empirical antimicrobial therapy and its impact on outcomes for patients with a clinical diagnosis of VAP. The primary outcome was adequacy of antimicrobial therapy. Secondary outcomes were duration of mechanical ventilation, hospital and intensive care unit (ICU) lengths of stay, and mortality due to VAP. Mean age was 62.9+/-15.2 years, mean APACHE (Acute Physiological Assessment and Chronic Health Evaluation) II score was 20.1+/-8.1 and mean MODS (Multiple Organ Dysfunction Score) was 3.7+/-2.5. Sixty-nine (45.7%) of 151 patients with a clinical diagnosis of VAP received inadequate antimicrobial treatment for VAP initially. There were 100 (66.2%) episodes of VAP caused by multidrug-resistant pathogens, of which 56% were inadequately treated, whereas the rate of inadequate antimicrobial therapy for VAP caused by susceptible-drug pathogens was 25.5% (P<0.001). Multiple logistic regression analysis revealed that the risk of inadequate antimicrobial treatment was more than twice as great for patients with late-onset VAP [odds ratio (OR), 2.93; 95% confidence interval (CI), 1.30-6.64; P=0.01], and more than three times for patients with VAP caused by multidrug-resistant pathogens (OR, 3.07; 95% CI, 1.29-7.30; P=0.01) or with polymicrobial VAP (OR, 3.67; 95% CI, 1.21-11.12; P=0.02). Inadequate antimicrobial treatment was associated with higher mortality for patients with VAP. Two of three independent risk factors for treatment inadequacy were associated with the isolation and identification of micro-organisms.

N6-substituted adenosine receptor agonists. Synthesis and pharmacological activity as potent antinociceptive agents.

Novel N6-(indol-3-yl)alkyl derivatives of adenosine were synthesized. The adenosine receptor affinity and the antinociceptive activity of these compounds were assessed in binding studies and the phenylbenzoquinone-induced writhing test. Most of these analogues exhibited a potent analgesic activity without side effects. Among them, compound 3c (UP 202-32) bound to A1 (Ki = 110 nM) and A2 (Ki = 350 nM) adenosine receptors in a specific manner since it did not interact with many other receptors, especially opioid binding sites. The antinociceptive activity in the phenylbenzoquinone assay (ED50 = 3.3 mg/kg po) was antagonized by 8-cyclopentyltheophylline, suggesting that an adenosinergic mechanism underlies the analgesic activity observed with this compound. The data obtained with these new N6-substituted adenosine receptor agonists emphasize the interest of such compounds in the treatment of pain.

Pharmacological profile of UP 5145-52, an original antiulcer and antisecretory agent.

The gastric and antiulcer effects of UP 5145-52, a new naphthyridinone derivative (1-phenyl-1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl)-4-acetoxy butane, were studied in rats. UP 5145-52 dose dependently prevented the formation of gastric lesions induced by a necrotizing agent such as absolute ethanol, indomethacin or stress (ED50 values were 0.065, 1.26 and 0.72 mg/kg p.o., respectively). A beneficial action was also observed against indomethacin-induced intestinal lesions. UP 5145-52 inhibited total acid output in the pylorus-ligated rat (ED50 on total acid output was 0.16 mg/kg p.o.) and in the rat chronic gastric fistula model. The mechanism of antisecretory activity currently remains unknown as UP 5145-52 fails to bind to receptors involved in gastric secretion (H2 or muscarinic) and to inhibit H+/K+ adenosine triphosphatase. The ability of UP 5145-52 (1 mg/kg p.o.) to restore synthesis of gastric acid glycoproteins depressed by previous administration of absolute ethanol suggests that cytoprotection could play a role in the antiulcer efficacy of the drug.

Comparative antiulcer and antisecretory effects of various calcium antagonists.

1. The antiulcer activity (ethanol or indomethacin-induced ulcers) and the antisecretory effects (pylorus-ligated rats) of various selective and non selective calcium antagonists were studied. 2. Flunarizine and pirenzepine reduce the ethanol-ulcer length whereas diltiazem and cimetidine are weakly active and verapamil, nifedipine and nicardipine are ineffective. 3. All tested compounds except verapamil prevent the development of indomethacin-induced ulceration. 4. All substances, except flunarizine decrease the total H+ output in Shay rats. 5. The activities of the different compounds are discussed in terms of their mode of action.

Modulation of immune responses in mice by oral administration of niflumic acid.

The in vivo effects of non-steroidal anti-inflammatory drugs (NSAIDs) on the host immune system are still poorly understood. However, through inhibition of prostaglandin synthesis, NSAIDs may exhibit immunomodulating properties. The present work was aimed at evaluating the influence of niflumic acid on immune responses when administered orally for 7 consecutive days to 8-week-old inbred mice. Immunological tests were performed 24 h after the arrest of the treatment. At a dosage of 50 mg/kg/day, niflumic acid exerted noticeable immunostimulating effects, as shown by an increase in plaque-forming cell numbers after in vivo immunization with sheep red blood cells, an augmentation of spleen cell proliferation responses to stimulation with T- or B-cell mitogens and of T-cell cytotoxic response to allogenic cells. Phagocytosis-induced chemiluminescence of peritoneal macrophages was also enhanced whereas interleukin-1 production by these cells was depressed, but without concomitant modification in interleukin-2 production by T-cells. Increasing the niflumic acid dosage to 75 mg/kg resulted in the disappearance of the immunostimulatory effects on lymphocytes responses. Macrophage activities were affected similarly in mice receiving 50 mg/kg. These results demonstrate that niflumic acid is able to stimulate in vivo several immunological functions and, consequently, to maintain host immune defenses. Interestingly, it depressed interleukin-1 production, known to play a major role in the inflammatory process.

Comparative effects of various calcium entry blockers and anti-asthmatic compounds on antigen-induced bronchoconstriction in rat and histamine release from rat mast cells.

The effects of four calcium entry blockers (diltiazem, nifedipine, mesudipine and verapamil) were studied on antigen-induced bronchoconstriction in sensitized rats and histamine release from rat mast cells, in comparison with compounds frequently used in atopic patients (theophylline, isoproterenol, disodium cromoglycate, ketotifen and clemastine). The four Ca2+ entry blockers produced a dose-related inhibition of the IgE-dependent bronchoconstriction in rat whereas the other drugs exhibited a weak effect or even were inactive. 48/80-induced histamine release was antagonized by nifedipine, verapamil and ketotifen. On the contrary, diltiazem, mesudipine, theophylline, isoproterenol, disodium cromoglycate and clemastine were not able to interfere with this release process. These data may suggest an important role of both extra- and intracellular calcium in such phenomena.

Effect of rat and beta-human interferons on hyperacute experimental allergic encephalomyelitis in rats.

Human interferon-beta (human IFN-beta) and rat interferon (rat IFN) were evaluated on experimental allergic encephalomyelitis (EAE) in rats, a delayed cellular reaction resembling human multiple sclerosis (MS). Rat IFN was active by intravenous and intracerebroventricular routes. It decreased the severity of clinical symptoms of paralysis during the 22 days of the assay. Human IFN-beta, on the contrary, had no effect when similarly tested in this rat model. Cyclophosphamide delayed the onset of paralysis, but levamisole enhanced the severity of the EAE.

Effects of various compounds on the accumulation of macrophages in mice.

The effects of different anti-inflammatory and anti-rheumatic compounds on the accumulation of macrophages in mice have been investigated. Glass coverslips were inserted subcutaneously and the cellular accumulation evaluated by measuring the surface covered by cells or the cellular potassium. Among the non-steroidal anti-inflammatory compounds tested, only niflumic acid and BW 755C were found active in this assay. Hydrocortisone, chloroquine and cyclophosphamide inhibited partially the migration of cells. Na- aurothiopropanol sulfonate, levamisole and methotrexate were inactive. MK 447 and d-penicillamine increased the accumulation of macrophages. The activity of the different substances is discussed in terms of their modes of action.

Pharmacology of free radicals; recent views on their relation to inflammatory mechanisms.

Production of free radicals from molecular oxygen during the inflammatory process can exhibit beneficial effects against the phlogistic stimulus and may act as a defence mechanism. Nevertheless, in many cases this production is associated with toxic reactions related to inflammatory response. Many compounds including bovine superoxide dismutase, non steroidal anti-inflammatory drugs, radical scavengers (e.g. acetaminophen), corticoids etc., have been shown to counteract this phenomenon. Their beneficial effects and mechanism of action are reviewed.

Effects of various substances on two types of inflammatory reaction in animals.

The effects of 16 substances, including non-steroidal anti-inflammatory agents, a corticoid, phenols, immunomodulators and gold salts, were studied using two types of acute inflammatory reaction, a non-specific reaction (carrageenan-induced oedema) and an immune reaction (reversed passive Arthus reaction in the rat or active Arthus reaction in the mouse). Results revealed that the active Arthus model appears to be more selective than the passive reversed Arthus model, which is itself less sensitive than the carrageenan model. The active Arthus reaction might be useful for secondary screening of molecules that act on mechanisms modulating the intervention of complement and the various functions of polymorphonuclear leucocytes, and the passive Arthus reaction appears to be more suitable for preliminary screening. The activities of the different substances studied are discussed in terms of their modes of action and toxicity.

Effects of calcium-antagonists on passive cutaneous anaphylaxis in the rat.

The actions of four Ca2+-antagonists (nifedipine, verapamil, diltiazem and D 600) were compared with those of four substances that are used clinically in treating asthma (theophylline, isoproterenol, disodium cromoglycate and clemastine), using the passive cutaneous anaphylaxis (PCA) reaction in the rat. Nifedipine, verapamil and diltiazem produced a partial, but dose-related inhibition of the PCA reaction. A slight, but significant inhibitory effect was also observed with D 600. Isoproterenol, theophylline and disodium cromoglycate also produced dose-related inhibition of the PCA reaction, their maximum effects being greater than those of the Ca2+-antagonists. As the histamine H1-antagonist clemastine was about as active as nifedipine, verapamil or diltiazem in inhibiting the PCA reaction, it seems possible that certain Ca2+-antagonists might be of value in treating allergic disorders in man.

Comparison of the analgesic actions of THIP and morphine.

The antinociceptive actions of intraperitoneally-administered 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP) and morphine were compared using three strains of mice. With the hot-plate assay, ED50 values for the action of THIP were about 4 mg/kg in OF1, CD1 and NMRI strains, whereas ED50 values for morphine varied among strains, being 6.8 mg/kg for OF1, 16.9 mg/kg for CD1, and about 29 mg/kg for NMRI mice; thus, the genetic control of the analgesic action of THIP appears to differ from that of morphine. The analgesic action of THIP in the hot-plate test was not blocked by naloxone, bicuculline, phentolamine or methysergide, but was partially reversed by a high dose of atropine, indicating that classic opiate-receptors, bicuculline-sensitive GABA-receptors, alpha-adrenoceptors and serotonin-receptors do not appear to mediate the action of THIP but that cholinergic receptors might be indirectly involved. THIP was about equipotent or more potent than morphine in the phenylbenzoquinone writhing test, evasion test, and traction test. Since the ED50 values for THIP in OF1 mice were similar for hot-plate, evasion and traction tests, the analgesic action of THIP might not be readily dissociated from its sedative or myorelaxant action.

Pharmacological properties of a new anti-inflammatory agent: 2-(2-isopropyl-5-indanyl)propionic acid (UP 517-03).

2-(2-Isopropyl-5-indanyl)propionic acid (UP 517-03) is a new anti-inflammatory agent with marked analgesic and antipyretic properties. The anti-inflammatory potency is greater than that of phenylbutazone but lower than that of indometacin. This effect is observed also in adrenalectomized rats. The analgesic activity in the Randall and Selitto test is equipotent to that of indometacin, but this potency is lower in the other tests. In lowering brewer's yeast-induced fever in rats, UP 517-03 is as potent as indometacin and 10 times more effective than phenylbutazone. Considering from pharmacological index, UP 517-03 is tolerated as well as phenylbutazone and better than indometacin.

The antipyretic effect of UP 517-03 in the rabbit.

The antipyretic effect of UP 517-03 was studied in rabbits, provided with a cannula in the lateral cerebral ventricle. Given orally as a curative treatment, UP 517-03 can abolish hyperthermic reactions induced by intracerebroventricular injection of sodium arachidonate or bacterial endotoxin. A comparison with acetylsalicylic acid and indomethacin is given. UP 517-03 does not modify the temperature of normothermic rabbits. These results suggests that the antipyretic action of UP 517-03 can be explained by an effect of this substance on the metabolism of arachidonic acid in brain.

Antiinflammatory and analgesic diastereoisomeric derivatives of indan-5-acetic acid.

Various 2-alkyl-alpha-methyl- and 2-alkylindan-5-acetic acids have been prepared. The acids, which can exist in two diastereoisomeric forms that cannot be separated by crystallization or chromatography, can be analyzed in their mixture by NMR in the presence of Eu(dpm)3. It has been possible to reconstitute the two pure racemic 2-isopropyl-alpha-methylindan-5-acetic acids from their enantiomers obtained after resolution of the mixtures through salts with various active bases. The relative configuration of the two asymmetric centers of one of the diastereoisomers salts with various active bases. The relative configuration of the two asymmetric centers of one of the diastereoisomers has been determined by X-ray crystallography. The absolute configurations of the resolved acids have been established by a comparative study of their CD curves. The antiinflammatory and analgesic properties of these compounds as functions of their structure and stereochemistry are discussed.