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500-mg ciprofloxacin tablet, and the serum half-life was 3.9 h. Consequently, 5 to 6 h after dosing, the serum level may be below 1.0 , ug ml. They also determined that 57% of the drug in the serum penetrated into blister fluid. Consequently, the concentration at the site of infection could very well be below 1.0 , g ml, which approaches the maximal MIC that we observed with P. aeruginosa. Enoxacin has similar pharmacokinetic properties, but higher serum levels can be achieved. Chin and Neu 1 ; expect serum levels in excess of 4.0 P, g ml for 6 to 8 after dosing. After our strains were exposed to enoxacin, we observed MICs as high as 32 pug ml, and that could be clinically significant. Our primary goal was to evaluate cross-resistance between the quinolone derivatives and related organic acids. Jones and Barry 5 ; demonstrated that Enterobacteriaceae with elevated MICs for cinoxacin, nalidixic acid, or oxolinic acid tended to be less susceptible to norfloxacin. Fass 3 ; observed a similar relationship between ciprofloxacin and norfloxacin. In the current study, we observed that resistance to one compound can be developed by serial transfers through subinhibitory concentrations of a different quinolone derivative or related organic acid. Presumably, the mechanism responsible for development of resistance affects all of the compounds that we have studied, although with the newer, more potent quinolone derivations, significant levels of resistance develop much more slowly. The mechanism of resistance may be analogous to that which has been defined for nalidixic acid, i.e., a change in the configuration of bacterial DNA gyrase 4 ; . Extremely high MICs for cinoxacin and nalidixic acid are obtained after a few serial transfers through subinhibitory concentrations of either drug 6, 10, 12 ; . Clinically significant resistance does occur during therapy with either drug 6, 10 ; . Our data indicate that selection of resistant populations by widespread use of cinoxacin or nalidixic acid might seriously diminish the efficacy of the newer quinolone derivatives, especially those intended for systemic therapy.
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40. The meeting agreed that in order to achieve comparability there is the need to work towards a new common instrument. Within the European Statistical System ESS ; important work has and is been done in order to arrive at comparable data on health and health related indicators in general and on a common methodology and instruments for surveys in particular. The operationalisation of these instruments by 2006 has started now and implementation is being overseen by a technical group with representatives of twenty eight countries. Any initiative at internationa l level arising from this joint WHO UNECE Eurostat meeting will need to build on.
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Faecal specimens from each dog were plated onto MacConkey agar containing 5 g each of gentamicin and enoxacin ml1 to ensure the dogs were free from multidrug-resistant enteric bacteria. The dogs were then vaccinated against canine distemper, hepatitis, parvovirus and parainfluenza virus infection Canvac 4 in 1; CSL ; , tested for heartworm and treated for fleas and intestinal worms with 50 mg praziquantel, 250 mg febantel, 49.8 mg pyrantel per 10 kg body weight Drontal; Bayer Animal Health Australia ; . The dogs were randomly divided into four treatment groups of four dogs and received treatments according to the schedule in Table 1. After a 10-day acclimatization period, dogs in groups A and C received a daily oral dose of 5 mg enrofloxacin kg1 Bayer Animal Health Australia ; for 21 days. Dogs in groups A and B were given a single dose of 10 ml broth containing MDREC strain C1 7.3 3 109 bacteria ; mixed into the food on day 7 of the antimicrobial treatment. Dogs in group D acted as untreated, uninoculated controls. Individual dogs were allowed to have contact with other dogs in the same treatment group but contact between treatment groups was prevented. Faecal specimens from each dog for viable total coliform and MDREC counts were obtained twice weekly until the conclusion of the trial on day 62 for groups A and B and day 48 for groups C and D.
Where L2 is the depth of the tension table and D 2 and v 2 are its transport parameters. The choice of a convective-dispersive pdf for the table is arbitrary. However, this choice has no impact on predicted concentrations, as predictions are always made at calibration depth, which was arbitrarily set to unit length L2 1 cm ; Mass conservation implies that flux concentrations at the inlet of the tension table be equal to flux concentrations at the outlet of the soil column. So, the concentrations at the exit of the table were evaluated by convoluting the outflow concentrations of the soil column with the pdf of the tension table and enoxaparin.
Regulatory Risks: Operations by the Company may require approvals from regulatory authorities which may not be forthcoming or which may not be able to be obtained on terms acceptable to the Company. While the Company has no reason to believe that all requisite approvals will not be forthcoming, Applicants should be aware that the Company cannot guarantee that any requisite approvals will be obtained. A failure to obtain any approvals would mean that the ability of the Company to develop or operate any project may be limited or restricted, either in part or absolutely. Risk as to Profitability: The ability of the Company to pay dividends will depend on it generating revenue and then deriving sufficient after-tax profits to be able to do so. At present, the Company does not generate any revenue. The Company is not presently profitable and it may not at any time be so. The key financial drivers that create risk in generating profit would ordinarily include: timing of entry into chosen markets; level of market share on entry and beyond; acceptance of price structures in particular for different markets and level of ongoing processing and operating costs. No Valuation: No formal or informal valuation has been completed of the intellectual property or assets of the Company. The Company makes no representation as to the value of its intellectual property. All investors and their advisers should make their own assessments as to these matters after having regard to all of the information contained in this Prospectus. Generally: The possibility exists that, for a wide range of reasons, the Company's present strategies, plans, policies, intentions and expectations may not be able to be implemented.
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Mesencephalic infarction. J Neurol Sci 1999; 163: 7073 Rapcsak SZ, Krupp LB, Rubens AB, et al: Mixed transcortical aphasia without anatomic isolation of the speech area. Stroke 1990; 21: 953956 Berthier ML, Starkstein SE, Leiguarda R, et al: Transcortical aphasia: importance of the nonspeech dominant hemisphere in language repetition. Brain 1991; 114: 14091427.
Heart problems often start after age 50. These include calcification of the coronary arteries the vessels that feed the heart ; . The aortic and mitral heart valves which separate chambers of the heart are most affected. The build-up of homogentisic acid can cause valves to calcify or harden, leading to narrowing of the valve causing problems with blood flow. Pigment deposits also can lead to the formation of atherosclerotic plaques hard spots in arteries ; containing cholesterol and fat and entecavir.
PLASMALOGEN CATABOLISM BY MYOCARDIAL PLA2 fonyl-labeled plasmenylethanolamine. Biochim Biophys Acta 1047: 3540, 1990. Itaya K and Ui M. A new micromethod for the colorimetric determination of inorganic phosphate. Clin Chim Acta 14: 361 366, Jurkowitz MS, Horrocks LA, and Litsky ML. Identification and characterization of alkenyl hydrolase lysoplasmalogenase ; in microsomes and identification of a plasmalogen-active phospholipase A2 in cytosol of small intestinal epithelium. Biochim Biophys Acta 1437: 142156, 1999. Karmazyn M and Dhalla NS. Physiological and pathophysiological aspects of cardiac prostaglandins. Can J Physiol Pharmacol 61: 12071225, 1983. Liu SJ, McHowat J, and Creer MH. Effects of lysoplasmenylcholine on membrane currents in rabbit ventricular myocytes Abstract ; . J Mol Cell Cardiol 31: A27, 1999. Markwell MAK, Haas SM, Tolbert NE, and Bieber LL. Protein determination in membrane and lipoprotein samples: manual and automated procedures. Methods Enzymol 72: 296 303, McHowat J and Creer MH. Lysophosphatidylcholine accumulation in cardiomyocytes requires thrombin activation of Ca2 independent PLA2. J Physiol Heart Circ Physiol 272: H1972 H1980, 1997. McHowat J and Creer MH. Thrombin activates a membraneassociated calcium-independent PLA2 in ventricular myocytes. J Physiol Cell Physiol 274: C447C454, 1998. McHowat J and Creer MH. Calcium-independent phospholipase A2 in isolated rabbit ventricular myocytes. Lipids 33: 12031212, 1998. McHowat J, Jones JH, and Creer MH. Gradient elution reversed-phase chromatographic isolation of individual glycerophospholipid molecular species. J Chromatogr B Biomed Appl 702: 2132, 1997. McHowat J, Liu S, and Creer MH. Selective hydrolysis of plasmalogen phospholipids by Ca2 -independent PLA2 in hypoxic ventricular myocytes. J Physiol Cell Physiol 274: C1727C1737, 1998. McHowat J, Yamada KA, Wu J, Yan G-X, and Corr PB. Recent insights pertaining to sarcolemmal phospholipid alterations underlying arrhythmogenesis in the ischemic heart. J Cardiovasc Electrophysiol 4: 288310, 1993. Portilla D and Creer MH. Plasmalogen phospholipid hydrolysis during hypoxic injury of rabbit proximal tubules. Kidney Int 47: 10871094, 1995. Portilla D, Shah SV, Lehman PA, and Creer MH. Role of cytosolic calcium-independent plasmalogen-selective phospholipase A2 in hypoxic injury to rabbit proximal tubules. J Clin Invest 93: 16091615, 1994. Qui Z-H, and Leslie CC. Protein kinase C-dependent and -independent pathways of mitogen-activated protein kinase activation in macrophages by stimuli that activate phospholipase A2. J Biol Chem 269: 1948019487, 1994. Ramanadham S, Hsu FF, Bohrer A, Ma Z, and Turk J. Studies of the role of group VI phospholipase A2 in fatty acid incorporation, phospholipid remodeling, lysophosphatidylcholine generation, and secretagogue-induced arachidonic acid release in pancreatic islets and insulinoma cells. J Biol Chem 274: 1391513927, 1999. Schonefeld M, Noble S, Bertorello AM, Mandel LJ, Creer MH, and Portilla D. Hypoxia-induced amphiphiles inhibit renal Na , K -ATPase. Kidney Int 49: 12891296, 1996. Williams SD and Ford DA. Activation of myocardial cAMPdependent protein kinase by lysoplasmenylcholine. FEBS Lett 420: 3338, 1997. Wolf MJ, Wang J, Turk J, and Gross RW. Depletion of intracellular calcium stores activates smooth muscle cell calciumindependent phospholipase A2. A novel mechanism underlying arachidonic acid mobilization. J Biol Chem 272: 15221526, 1997. Zeng Y, Han X, and Gross RW. Phospholipid subclass specific alterations in the passive ion permeability of membrane bilayers: separation of enthalpic and entropic contributions to transbilayer ion flux. Biochemistry 37: 23462355, 1998.
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Anaesthetized. Although doses of individual inhalation agents can readily be compared by describing them as fractions of the MAC, it is not possible to make a direct comparison with an i.v. agent. The CP50 of propofol for depression of bispectral index is 5.45 mg ml1, 8 whereas the IP50 of sevoflurane for depression of bispectral index was 1.14%.9 In our study, the average target propofol concentration was 3.67 0.46 ; mg ml1, and average end-tidal sevoflurane concentration was 1.13 0.19 ; %. Viewed against the above data for bispectral index, Group S may have been slightly more deeply anaesthetized than Group P. The sevoflurane group contained more posterior fossa cases than the propofol group 5 vs 2 ; Posterior fossa surgery poses different problems to supratentorial surgery and haemodynamic disturbance may be more common in these patients. We explored our data and found no excess of haemodynamic instability in the patients undergoing posterior fossa surgery who were anaesthetized with sevoflurane. We found small and clinically unimportant differences in recovery between Group P and Group S. There are many reports to compare recovery characteristics between propofol and sevoflurane anaesthesia. These reports concluded sevoflurane anaesthesia gave faster, 10 11 similar, 12 or slower7 13 recovery than propofol anaesthesia. Yli-Hankala and colleagues reported no difference of recovery time between propofol fentanyl nitrogen oxide and sevoflurane fentanyl nitrogen oxide anaesthesia under bispectral index control.14 We explored our data to evaluate whether hypotensive episodes, which might be a result of a deeper anaesthesia were associated with delayed recovery and found no correlation. The experiences of the two groups of patients whilst in the recovery area were similar, perhaps because this phase is dominated by clinical and nursing factors rather than the small differences between short-acting hypnotic agents. Many studies have reported that sevoflurane caused postoperative nausea and vomiting PONV ; more frequently than propofol anaesthesia.7 10 12 PONV occurs in about 30% of patients receiving sevoflurane.7 10 12 15 the present study, PONV occurred in only 15% of patients with no difference between propofol and sevoflurane. Although there was a small difference in drug acquisition costs between the two groups, these differences in costs.
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Mercuric chloride, mercuric oxide, mercuric iodide, mercurous acetate, and mercurous chloride are, or have been, used for their antiseptic, bactericidal, fungicidal, diuretic, and or cathartic properties in Europe, North America, Australia, and elsewhere. Inorganic mercury compounds are also widely used in skin-lightening soaps and creams, due to the ability of the mercury cation to block the production of melanin pigment in the skin. Such uses have resulted in reports of toxicity in a number of cases Millar, 1916; Warkany & Hubbard, 1953; Williams & Bridge, 1958; Barr et al., 1972; Tunnessen et al., 1987; Dyall-Smith & Scurry, 1990; Kang-Yum & Oransky, 1992 ; . Al-Saleh & Al-Doush 1997 ; examined 38 different skin-lightening creams and found that 45% contained mercury levels above the US Food and Drug Administration limit of 1 mg kg; two of the products had mercury concentrations over 900 mg kg. Forms of inorganic mercury have been used topically on a rather widespread basis for a variety of therapeutic uses. Cutaneous applications include treatment of infected eczema or impetigo various mercury salts ; , treatment of syphilis calomel ; , treatment of psoriasis mercuric oxide or ammoniated mercury ; , and topical use of metallic mercury ointments Bowman & Rand, 1980; Goodman Gilman et al., 1985; Bourgeois et al., 1986; O'Shea, 1990 ; . Previous uses of inorganic mercurials include laxatives Wands et al., 1974 ; . Such use has been abandoned in most industrialized nations due to the known toxicity of inorganic mercury compounds and the availability of equally or more effective, and less toxic, alternatives and eplerenone.
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Superhelical turns into covalently closed circular DNA. This reaction requires ATP, presumably as a source of energy to bring the DNA into this thermodynamically unfavorable state. Bacterial DNA gyrase is a tetrameric enzyme composed of two A subunits molecular mass 100, 000, products of gyrA gene ; and two B subunits molecular mass 90, 000, products of gyrB gene ; 4-7 ; . A normally functioning gyrA subunit isrequired for the action of nalidixic acid, oxolinic acid 4, 8 ; , and other congeners possessing a 4-quinolone nucleus see Fig. 1 ; . These drugs block all activities that are involved in breaking and rejoining DNA, but do not interferewith ATP hydrolysis. In contrast to the quinolone-related compounds, the coumarin derivatives novobiocin, coumermycm, and chlorobiocin affect the action of the gyrB protein 9 ; . These drugs apparently act by binding directly to the ATP-binding site of the B subunit 10, 11 ; . The ability of nalidixic acid to inhibit the critical stages of the DNA gyrase reaction prompted the further investigation of this class of compounds as antibacterial agents. Nalidixic acid itself is bactericidal to many gram-negative organisms [minimum inhibitory concentration MIC ; for E. coli is 13 jiM] and can be used clinically for susceptible organisms. This drug, developed by SterlingWinthrop in the early 1960's marketed under the trade name NegGram ; is well absorbed from the gastrointestinal tract and excreted rapidly by the kidneys. The concentration of nalidixic acid and its active derivative hydroxynalidixic acid achieved in the urine is 10 to times greater than that in the plasma. Owing to the high concentrations of active drug in the urine and the propensity of nalidixic acid to elicit a variety of side effects the most severe of which occur in the central nervous system ; , the use of nalidixic acid is limited to the treatment of urinary tract infections. Two other synthetic drugs, oxolinic acid and cinoxacin, exhibit similar pharmacological properties and are also restricted to the treatment of urinary tract infections. Several recently developed quinolones appear to be quite promising as broader-spectrum antimicrobials. These include, among others, norfioxacin Noroxin, Merck Sharpe & Dohme, West Point, PA ; and ciprofloxacm Cipro, Miles Pharmaceuticals, West Haven, CT ; , which have recently been licensed in the United States, enoxacin Warner-Lambert, Morris Plains, NJ ; , ofloxacm Ortho Pharmaceuticals, Raritan, NJ ; , and difioxacm Abbott, Abbott Park, IL ; . All of these drugs are significantly more potent antibacterials 100- to 500-fold ; than the previously marketed nalidi.xic and oxolinic acids. Because of this, the probability of side effects at effective plasma concentrations is markedly decreased, and it is expected that their use will not be limited to urinary tract infections. Most of these agents are active against the enteric gram-negative bacilli and cocci, including Neisseria gonorrlzoeae, as well as several other clinically important organisms such as Pseudomonos aeruginosa, Haemophilus inftuenzae, and Legionella pneumop zila 12 ; . These more recently developed compounds share several properties that make them attractive as adjuncts or replacements for the third-generation cephalosporins, the aminoglycosides, and perhaps even the extended-spec and epogen.
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MATERIALS AND METHODS Media. ML broth has been described previously 19 ; . For ML agar plates, 1.5% agar Difco Laboratories, Detroit, Mich. ; was added. Cation-supplemented Mueller-Hinton broth Difco ; was used for antimicrobial susceptibility testing, which was performed by standard methods 21 ; . Antibiotics when added for plasmid selection ; were used at the following final concentrations: 100 , ug ml, ampicillin; 50 , ug ml, kanamycin; 10 , ug ml, tetracycline for E. coli; and 200 , ug ml, tetracycline for P. aeruginosa. Tetracycline 2 , ug ml for E. coli and 200 , ug ml for P. aeruginosa ; also was used for plasmid maintenance during MIC determinations. Bacterial strains and plasmids. The bacterial strains and plasmids used or constructed in this study are listed in Table 1. Plasmid pSLS447 was kindly provided by Stephen Swanberg and James Wang, Harvard University, Cambridge, Mass. P. aeruginosa MP001 quinolone susceptible ; was recovered from a patient with a complicated infection prior to ciprofloxacin therapy. P. aeruginosa MP002 and MP003 were recovered from the same patient approximately 3 weeks after initiation of parenteral ciprofloxacin therapy. The isolates were verified as one strain by John Ogle University of Colorado School of Medicine, Denver ; using an epidemiological DNA probe 22 ; . MP002 and MP003 were quinolone-resistant gyrase A mutants which also lacked the long-chain O-polysaccharide component of lipopolysaccharide LPS ; 17 ; . P. aeruginosa MP004 and MP005 were uncharacterized clinical isolates. Antibiotics. The following antibiotics were obtained from the indicated sources: ciprofloxacin Miles Inc., Pharmaceutical Div., West Haven, Conn. nalidixic acid, ampicillin, tetracycline, kanamycin, and chloramphenicol Sigma Chemical Co., St. Louis, Mo. norfloxacin Merck Sharp & Dohme, Rahway, N.J. ofloxacin Ortho Diagnostics, Inc., Raritan, N.J. and enoxacin Warner-Lambert Co., Ann Arbor, Mich and eprosartan.
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