Prophylactic intravenous tranexamic acid and thromboembolism in non-cardiac surgery: a systematic review, meta-analysis and trial sequential analysis.

Tranexamic acid is an antifibrinolytic drug that is widely used during surgery, but there are concerns about its thromboembolic effects. We aimed to investigate the effect of prophylactic intravenous tranexamic acid on thromboembolic outcomes in patients undergoing non-cardiac surgery. The MEDLINE, EMBASE and Cochrane Central Register of Controlled Trials were searched. Randomised controlled trials comparing intravenous tranexamic acid with placebo or no treatment in patients undergoing non-cardiac surgery were included. The primary outcome was a composite of peri-operative cardiovascular thromboembolic events, defined as any deep vein thrombosis, pulmonary embolism, myocardial ischaemia/infarction or cerebral ischaemia/infarction. A total of 191 randomised controlled trials (40,621 patients) were included in the review. The primary outcome occurred in 4.5% of patients receiving intravenous tranexamic acid compared with 4.9% of patients in the control group. Our analysis showed that there was no difference between groups for composite cardiovascular thromboembolic events (risk ratio 1.02, 95%CI 0.94-1.11, p = 0.65, I2 0%, n = 37,512). This finding remained robust when sensitivity analysis was performed with continuity correction and in studies with a low risk of bias. However, in trial sequential analysis, our meta-analysis only achieved 64.6% of the required information size. There was no association between intravenous tranexamic acid and seizure rate or mortality rate within 30 days. Intravenous tranexamic acid was associated with a reduced blood transfusion rate compared with control (9.9% vs. 19.4%, risk ratio 0.46, 95%CI 0.41-0.51, p < 0.0001). It was encouraging to see the evidence that the administration of intravenous tranexamic in patients undergoing non-cardiac surgery was not associated with an increased risk of thromboembolic outcomes. However, our trial sequential analysis demonstrated that currently available evidence is not yet sufficient to reach a firm conclusion.

Delayed transcutaneous extrusion of embolic coils after embolization of facial artery pseudoaneurysm.

External carotid artery (ECA) pseudoaneurysm is a known complication of treatment for head and neck cancer. We report a case of facial artery pseudoaneurysm arising after irradiation and salvage surgery for advanced tonsillar cancer, that was treated with endovascular embolization. The case was complicated by delayed transcutaneous extrusion of embolization coils through the skin of the anterior neck. We review the literature for related cases of coil extrusion in the head and neck, and discuss the implications for pseudoaneurysm surveillance.

Persistent diffusion-restricted lesions in bevacizumab-treated malignant gliomas are associated with improved survival compared with matched controls.

BACKGROUND AND PURPOSE: A subset of patients with malignant glioma develops conspicuous lesions characterized by persistent restricted diffusion during treatment with bevacizumab. The purpose of the current study was to characterize the evolution of these lesions and to determine their relationship to patient outcome. MATERIALS AND METHODS: Twenty patients with malignant glioma with persistent restricted-diffusion lesions undergoing treatment with bevacizumab were included in the current study. Mean ADC and the volume of restricted diffusion were computed for each patient during serial follow-up. Differences in TTP, TTS, and OS were compared between patients with restricted diffusion and matched controls by using Kaplan-Meier analysis with the logrank test and Cox hazard models. RESULTS: Mean ADC values were generally stable with time (mean, 5.2 ± 12.6% change from baseline). The volume of restricted diffusion increased a median of 23% from baseline by 6 months. Patients with restricted-diffusion lesions had significantly greater TTP (logrank, P = .013), TTS (logrank, P = .008), and OS (logrank, P = .010) than matched controls. When available, advanced physiologic imaging of restricted-diffusion lesions showed hypovascularity on perfusion MR imaging and decreased amino acid uptake on (18)F-FDOPA PET scans. Atypical gelatinous necrotic tissue was confirmed in the area of restricted diffusion in 1 patient. CONCLUSIONS: Restricted-diffusion lesions in malignant gliomas treated with bevacizumab are generally stable with time and are associated with improved outcomes. These results combined with physiologic imaging and histopathologic data suggest that these lesions are not consistent with aggressive tumor.

Synthesis, chiral high performance liquid chromatographic resolution and enantiospecific activity of a potent new geranylgeranyl transferase inhibitor, 2-hydroxy-3-imidazo[1,2-a]pyridin-3-yl-2-phosphonopropionic acid.

3-(3-Pyridyl)-2-hydroxy-2-phosphonopropanoic acid (3-PEHPC, 1) is a phosphonocarboxylate (PC) analogue of 2-(3-pyridyl)-1-hydroxyethylidenebis(phosphonic acid) (risedronic acid, 2), an osteoporosis drug that decreases bone resorption by inhibiting farnesyl pyrophosphate synthase (FPPS) in osteoclasts, preventing protein prenylation. 1 has lower bone affinity than 2 and weakly inhibits Rab geranylgeranyl transferase (RGGT), selectively preventing prenylation of Rab GTPases. We report here the synthesis and biological studies of 2-hydroxy-3-imidazo[1,2-a]pyridin-3-yl-2-phosphonopropionic acid (3-IPEHPC, 3), the PC analogue of minodronic acid 4. Like 1, 3 selectively inhibited Rab11 vs. Rap 1A prenylation in J774 cells, and decreased cell viability, but was 33-60x more active in these assays. After resolving 3 by chiral HPLC (>98% ee), we found that (+)-3-E1 was much more potent than (-)-3-E2 in an isolated RGGT inhibition assay, approximately 17x more potent (LED 3 microM) than (-)-3-E2 in inhibiting Rab prenylation in J774 cells and >26x more active in the cell viability assay. The enantiomers of 1 exhibited a 4-fold or smaller potency difference in the RGGT and prenylation inhibition assays.

Synthesis and biological evaluation of alpha-halogenated bisphosphonate and phosphonocarboxylate analogues of risedronate.

Alpha-halogenated analogues of the anti-resorptive bisphosphonate risedronate (5, Ris) and its phosphonocarboxylate cognate (7, 3-PEHPC) were synthesized and compared with 5, 7, and the corresponding desoxy analogues in bone mineral affinity and mevalonate pathway inhibition assays. The Ris (5e-h) and 3-PEHPC (7e-h) analogues had decreased bone mineral affinity, confirming that the alpha-OH group in 5 and 7 enhances bone affinity. The 5 alpha-halo-analogues potently inhibited farnesyl pyrophosphate synthase (FPPS) with IC50 values from 16 (alpha-F) to 340 (alpha-Br) nM (5, 6 nM). In contrast, 7 alpha-halo-analogues were ineffective versus FPPS (IC50 > 600 microM), but inhibited Rab geranylgeranyl transferase (RGGT) (IC50 = 16-35 microM) similarly to 7 itself (IC50 = 24 microM). The alpha-F analogue 7e was 1-2 times as active as 7 in J774 cell viability and Rab11 prenylation inhibition assays.

Mercuric ion sensing by a film bulk acoustic resonator.

This paper describes a film bulk acoustic resonator (FBAR) mass sensor for detecting Hg2+ ion in water with excellent sensitivity and selectivity. When a thin Au film was deposited on the surface of an FBAR, the resonant frequency shifted to a lower value when the film was exposed to Hg2+ in aqueous solution. The FBAR sensor detected as low as 10(-9) M Hg2+ (0.2 ppb Hg2+) in water. Other ions such as K+, Ca2+, Mg2+, Zn2+, and Ni2+ had little or no effect on the resonant frequency of the FBAR. Coating of the FBAR Au surface with a self-assembled monolayer (SAM) of 4-mercaptobenzoic acid decreased the Hg2+ response.

Effects of cobalt-60 exposure on health of Taiwan residents suggest new approach needed in radiation protection.

The conventional approach for radiation protection is based on the ICRP's linear, no threshold (LNT) model of radiation carcinogenesis, which implies that ionizing radiation is always harmful, no matter how small the dose. But a different approach can be derived from the observed health effects of the serendipitous contamination of 1700 apartments in Taiwan with cobalt-60 (T(1/2) = 5.3 y). This experience indicates that chronic exposure of the whole body to low-dose-rate radiation, even accumulated to a high annual dose, may be beneficial to human health. Approximately 10,000 people occupied these buildings and received an average radiation dose of 0.4 Sv, unknowingly, during a 9-20 year period. They did not suffer a higher incidence of cancer mortality, as the LNT theory would predict. On the contrary, the incidence of cancer deaths in this population was greatly reduced-to about 3 per cent of the incidence of spontaneous cancer death in the general Taiwan public. In addition, the incidence of congenital malformations was also reduced--to about 7 per cent of the incidence in the general public. These observations appear to be compatible with the radiation hormesis model. Information about this Taiwan experience should be communicated to the public worldwide to help allay its fear of radiation and create a positive impression about important radiation applications. Expenditures of many billions of dollars in nuclear reactor operation could be saved and expansion of nuclear electricity generation could be facilitated. In addition, this knowledge would encourage further investigation and implementation of very important applications of total-body, low-dose irradiation to treat and cure many illnesses, including cancer. The findings of this study are such a departure from expectations, based on ICRP criteria, that we believe that they ought to be carefully reviewed by other, independent organizations and that population data not available to the authors be provided, so that a fully qualified epidemiologically-valid analysis can be made. Many of the confounding factors that limit other studies used to date, such as the A-bomb survivors, the Mayak workers and the Chernobyl evacuees, are not present in this population exposure. It should be one of the most important events on which to base radiation protection standards.

Synthesis and stability studies of phosphonoformate-amino acid conjugates: a new class of slowly releasing foscarnet prodrugs.

Prodrugs of phosphonoformic acid (PFA), an anti-viral agent used clinically as the trisodium salt (foscarnet), are of interest due to the low bioavailability of the parent drug, which severely limits its utility. Neutral PFA triesters are known to be susceptible to P-C bond cleavage under hydrolytic de-esterification conditions, and it was previously found that P,C-dimethyl PFA P-N conjugates with amino acid ethyl esters did not release PFA at pH 7, and could not be fully deprotected under either acid or basic conditions, which led, respectively, to premature cleavage of the P-N linkage (with incomplete deprotection of the PFA ester moiety), or to P-C cleavage. Here we report that novel, fully deprotected PFA-amino acid P-N conjugates 4 can be prepared via coupling of C-methyl PFA dianion 2 with C-ethyl-protected amino acids using aqueous EDC, which gives a stable monoanionic intermediate 3 that resists P-C cleavage during subsequent alkaline deprotection of the two carboxylate ester groups. At 37 degrees C, the resulting new PFA-amino acid (Val, Leu, Phe) conjugates (4a-c) undergo P-N cleavage near neutral pH, cleanly releasing PFA. A kinetic investigation of 4a hydrolysis at pH values 6.7, 7.2, and 8.5 showed that PFA release was first-order in [4a] with respective t(1/2) values of 1.4, 3.8, and 10.6 h.

Identification of two new hydrophobic residues on basic fibroblast growth factor important for fibroblast growth factor receptor binding.

Basic fibroblast growth factor (bFGF) is implicated in the pathogenesis of several types of vascular and connective diseases. A key step in the discovery of bFGF receptor antagonists to mitigate these actions is to define the functional epitopes required for receptor binding of the growth factor. Using structure-based site-directed mutagenesis, two critical areas on the bFGF surface for the high affinity receptor binding have already been identified [Springer, B.A., Pantoliano, M.W., Barberal, F.A., Gunyuzlu, P.L., Thompson, L.D., Herblin, W.F., Rosenfeld, S.A. and Book, G.W. (1994) J. Biol. Chem., 269, 26879-26884; Zhu, H.Y., Ramnarayan, K., Anchin, J., Miao, Y., Sereno, A., Millman, L., Zheng, J., Balaji, V.N. and Wolff, M.E. (1995) J. Biol. Chem., 270, 21869-21874; Zhu, H.Y., Anchin, J., Ramnarayan, K., Zheng, J., Kawai, T., Mong, S. and Wolff, M.E. (1997) Protein Engng, 10, 417-421]. According to these studies, one receptor binding site includes two polar residues Glu96 and Asn104 on bFGF whereas the other includes four hydrophobic residues Tyr24, Tyr103, Leu140 and Met142. Using a protein modelling technique, we report here the identification of a new hydrophobic patch on bFGF which includes residues Tyr73, Val88 and Phe93. The role of this area on receptor binding affinity was evaluated by mutating each of these residues individually and determining the mutated protein's (mutein's) receptor binding affinity. In addition, we examined the role of two other hydrophobic residues, Phe30 and Leu138, on bFGF for high-affinity receptor binding. These two residues are the neighbors of the hydrophobic residues Tyr24 and Tyr103, respectively. Replacement of Val88 and Phe93 with alanine reduced the receptor binding affinity about 10- and 80-fold, respectively, compared with wild-type bFGF. In contrast, substitution of Phe30 and Leu138 with alanine has no effect on the receptor binding affinities. We conclude that the newly identified hydrophobic residues, Val88 and Phe93, are crucial for the receptor binding. The present data, together with the previous identification of four hydrophobic residues (Tyr24, Tyr103, Leu140 and Met142), suggests that there are two hydrophobic receptor binding sites on the bFGF surface. Our findings can be employed in the discovery and design of potent bFGF antagonists using computational methods.

Discovery of TBC11251, a potent, long acting, orally active endothelin receptor-A selective antagonist.

Previously we reported the discovery of amidothiophenesulfonamides as endothelin receptor-A antagonists with high potency and selectivity. Replacement of an amide group in this class of compounds with an acetyl group maintained the in vitro binding affinity and in vivo activity while providing a compound with oral bioavailability and longer duration of action. The optimal compound discovered during these studies, 15q (TBC11251), binds competitively to human ETA receptors with a Ki of 0.43 +/- 0.03 nM and an IC50 of 1.4 nM (IC50 for ETB = 9800 nM). This compound inhibits ET-1-induced stimulation of phosphoinositide turnover with a Ki of 0.686 nM and a pA2 of 8.0. The compound has a serum half-life in the rat and the dog of 6-7 h and 60-100% oral bioavailability. This compound is one of the most selective ETA antagonists reported and therefore is suitable for additional pharmacological and clinical investigation of the role of ETA receptors in diseases.

Analysis of high-affinity binding determinants in the receptor binding epitope of basic fibroblast growth factor.

Basic fibroblast growth factor (bFGF) is implicated in the pathogenesis of several vascular and connective diseases. A key step in the discovery of bFGF receptor antagonists to mitigate these actions is to define the functional epitope required for receptor binding of the growth factor. In previous studies, we identified Glu96 as an essential residue in this epitope using site-directed mutagenesis. Here we examined the role of solvent accessible neighboring residues of Glu96 of bFGF on receptor binding affinity. Wild-type bFGF and its muteins were cloned and expressed in Escherichia coli and evaluated for FGF receptor binding affinity. Replacement of Asn104 of bFGF by alanine reduced receptor binding affinity over 400-fold compared with wild-type bFGF. We next explored the effect of neighboring residues of Asn104 on receptor binding affinity-Muteins in which Arg97, Leu98, Glu99, Asn101, Asn102, Thr105 and Pro141 were individually replaced by alanine exhibited receptor binding similar to wild-type bFGF. By contrast, substitution of Tyr103 or Leu140 by alanine reduced receptor binding affinity about 400- and 150-fold, respectively, in accord with a previous report. We conclude that at least six solvent-accessible residues in bFGF are crucial for high-affinity receptor binding, as evidenced by at least a 10-fold diminution in the affinity of the corresponding alanine muteins. The polar residues Glu96 and Asn104 appear to form an area important for facilitating the initial contact between ligand and receptor, whereas Tyr24, Tyr103, Leu140 and Met142 form a hydrophobic patch that may stabilize the complex. The detailed structure of this functional epitope can be employed in the discovery and design of bFGF antagonists using computational methods.

Pingyangmycin as a 99mTc carrier in tumor localization.

A simple method of preparation of 99mTc-pingyangmycin (PYM) for clinical use has been established using super-micro-amounts of SnCl2 as a reductant under dark conditions. The labeling efficiency was higher than 96%, and further purification was not necessary. The effect of ascorbic acid on the distribution of 99mTc-PYM had been investigated. Ascorbic acid increased uptake of 99mTc-PYM in the tumor. Tumor uptake increased with increasing concentration of ascorbic acid. Tumor-blood, tumor-liver, tumor-lung ratios at 1.5 h after 99mTc-PYM administration were 5.19 +/- 1.64, 2.71 +/- 0.51 and 4.15 +/- 0.57, respectively. Preliminary clinical trials in nine patients showed that 99mTc-PYM is a potentially useful tracer for tumor detection with good sensitivity and specificity (true positive 7/7, true negative 1/1, and false positive 1/1).

Normocalcemic effect of gallium nitrate in a hypercalcemic rat model.

An established rat hypercalcemia model was used to study the effects of gallium nitrate on elevated serum calcium levels. Gallium nitrate was administered by i.v. or i.p. injection at daily doses of 0.07-0.45 mmol/kg for 5 days to the hypercalcemic rats beginning 1 day following surgery. A dose-correlated normocalcemic response was observed. Gallium nitrate administered late after the induction of the hypercalcemic state was also effective in reducing serum calcium levels. The p.o. administration, however, even at doses as high as 0.45 mmol/kg, did not reduce serum calcium to normal levels. The values of area under the concentration versus time curve (0-24 h) of gallium in normal rats were comparable after i.v. [49.2 (micrograms/ml)h] or i.p. [57.0 (micrograms/ml)h] injections. In contrast, the p.o. route achieved only 15% bioavailability, which may explain the ineffectiveness of p.o. administered gallium nitrate at that dose level. This study suggests that daily i.v. bolus injections of gallium nitrate for managing hypercalcemia may be potentially as effective as the current regimen of continuous i.v. infusion.

Inhalation toxicity of aerosolized pentamidine isethionate in rats and dogs.

The toxicity of inhaled aerosolized pentamidine isethionate solutions in rats and dogs was evaluated. Nose-only exposure equipment and a mass mean aerodynamic particle size of < or = 2 microns were employed. Rats received either a single inhaled dose estimated at 0, 1.4, 2.1, or 6.0 mg/kg/exposure day or 4 inhaled doses evenly spaced over 13 weeks estimated at 0, 0.35, 0.7, or 1.4 mg/kg/exposure day. Dogs were administered a single inhaled dose estimated at 0, 1.1, 3.4, or 5.0 mg/kg/exposure day. Rats administered a single inhaled dose of 6.0 mg/kg/exposure day exhibited respiratory distress. The lung-with-trachea weights of these animals were elevated relative to controls. The histopathology of acutely exposed rats consisted of dose-related neutrophil infiltration in the turbinates, larynx, and bronchi; erosion of epithelium in the turbinates and larynx; thickening of the alveoli walls with alveolar accumulation of mononuclear cells and neutrophils; and rhinitis. Rats in the highest dose group in the subchronic evaluation exhibited decreased body weight gains and reduced lung-with-trachea-to-body weight ratios relative to controls. Hematology, clinical chemistry, and urinalysis values were within normal ranges. Microscopic pulmonary tissue changes were similar to those found in acute exposure with certain lesions (e.g., mucous cell hyperplasia) suggestive of a more chronic process. In addition, lung fibrosis was seen at the highest dose. In dogs, pentamidine isethionate did not cause a change in the respiratory minute volume (not measured in rats). Elevated lung-with-trachea weights were noted in the high- dose females. Hematology, clinical chemistry, and urinalysis values were within normal ranges.(ABSTRACT TRUNCATED AT 250 WORDS)

The pharmacokinetics of 1,3-di(4-imidazolino-2-methoxyphenoxy) propane.lactate (DMP.lactate), a new agent against opportunistic infections, in male beagle dogs.

The pharmacokinetics and oral bioavailability of 1,3-di(4-imidazolino-2-methoxyphenoxy) propane.lactate (DMP) was determined in male dogs following iv and po administrations of DMP.lactate containing trace amounts of [14C]DMP.HCl. Following the iv administration of [14C]DMP.lactate (2.5 mg/kg), plasma concentrations of DMP declined in a biexponential manner and were measurable to 48 hr. The terminal elimination half-life was 37.7 hr. The mean AUC0-infinity of DMP was 1.58 micrograms.hr/ml. The volume of distribution was 89 liters/kg and the body clearance was 27 ml/min/kg. The disposition of total radioactivity was similar to that of DMP. Approximately 14% of the dose was eliminated in urine as DMP or total radioactivity. Renal clearance was 10% of the body clearance. Following the po administration of [14C]DMP.lactate (14 mg/kg) the mean Cmax of total radioactivity and DMP was 0.20 and 0.17 micrograms/ml, respectively. The respective mean AUC0-T was 0.37 and 0.21 micrograms.hr/ml. The mean oral bioavailability based on DMP plasma concentrations was 2.4%. The mean Cmax of DMP following a 100 mg/kg po dose of DMP.lactate was 14 micrograms/ml and the AUC0-T was 1.87 micrograms.ml/hr; the bioavailability was 3.2%. Approximately 1% of the orally administered dose was eliminated in urine as DMP.

Determination of 1,3-di(4-imidazolino-2-methoxyphenoxy)propane in rat, dog and human plasma and urine by high-performance liquid chromatography with fluorescence detection.

A sensitive and selective high-performance liquid chromatographic (HPLC) method was developed for the determination of 1,3-di(4-imidazolino-2-methoxyphenoxy)propane (DMP) in rat, dog and human plasma (50-5000 ng/ml) and urine (0.1-10 micrograms/ml). DMP and DMPent (dimethoxyimidizolinopentamidine, the internal standard), are extracted from alkanized plasma with n-butyl chloride-n-butanol (9:1, v/v). The organic phase is dried under nitrogen, reconstituted in mobile phase, and washed with hexane. Separation is achieved by ion-pair chromatography on a Zorbax Rx C8 column with fluorescence detection. The analysis of pooled plasma (80, 400, and 4000 ng/ml) and urine controls (0.3, 1.6, and 8 micrograms/ml) demonstrated excellent precision and accuracy over a three-day period. The recovery of DMP is > 90% from rat, dog, and human plasma and > 85% from rat and human urine, and 60-70% from dog urine. The limit of quantitation (LOQ) of the assay is 50 ng/ml in rat, dog and human plasma. Using the high-sensitivity assay, the limit of quantitation was decreased to 5, 2 and 0.6 ng/ml in rat, dog and human plasma, respectively. The LOQ of the assay is 0.1 microgram/ml in rat, dog and human urine. The assay was used to determine plasma and urine concentrations of DMP in pharmacokinetic studies in rat and dog.

Disposition of a new antiinfective agent 1,3-di(4-imidazolino-2-methoxyphenoxy)propane in male rats.

The disposition of 1,3-di[4-imidazolino-2-methoxyphenoxy]propane (DMP) is described in male rats following a single 2.5 mg/kg intravenous or 10 mg/kg oral administration of DMP lactate in an aqueous (5% dextrose) solution. Following the intravenous administration, plasma concentrations of DMP declined in an apparent biexponential manner and were nonmeasurable after 24 hr. The mean terminal plasma elimination half-life was 14.9 hr. A volume of distribution of 18.7 liters/kg and a body clearance of 14.5 ml/min/kg were estimated. After oral administration, mean plasma concentrations of DMP reached a maximum of 39.6 ng/ml at 15 min and were nonmeasurable after 4 hr. The areas under the curve (AUC)0-24 of DMP was 2276 ng.hr/ml following the intravenous dose. The AUC0-4 was 68 ng.hr/ml following the oral dose. The AUC0-4 was 68 ng.hr/ml following the oral dose. Based on a comparison of AUC0-4, the oral bioavailability was 0.9%. A mean of 41.7 and 0.4% of the dose was excreted in urine as DMP following intravenous and oral administration, respectively. The tissue distribution and mass balance of total 14C were determined following a single 2.5 mg/kg intravenous administration of [14C]DMP.lactate. The concentrations of total 14C in all tissues were highest at 0.5 hr and declined with time thereafter. The highest concentration of 14C was in the kidneys, whereas the highest total amount was in the liver.(ABSTRACT TRUNCATED AT 250 WORDS)

New leukotriene B4 receptor antagonist: leucettamine A and related imidazole alkaloids from the marine sponge Leucetta microraphis.

Three new imidazole alkaloids, leucettamines A [1] and B [2] and leucettamidine [3], have been isolated from the Palauan sponge Leucetta microraphis. Their structures were established on the basis of extensive spectral analyses. Leucettamine A showed potent leukotriene B4 receptor binding activity (K(i) = 1.3 microM), while leucettamine B was essentially inactive (K(i) = 100 microM) and leucettamidine showed significant activity (K(i) = 5.3 microM). With leucettamine A identified as a pure LTB4 receptor antagonist, a new structure lead is presented to inflammation therapy.

Reduction of eicosanoid production by essential fatty acid depletion does not attenuate the inflammatory response induced by Pseudomonas aeruginosa pneumonia in rat lung.

Sipid mediators of inflammation have been implicated in the pathogenesis of Pseudomonas aeruginosa (PA) related pulmonary damage in patients with cystic fibrosis. We studied the role of these mediators in a rat model of PA endobronchitis using essential fatty acid deficient (EFAD) animals. Whole blood from EFAD animals produced significantly less leukotriene B4 (LTB4) and hydroxyheptadecatrienoic acid when stimulated ex vivo than did whole blood from control animals (p less than 0.005). Similarly, lung lavage fluid from EFAD animals infected with PA contained less LTB4 and thromboxane B2 (TXB2) than that from control animals. Despite these differences, cellular infiltration of airways in response to PA infection was virtually identical in animals from the regular diet and the EFAD groups. Both EFAD and control animals had a significant increase in white blood cells (WBC) in lung lavage fluid at 1, 3 and 6 days following infection with PA when compared to animals receiving sterile beads. Localized areas of consolidation and nodularity were grossly evident in the lungs of all PA infected animals irrespective of their ability to generate the lipid inflammatory mediators. Microscopic examination of lung sections demonstrated similar changes in all infected animals. We conclude that LTB4 and TXB2 production occurs early in the course of PA pulmonary infection in rats. This early rise in lipid mediators is temporally associated with an influx of WBC into the airways. However, attenuation of eicosanoid production by use of an EFAD diet does not lead to a reduction in the inflammatory response to PA infection.(ABSTRACT TRUNCATED AT 250 WORDS)

Gallium nitrate inhibits bone resorption and collagen synthesis in neonatal mouse calvariae.

Gallium nitrate (GN) is an agent used in the treatment of hypercalcemia. To more fully characterize the direct actions of GN on bone, we examined its effects on medium calcium, medium beta-glucuronidase (beta-GLU), and collagen synthesis in control and hormone-stimulated neonatal (4-6 days) mouse calvariae in vitro. GN (10 micrograms/ml) inhibited parathyroid hormone-stimulated (PTH; 1 nM) calcium release. A 24 h preincubation with 10 micrograms/ml of GN was required for complete inhibition; partial inhibition was seen with 12 h preincubation; 1, 3, or 6 h was inadequate. A dose-response study showed that with 24 h preincubation, 5, 3, and 1 microgram/ml of GN inhibited 81, 62, and 0% of PTH-induced calcium release. The effects of GN on the release of beta-GLU generally paralleled those on the release of calcium except that 10 micrograms/ml of GN stimulated beta-GLU release. Collagen synthesis was inhibited 50% by 3 micrograms/ml of GN, whereas noncollagen protein synthesis was unaffected. With PTH + GN no further decrease was observed. When GN was withdrawn from the medium after 24 h of preincubation, the inhibitory effect on calcium release and beta-GLU activity, but not on collagen synthesis, persisted through the 72 h of culture. GN also inhibited the resorption elicited by thyroxine (1 microM) and interleukin-1 beta (10 nM) but not by 1,25-dihydroxyvitamin D3 (30 pM). Our results indicate that GN is a powerful inhibitor of bone resorption in neonatal mouse calvariae even at low doses.(ABSTRACT TRUNCATED AT 250 WORDS)