Activity of trimethoprim/ sulfamethoxazole plus polymyxin B against multiresistantStenotrophomonas maltophilia

The inhibitory activity of eight antibiotics and the inhibitory and bactericidal activities of combinations of trimethoprim/sulfamethoxazole (TMP/SMX) plus three fixed concentrations of polymyxin B (0.01 g/ml, 0.1 g/ml and 0.5 g/ml) against 30 multiresistant strains ofStenotrophomonas maltophilia were tested. Polymyxin B at 0.01 g/ml modified the inhibitory activity of TMP/SMX against only 40% of strains. At 0.1 g/ml and 0.5 g/ml, polymyxin B enhanced the inhibitory activity of TMP/SMX activity against all strains. Polymyxin B enhanced the bactericidal activity of TMP/SMX only at concentrations near the minimum inhibitory concentration of polymyxin B alone.     

Provisional quality control parameters and interpretive criteria for testing susceptibility ofStreptococcus pneumoniae andHaemophilus influenzae to quinupristin/dalfopristin (RP59500)

Studies were undertaken to select tentative criteria for susceptibility testing of quinupristin/dalfopristin againstStreptococcus pneumoniae andHaemophilus influenzae. Against 612 isolates ofStreptococcus pneumoniae, MICs of quinupristin/dalfopristin were 1.0 g/ml for all but one strain. With a tentative MIC breakpoint of either 1.0 g/ml or 2.0 g/ml for susceptible, a disk diffusion zone diameter breakpoint of 19 mm embraced all but two of the susceptible pneumococci; 16 mm included all strains. ForHaemophilus influenzae, MICs of quinupristin/dalfopristin clustered near the tentative breakpoints; 91.5% of the MICs were 2.0 to 8.0 g/ml. This precluded satisfactory performance of the disk diffusion test in discriminating between resistant and susceptible isolates unless MIC breakpoints are modified for this species: clinical experience will be needed before that can be justified. Based on data from a multilaboratory study, the following quality control limits are proposed forStreptococcus pneumoniae ATCC 49619 when testing quinupristin/dalfopristin: 0.25 to 1.0 g/ml for broth microdilution tests and 19 to 24 mm for disk diffusion tests. For tests ofHaemophilus influenzae ATCC 29247, MIC limits are 2.0 to 16 g/ml; disk tests were very reproducible but are not yet recommended.     

In vitro efficacy and fungicidal activity of voriconazole againstAspergillus andFusarium species

Twenty-nineAspergillus isolates and 25Fusarium isolates underwent in vitro antifungal susceptibility testing by a broth macrodilution procedure adapted from the National Committee for Clinical Laboratory Standards guidelines. The MIC50s of both voriconazole and amphotericin B were 0.5 g/ml and 1 g/ml against species ofAspergillus andFusarium, respectively, while the MIC90s of both agents were 1 and 2 g/ml. Voriconazole was more active in vitro than amphotericin B: the geometric mean MICs of voriconazole and amphotericin B againstAspergillus spp. were 0.36 g/ml and 0.64 g/ml, respectively. Voriconazole also demonstrated fungicidal activity againstAspergillus spp., with 86% (24/29) of isolates exhibiting minimum lethal concentrations of 4 g/ml.     

Naegleria fowleri andN. lovaniensis: Differences in sensitivity to trimethoprim and other antifolates

The growth ofNaegleria fowleri cultures in a BCS medium was not affected either by trimethoprim at 400 g/ml or by aminopterine, 3,5-diaminopterine and methotrexate at 500 g/ml.N. lovaniensis propagation in the same medium was inhibited with 10 g/ml of trimethoprim, 50 g/ml methotrexate and 100 g/ml 3,5-diaminopteridine. Aminopterine was ineffective at a concentration of 500 g/ml. The inhibitory effect of trimethoprim onN. lovaniensis cultures depended on the medium composition and could be neutralized by an addition of folic or tetrahydrofolic acids and a suspension of heat-killedEnterobacter aerogenes. Thymine, thymidine, hypoxantine and 2-amino-4-hydroxy-6-(tatrahydroxybutyl)-pteridine did not have an adverse effect. Trimethoprim activity inN. fowleri cultures could not be enhanced by the addition of Triton X-100 and Polymyxine B. Cryolyzate ofN. fowleri amoebae did not influence the trimethoprim inhibition ofN. lovaniensis cultures. Deviation in dihydrofolatereductase chemical structure or thymine dependency seems to be the probable explanation forN. fowleri antifolate resistance.     

Effect of praziquantel on the free-living stages ofSchistosoma mansoni

Summary The effect of the new schistosomicide praziquantel (2-cyclohexyl-carbonyl-1,2,3,6,7,11b-hexahydro-2H-pyrazino[2,1a]isoquinolin-4-one) on the miracidia and cercariae ofSchistosoma mansoni was investigated.In vivo praziquantel inhibits hatching of miracidia for 24 h after administration of 500 mg/kg to infected mice. In vitro a concentration of 10 g/ml inhibits subsequent hatching in drug-free water. Free swimming miracidia are rapidly killed by 1 g/ml. Even 0.01 g/ml is still partially effective.In a solution of 0.03 g/ml cercariae lose their ability to swim within 10 min. This effect is reversible in drug-free water. Morphological damage to cercariae incubated in 0.1 g/ml is clearly evident. However, cercariae are fully infective when given subcutaneously to mice after a 3-h incubation period. Incubation in 1 g/ml reduces the infection rate by 80%. A 2-h incubation in 0.1 g/ml almost completely inhibits the percutaneous infection through the abdominal skin. The number of cercariae that develop to schistosomules is reduced by more than 90%. After a 2-h incubation in a concentration of 0.01 g/ml the swimming ability of cercariae is impaired in such a way that the number of cercariae penetrating in the tail immersion test and developing to schistosomules is reduced by half.Praziquantel is a more potent protective agent than the molluscicides copper sulphate, sodium pentachlorophenate and Bayluscide^® or cadmium and zinc ions.

---

Zusammenfassung Es wurde der Einfluß des neuen Schistosomenmittels Praziquantel (2-Cyclohexylcarbonyl-1,2,3,6,7,11b-hexahydro-2H-pyrazino[2,1 a]isochinolin-4-on) auf die Miracidien und Cercarien vonSchistosoma mansoni untersucht.In vivo verhindert Praziquatel das Schlüpfen von Miracidien aus Eiern für 24 h nach einer Behandlung infizierter Mäuse mit 500 mg/kg. Nach Inkubation von Eiern in 10 g/ml schlüpfen anschließend keine Miracidien in präparatfreiem Wasser. Frei schwimmende Miracidien werden durch 1 g/ml schnell abgetötet und noch 0,01 g/ml haben eine deutliche Wirkung.Cercarien werden in vitro durch 0,03 g/ml innerhalb von 10 min schwimmunfähig. Dieser Effekt ist in präparatfreiem Wasser reversibel. Nach 3stündiger Vorbehandlung in 0,1 g/ml sind die Cercarien deutlich morphologisch geschädigt. Trotzdem sind sie noch normal entwicklungsfähig, wenn sie Mäusen subcutan injiziert werden. Nach Inkubation in 1 g/ml ist der Infektionserfolg allerdings um 80% reduziert. Nach nur 2stündiger Inkubation in 0,1 g/ml ist die Zahl der Cercarien, die sich nach percutaner Infektion durch die Bauchhaut der Maus zu Schistosomulae entwickelt, um mehr als 90% reduziert. Nach 2stündiger Inkubation in nur 0,01 g/ml ist das Schwimmvermögen der Cercarien so beeinträchtigt, daß sich nach percutaner Schwanzinfektion nur noch halb so viele zu Schistosomulae entwickeln wie in der Kontrolle.Praziquantel ist in seiner infektionsverhindernden Wirkung den Molluskiziden Kupfersulfat, Pentachlorphenolnatrium und Bayluscid^® sowie auch Cadmium- und Zinkionen überlegen.

     

Criteria for testing the susceptibility ofStreptococcus pneumoniae to cefotaxime and its desacetyl metabolite using 1 μg or 30 μg cefotaxime disks

In vitro susceptibility tests were performed with 350 selected strains ofStreptococcus pneumoniae to evaluate disk diffusion tests with 30 g and 1 g cefotaxime disks. Zones were compared to MICs of cefotaxime with and without its desacetyl metabolite. Cefotaxime was two to eight times more active than desacetyl cefotaxime, but the two compounds were additive when combined in vitro. For 30 g disks, zone size breakpoints were 27 mm, 28–30 mm and 31 mm for resistant, intermediate and susceptible, respectively. For 1 g disks, those zone size criteria were reduced to 13 mm, 14–16 mm and 17 mm. The 30 g disk that is currently available for testing other species can be used for testing pneumococci; however, the 1 g disk has some important advantages.     

2 μm plasmid copy number in different yeast strains and repartition of endogenous and 2 μm chimeric plasmids in transformed strains

By using the renaturation kinetics technique we tried to get informations about the maintenance of the 2 m plasmid in yeast cells. For this purpose we determined the 2 m plasmid copy number: in various yeast strains, in a special set of mutants, in cells treated with ethidium bromide and cycloheximide and in different yeast strains obtained by transformation with 2 m chimeric plasmids.According to the strain used the proportion of 2m DNA varied from 1.1% to 3.9%, which corresponds to 24 to 88 2 m molecules per haploid genome. The particular multiresistant mutant, where the frequent loss of oligomycine resistance is correlated with the loss of extractible covalently closed circular DNA, contained 39 2 m copies per haploid genome. In the partial revertant oligomycine sensitive all the 2 m DNA sequences were lost. (Less than 0.1 copy per haploid genome.)Ethidium bromide did not affect the 2 m copy number while cycloheximide induces an increase of 36%.When a strain containing 88 2 m DNA copies per haploid genome is transformed with 2 m chimeric plasmids there is no significative change in the total number of plasmid: 36 copies of endogenous and 44 of chimeric plasmid per haploid genome. When 2 m chimeric plasmids were introduced in our 2 m-less strain despite the stability of the transformants, there is only 8 copies per haploid genome.     

In vitro activity of LY146032 (Daptomycin), a new peptolide

The in vitro activity of LY146032, a new peptolide antibiotic, was compared with those of vancomycin, teicoplanin, imipenem, amoxicillin and erythromycin. LY146032 inhibited 90% ofStaphylococcus aureus andStaphylococcus epidermidis, including methicillin-resistant isolates at 1g/ml. Its activity was comparableto those of vancomycin and teicoplanin. MIC90s for the beta-hemolytic streptococci varied from 0.25 g/ml for group B streptococci to 4g/ml for some group C and F streptococci. MICs forStreptococcus faecalis were in the range of 0.5 to 8 g/ml,and the MIC90 4 g/ml,compared to 4 g/ml for vancomycin and 1g/ml for teicoplanin. For some viridans streptococci the MICs were 4g/ml, whereasStreptococcus pneumoniae were inhibited by 0. 5g/ml.Corynebacterium JK species were inhibited by 0. 5g/ml, similar to vancomycin, andListeria monocytogenes by 4g/ml.Neisseria species,Haemophilus species and enteric species were not inhibited. Most MBCs were within two-fold of the respective MICs. After 14 days passage in subinhibitory concentrations of LY146032,Staphylococcus aureus, Staphylococcus epidermidis andStreptococcus faecalis showed minimal increase in MICs. The activity of LY 146032 was increased by adding Ca²⁺ and was reduced in an anaerobic environment. Overall, LY146032 is an extremely interesting new agent that inhibits gram-positive species.     

In vitro activity of the aryl-fluoroquinolones A-56619 and A-56620 and evaluation of disk susceptibility tests

The activity of two new quinolones, A-56619 and A-56620, was compared in vitro to that of norfloxacin and ciprofloxacin against 6,699 bacterial isolates in four separate clinical laboratories. The overall percentage of strains susceptible to designated concentrations were as follows: 99.1% for norfloxacin (MIC4.0 g/ml), 96.1% for ciprofloxacin (MIC1.0 g/ml), 96.8% for A-56620 (MIC 2.0 g/ml) and 96.1% for A-56619 (MIC 4.0 g/ml). For disk diffusion susceptibility tests 10 g A-56619 disks are tentatively recommended with interpretive standards of 18mm for susceptibility and 13mm for resistance; 5 g A-56620 disks may be used with tentative standards of 19mm for susceptibility and 14mm for resistance.     

Molecular Characterization of Complement Components (C3, C4, and Factor B) in Human Saliva

A molecular analysis of complement components (C3, C4, and factor B) in human saliva was performed by SDS-PAGE and immunoblotting. Complement C3 was detected as a molecule composed of a 115-kDa -chain linked to a 70-kDa chain by disulfide bonds, and C3 levels ranged from 0.52 to 15.0 /g/ml (n = 15). C4 was detected as a triple-chain molecule (98-kDa chain, 73-kDa chain, and 33-kDa chain) linked by disulfide bonds, and C4 levels ranged from 0.086 to 4.8 g/ml. Factor B was detected as a 100-kDa single chain, and factor B levels ranged from 0.042 to 0.62/g/ml. The sizes and subunit structures of the complement components in human saliva were compatible with those reported in human serum. The results of a hemolytic assay indicated that the complement molecules in human saliva were functionally active. These complement components may participate in the local immune and inflammatory responses in the oral cavity.     

Treatment of fish parasites

For chemotherapy of fish parasitized by monogeneans, a novel triazine derivative, 2-[3,5--dichloro-4-(4-methyl-sulfonylphenoxy)-phenyl]-1-methyl-hexahydro-1,2,4-triazine-3,5-dion (HOE 092 V), was tested in vivo against the gill- and skin-parasitizing speciesDactylogyrus extensus, D. vastator, andGyrodactylus arcuatus. Naturally infected fish were incubated in aerated, separate tanks at 22°C for 1,2,3, and 4 h in water containing 0, 1, 5, 10, or 15 g HOE 092 V/ml, whereasPseudodactylogyrus bini was tested in vitro at 10 g HOE 092 V/ml for 2.25 h. As seen by means of transmission electron microscopy, in vivo treatment againstD. extensus caused vacuolization and lysis of the parasite's tegument at a dose as low as 1 g/ml over a 3-h exposure period. Higher doses, such as 5 and 10 g/ml over the same exposure period, produced lesions in the circular and longitudinal musculature ofD. extensus and differing degrees of damage to the ciliary cells of protonephridia and immature vitelline cells. There was 100% mortality inD. vastator when incubation was done with 10 g HOE 092 V/ml for 4 h (G. arcuatus: 5 g/ml for 4 h; 10 g/ml for 1 h) and inP. bini after 2.25 h in vitro exposure. In all species tested, the anterior portion and the opisthaptor region were most sensitive to the drug action. This study shows that fish infected withGyrodactylus spp.,Dactylogyrus spp., and/orPseudodactylogyrus spp. can be treated successfully in a water bath containing 10 g HOE 092 V/ml.Abbreviations BL basal lamina - BM basal membrane - C caverna - CC canal cell - CI cilium - CIT cilium destroyed by treatment - CM circular musculature - CT connective tissue - DB dense body - EI electron-dense inclusion - EP electron-dense particles marking the boundary of holes - HC heterochromatin - I invagination of the tegument - IC immature vitelline cell - L lumen - LD lipid droplet - LM longitudinal musculature - LV lyzed immature vitelline cell - M mitochondrion - MC mature vitelline cell - MF myosin filament - MFI muscle fiber - MS membrane stack - N nucleus - NM nuclear membrane - OC outer membrane of cilium - OM outer membrane - P parenchyma - R ribosome - V vesicle - VA vacuole - VD vitellary droplet - VF vitelline follicle - YG Yolk globule - YL content of yolk globule     

Trypanosoma congolense: the in vitro akinetoplastic induction sensitivity assay

Incubation ofTrypanosoma conglense in diminazene aceturate (Berenil) or isometamidium chloride (Samorin) induced akinetoplastic (AK) forms in vitro. The AK values (expressed in percent) obtained were found to be useful for rapid assessment of relative drug sensitivities. In susceptible clones, AK forms were induced at all drug concentrations tested, whereas in resistant clones they were induced only at higher concentrations. The Berenil-resistant clone exhibited AK values of 0.9%±0.6%–8.9±2% at concentrations of 1–100 g/ml at 4–10 h post-inoculation (p.i.), whereas the Berenil-susceptible clone displayed values of 9.3%±3%–19.2%±5% at 0.1–50 g/ml. Motile trypanosomes were not seen at 100 g/ml at 4 h p.i. or at 10 or 50 g/ml at 10 h p.i. The Samorin-resistant clone showed AK values of 0.5%±0.1%–43%±3% at concentrations of 0.1–100 g/ml at 4 and 10 h p.i., whereas the Samorin-susceptible clone exhibited values of 5.3%±2%–45%±4% at 0.0005–100 g/ml. These results were supported by the findings obtained using a mouse infectivity test.     

Interpretive criteria and quality control for antimicrobial susceptibility tests of levofloxacin

To confirm preliminary interpretive breakpoints for prototype 5 µg levofloxacin disks, 490 strains were tested in vitro using commercially manufactured disks. For in vitro susceptibility testing, 5 µg levofloxacin disks can be used with interpretive criteria of 12 mm for resistant (MIC 8.0 µg/ml) and 16 mm for susceptible (MIC 2.0 µg/ml). Proposed quality control limits for tests of levofloxacin are as follows:Escherichia coli ATCC 25922, zones 29–37 mm or MIC 0.008–0.03 µg/ml;Pseudomonas aeruginosa ATCC 27853, zones 19–26 mm or MIC 0.5–2.0 µg/ml;Staphylococcus aureus ATCC 25923, zones 24–31 mm;Staphylococcus aureus ATCC 29213, MIC 0.06–0.25 µg/ml andEnterococcus faecalis ATCC 29212, MIC 0.25–2.0 µg/ml.     

Comparison of disk diffusion,the E test,and detection ofmecA for determination of methicillin resistance in coagulase-negative staphylococci

The aim of this study was to find a reliable, fast, and simple alternative to the methicillin disk method for determination of methicillin resistance in coagulase-negative staphylococci, since results of this method are often difficult to read due to growth within the zone of inhibition. The sensitivity of 319 strains of coagulase-negative Staphylococci to a 5 g methicillin disk on Mueller-Hinton agar using an incubation period of 48 h was compared with that of 1 (1 g and 5 g oxacillin disks on Mueller-Hinton agar with or without 2% NaCl, using an incubation period of 24 h. The detection ofmecA (MecAgen) by the polymerase chain reaction was used as a standard. Minimum inhibitory concentrations were determined by means of the E test. Of the 225mecA-positive strains, 190, 215, and 193 were resistant to 5 g methicillin, 1 g oxacillin and 5 g oxacillin disks on Mueller-Hinton agar, respectively, and 216, 218, and 223 were resistant on Mueller-Hinton agar with 2% NaCl. Of the 94mecA-negative strains, 89, 93, and 94 were susceptible to 5 g methicillin, 1 g oxacillin, and 5 g oxacillin disks on Mueller-Hinton agar, respectively, and 92, 93, and 94 were susceptible on Mueller-Hinton agar with 2% NaCl. Using breakpoints of 2 g/ml for oxacillin resistance and 8 g/ml for methicillin resistance, the E test yielded sensitivities of 99.6 and 99.1% and specificities of 97.9 and 98.9% after 48 h of incubation. The 5 g oxacillin disk was faster and easier to read than the methicillin disk and correlated better with detection ofmecA than the methicillin disk or the 1 g oxacillin disk.     

A diffractometer using a lateral effect photodiode for the rapid determination of sarcomere length changes in cross-striated muscle

A simple method is devised to record rapid sarcomere length changes of muscle fibres using a lateral effect diode. In the standard position the diffractometer records length changes between 1.65 and 3.8 m, the output being linear 1 V/m with a frequency response of –3 dB at 1.2 kHz. The absolute error is<0.05 m between 1.65 and 2.80 m and <0.1 m between 2.81 and 3.30 m. The resolution of length changes is<0.005 m over the whole range. By varying the detector position the length range can be extended to either side, and spatial resolution can be improved at the expense of length range.     

Effect of epidermal growth factor on non-steroidal anti-inflammatory drug-induced intestinal damage

Epidermal growth factor (EGF, 10 g/kg po, ip, or sc, BID, and 20 g/kg iv) had no protective activity in the indomethacin-induced intestinal lesion model (6 h model). In the ethanol-induced gastric lesion model, EGF (10 g/kg sc) reduced lesions by 52% and reduced gastric acid secretion by 68% (5 g/kg iv). In the 24 h indomethacin-induced intestinal lesion model, pretreatment with EGF (10 g/kg sc, BID; 1 day before and during indomethacin treatment) had no beneficial effects. Therefore, EGF had no protective effects against non-steroidal antiinflammatory drug (NSAID)-induced intestinal lesions at doses that protect against the necrotizing action of ethanol and that inhibit gastric acid secretion in the rat.     

Inhibitory effects ofγ-interferon on bradykinin-induced bone resorption and prostaglandin formation in cultured mouse calvarial bones

The effects of mouse recombinant-interferon (-IFN) and indomethacin on bone resorption stimulated by bradykinin, Lys-bradykinin, Met-Lys-bradykinin, des-Arg⁹-bradykinin and prostaglandin E₂ (PGE₂) have been studied using cultures of neonatal calvarial bones and analyzing the release of⁴⁵Ca from prelabelled bones as a paramenter of bone resorption. In addition, the effects of-IFN and indomethacin on formation of PGE₂ in bone cultures stimulated by bradykinin was analyzed. Indomethacin (1 mol/l) totally abolished bradykinin (1 mol/l) induced⁴⁵Ca release. The inhibitory effect of indomethacin could be fully reversed by addition of PGE₂ (1 mol/l).-IFN (1000 U/ml) almost totally inhibited⁴⁵Ca release stimulated by bradykinin (1 mol/l), but the inhibitory effect could only be partially overcome by PGE₂.-IFN and indomethacin also inhibited the stimulatory effects of Lys-bradykinin, Met-Lys-bradykinin and des-Arg⁹-bradykinin (1 mol/l) on⁴⁵Ca release. The stimulatory effects of PGE₂ (1 mol/l) on radioactive calcium mobilization was partially inhibited by-IFN (1000 U/ml), whereas indomethacin (1 mol/l) was without effect. The inhibitory effect of-IFN on⁴⁵Ca release stimulated by bradykinin and PGE₂ was dose-dependent with threshold for action at 3–30 U/ml. Comparative dose-response curves showed that-IFN was most potent as inhibitor of bradykinin induced⁴⁵Ca release. Bradykinin (1 mol/l) significantly stimulated PGE₂ formation by a mechanism that was completely inhibited by indomethacin (1 mol/l).-IFN (1000 U/ml) partially inhibited the stimulatory effect of bradykinin on PGE₂ formation. These data show that i)-IFN is a potent inhibitor of bone resorption induced by bradykinin and bradykinin analogues and ii) that the mechanism of action can be mainly explained by an inhibition of kinin induced prostaglandin biosynthesis. The results, however, also show that-IFN can inhibit bone resorption by mechanisms unrelated to prostaglandin formation.     

Potentiation of antifungal activity of amphotericin B by azithromycin againstAspergillus species

The potential role of azithromycin in combination with amphotericin B against 25 clinical isolates ofAspergillus was assessed. The MIC of amphotericin B was 1 g/ml for 44% of the isolates, 0.5 g/ml for 48%, and 0.25 g/ml for 8%. All isolates were resistant to azithromycin. Synergism, defined as a twofold reduction in the MIC of both drugs upon combination, was demonstrated between amphotericin B and azithromycin for all 25 isolates. To prove that azithromycin exerts its antifungal effect by inhibiting protein synthesis, we studied [³⁵S]-methionine incorporation into protein inone Aspergillus isolate. Neither amphotericin B at 0.125 g/ml (fourfold below its MIC) nor azithromycin at 16 g/ml ( 16-fold below its MIC) had any effect on protein synthesis when tested alone. Upon combination, however, a 68% inhibition in protein synthesis was evident by the inhibition of [³⁵S]-methionine incorporation.     

Comparison of histamine release from peritoneal mast cells derived from diabetic and control rats

Clinical and experimental diabetes are associated with an increased number of mast cells and elevated tissue histamine concentrations. This study compared histamine release from peritoneal mast cells derived from diabetic and control rats. Experimental diabetes was induced by a single i.v. injection of streptozotocin (50 mg/kg body weight). Measurement of plasma glucose levels confimed the diabetic state. Peritoneal mast cells were stimulated for 10 min with the lectin concanavalin A (0.5–100 g/ml) in the presence or absence of phosphatidylserine, clinical dextran (0.6–1200 g/ml) in the presence of phosphatidylserine, the calcium ionophore A23187 (0.1–1 M) or the basic releasing agent compound 48/80 (0.1–10 g/ml). Histamine release induced by these agents was similar in both populations. Further studies will compare the differences in histamine release from mast cells isolated from different tissues, e.g. heart and lung. In addition, physiological stimuli which are altered in the diabetic state (e.g. hyperosmolalar solutions and free radical generating systems) are under investigation.     

In vitro effect of cetirizine on PGE2 release by rat peritoneal macrophages and human monocytes

Cetirizine was first described as a specific anti-H₁ molecule displaying potent antiallergic activity. It was later found that its pharmacological properties extended to cellular actions as on eosinophil recruitment at inflammatory sites in allergic patients. Monocytes and macrophages participate in allergic mechanisms, particularly through high affinity H₁ and H₂ membrane receptors and generation of pro- and anti-inflammatory agents; among them histamine-induced factors, IL-1 and prostanoids are of importance. The aim of this work was to investigate the effect exerted by various concentrations of cetirizine (0.1–10 g/ml) appliedin vitro to human monocytes and peritoneal rat macrophages cultured for 24 h. Peritoneal macrophages were collected either from normal or experimentally inflamed rats. Human monocytes, isolated from peripheral blood, were studied either in a resting state or after stimulation by LPS fromEscherichia coli (1 and 10 g/ml). Cetirizine (10 g/ml) significantly enhanced IL-1 release by human monocytes stimulated by a weak LPS concentration (1 g/ml) but could not modify the maximal increase of IL-1 release induced by 10 g/ml of LPS. It did not exert any effect on resting cells. Cetirizine (0.1–10 g/ml) enhanced PGE₂ release by resting human monocytes. Concentrations of 1 and 10 g/ml enhanced PGE₂ release by LPS-stimulated monocytes, and by healthy and inflamed rat macrophages. This effect was concentration-dependent. Our findings point to an anti-inflammatory action of cetirizine via PGE₂ release and histamine H₂ interactions. Cetirizine did not directly modify IL-1 generation by resting monocytes but the IL-1 production observed after LPS stimulation could promote the mechanisms by which PGE₂ is released.