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Biomedical subjects

A Wildfeuer

Publications and source records attributed to A Wildfeuer.

At least 55 records · Page 3Linked to original sources
PubMed1990

Mechanism of azithromycin uptake in human polymorphonuclear leucocytes.

The new antibiotic azithromycin (CP-62.993) is enriched in human polymorphonuclear leucocytes by up to 300-fold the extra-cellular concentrations. To approach an understanding of the underlying mechanism of this unique behavior of azithromycin, some characteristics of the uptake process were investigated in vitro. The speed of the uptake in human polymorphonuclear leucocytes was found to be independent of the extracellular starting concentrations of azithromycin. There was no indication of saturation up to extracellular concentrations of 100 micrograms/ml. The uptake was largely determined by incubation temperatures. At 4 degrees C no penetration into the cells could be observed. The activation energy of azithromycin uptake came to 144 kJ mol-1, twice the value of erythromycin uptake. The presence of various inhibitors of cell metabolism did not change the intracellular accumulation compared to control, nor did the presence of some agents which interfere with certain transport channels. These findings suggest that passive diffusion is an essential mechanism of azithromycin transport through the phagocyte membrane, while active transport is less important. The high cellular enrichment of azithromycin and the relatively high activation energy of the uptake process could be explained by accumulation of the drug in phagocytic lysosomes and this would also be in keeping with pH partition considerations.

Adult↗
PubMed1990

In vitro activity against clinically important gram-positive and gram-negative bacteria of sulbactam, alone and in combination with ampicillin, cefotaxime, mezlocillin, and piperacillin.

The in vitro effects of the single agents, and the synergistic/antagonistic action of three different combinations of ampicillin (AMP, CAS 69-53-4), cefotaxime (CTX, CAS 63527-52-6), mezlocillin (MEZ, CAS 51481-65-3), and piperacillin (PIP, CAS 61477-96-1) with the beta-lactamase inhibitor sulbactam (SUL, CAS 68373-14-8) were determined against 675 gram-positive and gram-negative, both aerobic and anaerobic bacteria. All the combinations of sulbactam and the antibiotics (1: 1, 1:2 and 1:4) exhibited very similar synergistic action. The percentage of the total strains tested for which synergistic activity was found was 51% with SUL + AMP (1:1), 24% with SUL + CTX (1:1), 31% with SUL + MEZ (1:1), and 28% with SUL + PIP (1:1). A fourfold or greater reduction of MIC's in the comparison with the antibiotics alone was found with 23% of the total strains tested for the SUL + AMP, with 9% of the strains tested with SUL + CTX, with 11% of the strains tested with SUL + MEZ, and with 15% of the strains tested with the SUL + PIP-combination. In the presence of sulbactam, 18% of the strains tested showed a significant reduction in the number of resistant strains with ampicillin, 7% with cefotaxime, 16% with mezlocillin, 14% with piperacillin, and in parallel there was an increase in the number of fully susceptible strains (shift from resistant or moderately sensitive to sensitive) by about 14%. In comparison with the antibiotic alone, the most marked reductions in the number of resistant strains on combination with sulbactam were as follows (the percentage of reduction is shown in brackets): for SUL + AMP and Acine-tobacter spp. (39% fewer resistant strains). Citrobacter spp. (-60%), Enterobacter aerogenes (-48%), Klebsiella oxytoca (-49%), Klebsiella pneumoniae (-63%), Morganella morganii (-74%), and Proteus vulgaris (-55%); for SUL + CTX and Acinetobacter spp. (-38%), Enterobacter cloacae (-6%), Klebsiella pneumoniae (-16%), Serratia marcescens (-9%), and Bacteroides fragilis (-31%); for SUL + MEZ and Acinetobacter spp. (-68%), Citrobacter spp. (-27%), Enterobacter spp. (-23%), Klebsiella pneumoniae (-32%), and Serratia marcescens (-19%); for SUL + PIP and Acinetobacter spp. (-41%), Citrobacter spp. (-30%), Klebsiella spp. (-30%), and Serratia marcescens (-33%).

Ampicillin↗
PubMed1989

Perioperative systemic antibiotics for prophylaxis of infections in breast surgery: sulbactam/ampicillin versus mezlocillin/oxacillin.

In a prospective, randomized, open trial, efficacy of one dose of sulbactam/ampicillin (1 g:2 g) was compared to three doses of mezlocillin/oxacillin (2 g:1 g), starting with induction of anesthesia in 80 breast surgery patients with an increased risk of postoperative infection. No infections at the site of operation were seen in either group. Fever due to postoperative pulmonary complications occurred in one patient in the sulbactam/ampicillin group. The only side effect was a moderate exanthema observed in one patient in the mezlocillin/oxacillin group. In this study of the prophylaxis of patients with an increased risk of postoperative infections having the potential to jeopardize the results of surgery, a single dose of sulbactam/ampicillin was as effective as a short term course of three doses of mezlocillin/oxacillin.

Adult↗
PubMed1989

Suppression of experimental autoimmune encephalomyelitis by dual cyclo-oxygenase and 5-lipoxygenase inhibition.

The release of leukotriene C4 (LTC4), an important 5-lipoxygenase product of the arachidonic acid metabolism from polymorphonuclear leucocytes (PMNLs) of guinea pigs with experimental allergic encephalomyelitis (EAE), the animal model of MS, has been found to be significantly increased compared with healthy animals. Subsequently, the dual cyclo-oxygenase and 5-lipoxygenase inhibitor BW755C was applied to 15 guinea pigs with EAE. Two control groups (15 each) were treated with the cyclo-oxygenase inhibitor indomethacin or physiological saline, respectively. In the BW755C treated group, no animal developed symptoms of the disease in contrast to, respectively, 5 and 3 animals in the 2 other groups. Histological examination of the CNS revealed a highly significantly lower inflammation score in the BW755C treated animals, and the release of LTC4 from PMNLs was highly significantly decreased in this group compared with each of the others. The findings suggest that the vascular permeability enhancing LTC4 plays a pathogenetic role in EAE and indicate that inhibition of this sulfidopeptide leukotriene suppresses the disease. Therefore, the application of leukotriene inhibitors could contribute to the future treatment of MS.

4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗
PubMed1989

Interaction of azithromycin and human phagocytic cells. Uptake of the antibiotic and the effect on the survival of ingested bacteria in phagocytes.

14C-labeled azithromycin, a new macrolide antibiotic, was accumulated by various phagocytic cells isolated from volunteers or patients. The concentration of the antibiotic in monocytes, polymorphonuclear leucocytes (PMNLs), and alveolar macrophages was greater than that in the surrounding medium by a factor of between 200 and 668. Azithromycin penetrated somewhat more rapidly into PMNLs and monocytes than into alveolar macrophages. On the other hand the final concentration in the alveolar macrophages was greater by a factor of about 3 than that in the other two phagocytic cells. Staphylococcus aureus, Legionella pneumophila and Haemophilus influenzae previously taken up by the phagocytes were rapidly inactivated by low (0.031-0.5 micrograms/ml) concentrations of the antibiotic, which in the presence of the cells were subinhibitory. There is thus a clear synergism between azithromycin and the phagocytic cells which leads to increased intracellular killing of the bacteria.

Azithromycin↗
PubMed1989

Kinetics of the uptake of antimicrobial agents by human polymorphonuclear leucocytes.

The in-vitro rate constants of the cellular uptake and elimination of the antimicrobial agents josamycin (Wilprafen), erythromycin and tetracycline were measured in normal human polymorphonuclear leucocytes (PMNs) using the velocity gradient centrifugation technique with radiolabelled drugs at extracellular concentrations corresponding to therapeutically effective serum levels. The rate of antibiotic uptake increased stepwise in the order tetracycline less than erythromycin less than josamycin. The half-lives of the uptake came to 0.8 min for josamycin, 4.7 min for erythromycin, and 14.8 min for tetracycline. The extraordinarily rapid uptake of josamycin by PMNs corresponds to the high lipophility of the drug. The accumulation of the three tested antibiotics in PMNs occurred much faster than their elimination from the cells, suggesting directional transport of the molecules through the leucocyte membrane and/or rate limiting dissociation from intracellular binding sites. Significant differences between the drugs tested were observed in the temperature dependence of their rates of uptake. The apparent activation energies of cellular uptake amounted to 114.2 kJ mol-1 (josamycin), 68.6 kJ mol-1 (erythromycin) and 52.2 kJ mol-1 (tetracycline). There is experimental support for a contribution of the nucleoside carrier system to the membrane transport of josamycin.

Adult↗
PubMed1989

Studies on the synergism of sulbactam and beta-lactam antibiotics under in vitro conditions and in healthy volunteers after intravenous administration. Antibacterial activity in vitro, compatibility and pharmacokinetics of the drugs in combination.

Sulbactam, a new beta-lactam inhibitor, increased the in vitro activity of cefotaxime, mezlocillin and piperacillin against 803 clinical bacterial isolates. The synergism of sulbactam and these antibiotics was particular marked against 467 beta-lactamase positive strains, both aerobic and anaerobic. In the presence of sulbactam the mean minimal inhibitory concentrations (MICs) of the antibiotics against beta-lactamase positive bacteria were greatly reduced: with cefotaxime by 58%, with mezlocillin by 64% and with piperacillin by 70%. Sulbactam alone at low concentrations inhibited the growth of only a few strains (Neisseria spp., Acinetobacter spp.). The inhibitor proved to be very stable in infusion media under a variety of conditions and was compatible in vitro with 14 different beta-lactam antibiotics. The pharmacokinetics profiles of sulbactam and the antibiotics cefotaxime, mezlocillin and piperacillin were similar after infusion to healthy volunteers. The relevant pharmacokinetic parameters of the single substances were essentially unchanged when administered in combination. The general similarity between the pharmacokinetics of sulbactam and of the beta-lactam antibiotics appears to be an essential precondition for the therapeutic success of such a synergistic combination. Thus the physicochemical and pharmacological properties of sulbactam apparently permit flexible dosage in combination with different penicillins or cephalosporins and sulbactam can be administered as non-fixed combination in the clinical treatment of bacterial infections.

Adult↗
PubMed1988

Pharmacokinetics of sulbactam and ampicillin intravenously applied in combination to healthy volunteers and patients. Determination of the ratio of the two drugs in serum and in various tissues.

The pharmacokinetics of sulbactam, a new beta-lactamase inhibitor, and ampicillin were investigated in 9 healthy volunteers and 125 patients. The two drugs were administered intravenously in combination (Unacid). Each subject received 1 g sulbactam and 2 g ampicillin. The two drugs showed a similar pharmacokinetic profile in humans. Relevant pharmacokinetic parameters were calculated using a 2-compartment model on the basis of the serum and urine concentrations determined in healthy volunteers. The ratio of sulbactam to ampicillin was found to be nearly constant (approx. 1:2), both in the blood, in several tissues and at various time points. The two compounds apparently penetrated well into the myometrium, renal cortex and medulla, the gall bladder wall, the tonsils and the cutis of the skin. The sulbactam/ampicillin ratios in the bile ranged from 1:3 to 1:13 over 2 h after the infusion. The concentrations of the two compounds measured in the various fluids and tissues of the body reached levels which are effective against beta-lactamase producing bacteria. The similar pharmacokinetics of sulbactam and ampicillin in humans are considered an essential prerequisite for the therapeutic efficacy of such a combination product.

Adult↗
PubMed1988

Comparative pharmacokinetics of isosorbide nitrates after repeated doses of sustained release isosorbide dinitrate.

The plasma kinetics of isosorbide dinitrate (ISDN), isosorbide-5-nitrate (IS-5-N) and isosorbide-2-nitrate (IS-2-N) were investigated in 20 healthy male and female volunteers, after b.i.d. administration over 2 days of sustained release ISDN 20 mg and 40 mg capsules (Iso Mack Retard 20 mg and 40 mg) and of a 40 mg sustained release ISDN tablet as reference formulation. The means of the individual maximum ISDN concentrations during the complete 2-day treatment amounted to 10.4 ng/ml after the 40 mg capsule, 5.3 ng/ml after the 20 mg capsule and 5.3 ng/ml after the reference tablet. The corresponding figures of the metabolically generated IS-5-N were 355.5 ng/ml, 168.8 ng/ml and 161.5 ng/ml, respectively. The measured amounts of IS-5-N are expected to contribute to the overall antianginal effect of at least the 40 mg capsule. According to the b.i.d. schedule, ISDN and the two mononitrates accumulated in the plasma after all three tested formulations. However, during the treatment with the 20 mg and the 40 mg capsules, accumulation was practically completed at the second day, while it was found to be more extended during treatment with the reference product. In terms of areas under the curve, the mean bioavailability of the 40 mg sustained release capsule relative to the reference formulation was 198% with respect to ISDN, and 197% both with respect to IS-2-N and IS-5-N. On the other hand, perfect dose-linearity of all relevant pharmacokinetic parameters of all three measured isosorbide nitrates was observed for the 20 mg and the 40 mg dose of the capsule.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1987

[Functions of intrinsic defense against anaerobic bacteria in healthy probands and patients with chronic-septic granulomatosis].

Different strains of Bacteroides fragilis exhibit great differences in sensitivity towards serum from healthy volunteers. In the presence of 10% autologous serum, neutrophilic granulocytes and monocytes (macrophages) caused significant killing of B. fragilis. The measured phagocytic and killing activity of the cells is comparable to their activity against aerobic bacteria (S. aureus). In four patients with chronic granulomatous disease of childhood, phagocytosis was normal but killing of B. fragilis and S. aureus in granulocytes or monocytes (macrophages) was appreciably lowered. This malfunction of the cells was accompanied by a disturbance in oxidative metabolism and inadequate iodination after phagocytosis of B. fragilis. The results suggest that granulocytes and monocytes play an important role in host defense against endogenous infections with anaerobes.

Abscess↗
PubMed1987

Leukotrienes B4 and C4 in MS.

Release of leukotriene B4 (LTB4) and leukotriene C4 (LTC4) from neutrophils and platelet-neutrophil suspensions in response to ionophore A23187 was measured in 12 multiple sclerosis (MS) patients and 8 healthy volunteers. LTC4 release from neutrophils, as well as from platelet-neutrophil suspensions, was significantly decreased in MS patients compared with the controls. There was no significant difference in the release of LTB4 between MS patients and controls. The findings suggest that permanent stimulation of platelets and neutrophils e.g., by encephalitogenic peptide leads to continuous LTC4 release with subsequent depletion of intracellular substrates serving as precursors for the formation of 5-lipoxygenase products. Since the target of microvascular actions of LTC4 are postcapillary venules, the release of this sulfidopeptide leukotriene might play a pathogenetic role in the formation of MS lesions.

Adult↗
PubMed1987

The effect of antibiotics on the intracellular survival of bacteria in human phagocytic cells.

[14C]-labeled josamycin (Wilprafen) readily enters several types of human phagocytic cells-polymorphonuclear leucocytes (PMNLs), adherent monocytes and alveolar macrophages - and is accumulated by these cells to a concentration about 20 times that in the extracellular medium. Similar studies using [14C]-benzyl penicillin revealed that the beta-lactam antibiotic penetrated these cells very poorly. Low concentrations of josamycin and the various phagocytes acted synergistically to inhibit the intracellular proliferation of L. pneumophila or H. influenzae. In contrast, penicillin G was not effective against legionellae ingested by PMNLs, monocytes or alveolar macrophages, even at high concentrations. The uptake of the antibiotics apparently correlates well with its efficacy against the intracellular survival of bacterial pathogens in human phagocytic cells.

Erythrocytes↗
PubMed1986

[Intracellular effects of josamycin].

Josamycin (Wilprafen) is accumulated in human polymorphonuclear leucocytes and monocytes (macrophages) by a factor of 12-20fold, in comparison with extracellular fluid. The uptake of the antibiotic by lymphocytes and erythrocytes is much less than with the two types of phagocytic cells. The distribution of 14C-josamycin was measured after lysing the polymorphonuclear leucocytes and the results confirmed that the antibiotic penetrates through the cell membrane and accumulates in the cytoplasm. The results indicate that josamycin is taken up into the cell by an active transport mechanism. It is significant for the clinical application of josamycin that the active drug is present inside the cells and can thus support the bactericidal activity of polymorphonuclear leucocytes or monocytes against intracellularly localized microorganism. This localization of the antibiotic in the two types of phagocytosing cells of the defense system could be important for the treatment of several infectious diseases.

Biological Transport, Active↗
PubMed1985

[The pharmacokinetics of josamycin].

Determination of the distribution coefficients in vitro demonstrates that josamycin (Wilprafen) is at least 15 times more lipophilic than erythromycin. On the other hand the distribution coefficients of penicillin G and of amoxicillin be in the hydrophilic range. The serum protein binding of josamycin is 15%, which is markedly less than with the other macrolides. These in vitro experiments show that small structural differences can alter the physicochemical and biological behaviour of an antibiotic, even when the molecules are closely related. A cross-over experiment with 12 volunteers and multiple application of 1 g of josamycin base or 1.175 g of erythromycin ethyl succinate showed that both macrolides are rapidly absorbed and reach their maximum within the first hour. In 21 patients the concentration of josamycin in lung tissue was 2 to 3 times that in the blood. The highest concentration of josamycin reached was 3.68 micrograms/g lung tissue (mean of 12 patients) and this was found for the group of patients from whom the tissue samples had been taken 2-3 h after the last administration of the drug. Lower mean concentrations of erythromycin were found in the serum and lung tissue of a similar group of 31 patients. The results indicate that the new macrolide antibiotic josamycin accumulates well in lung tissue and that the concentrations necessary for the treatment of infections (minimal inhibitory concentrations [MIC]) are rapidly reached also in the tissue.

Adult↗