Meningococcal septicaemia in a patient with a prosthetic valve-a sucessfully treated case.
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Aortic Valve↗
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Nasal membrane and intracellular protein and enzyme release by bile salts and bile salt-fatty acid mixed micelles: correlation with facilitated drug transport.
The effects of four bile salts, one fusidate derivative, and one mixed micellar formulation of bile salt-fatty acid combination on the nasal mucosal protein and enzyme release have been investigated in rats using an in situ nasal perfusion technique. Deoxycholate (NaDC) was found to possess the maximum protein solubilizing activity, followed by taurodihydrofusidate (STDHF), cholate, glycocholate (NaGC), and taurocholate (NaTC) in a descending order. The difference in protein solubilization of NaDC and NaGC was further characterized by the release of 5'-nucleotidase (5'-ND), a membrane-bound enzyme, and lactate dehydrogenase (LDH), an intracellular enzyme, in the perfusate. While both NaDC and NaGC caused comparable 5'-ND release from nasal membrane, intracellular LDH release was significantly higher with NaDC. The greater protein and LDH solubilizing effects of NaDC corresponded well with its faster rate of disappearance from the nasal perfusate. Therefore, the dihydroxy bile salt NaDC tends to cause intracellular damage and cell lysis, whereas the trihydroxy bile salt NaGC appears to produce primarily mucosal membrane perturbations. Linoleic acid in the form of soluble mixed micelles with glycocholate caused a further increase in nasal protein release. However, the rate and extent of nasal membrane protein release by the mixed micelles composed of 15 mM glycocholate and 5 mM linoleic acid were significantly lower than those caused by either deoxyholate or STDHF at the same concentrations. Nasal absorption of acyclovir, a non-absorbable hydrophilic model antiviral agent, was found to be enhanced in the presence of conjugated trihydroxy bile salts and bile salt-fatty acid mixed micelles.(ABSTRACT TRUNCATED AT 250 WORDS)
5'-Nucleotidase↗
A comparison of sodium fusidate ointment and mupirocin ointment in superficial skin sepsis.
Sodium fusidate ointment and mupirocin ointment were compared in 354 patients with superficial skin sepsis. The ointments were applied 3-times daily, or once daily when covered by a dressing, and the response assessed after 6 to 8 days. Both preparations proved effective clinically with 86% of patients responding. There was no difference between the two preparations in cases of primary infection (85% to both ointments), including a sub-group with impetigo (sodium fusidate 88% and mupirocin 84%), or secondary infection (sodium fusidate 81% and mupirocin 89%). Sodium fusidate ointment (98%) was significantly better (p less than 0.05) than mupirocin (82%) in patients with other superficial infections. Both ointments were equally effective in cases where Gram-positive, Gram-negative or mixed Gram-positive/Gram-negative bacteria were isolated. Adverse effects were reported in 1.0% of patients using sodium fusidate ointment and in 7.4% of patients using mupirocin ointment. The majority of complaints concerned the greasiness of mupirocin ointment.
Adolescent↗
Regulation of 3-hydroxy-3-methylglutaryl CoA reductase by analogs of cholesterol and bile acids in cultured intestinal mucosa.
Sodium fusidate and its glycine conjugate, which have the same detergent properties as bile acids, significantly (p less than 0.05) stimulate HMG-CoA reductase of cultured intestine below the critical micellar concentration (CMC) without affecting brush border enzymes. Above CMC, both amphiphiles are cytotoxic. At concentrations between 1 and 5 mM, sodium fusidate decreased cholesterol contents of cultured mucosa (P less than 0.05), the increase in synthesis only partially compensating for the sterol loss. Oxygenated sterols, 7-keto- and 25-hydroxycholesterol, also depleted mucosal cholesterol at 0.5 mM, exerting their effect differently by inhibiting HMG-CoA reductase (p less than 0.01). In contrast to their marked effect on total mucosal cholesterol contents, brush border cholesterol was unaffected by both cholesterol and bile acid analogs.
Animals↗
Kinetics and mechanisms of drug action on microorganisms. XX. Integrated receptor site model rationalizing observed microbial rate dependencies on drug concentration and microbial kinetics affected by sodium fusidate.
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Amino Acids↗
Micellar properties of sodium fusidate, a steroid antibiotic structurally resembling the bile salts.
The properties of sodium fusidate micelles were determined by a spectral shift technique, surface tension measurements, and ultracentrifugal analysis. The critical micellar concentrations, mean molecular areas, and apparent aggregation numbers were estimated as a function of the concentration of counterion (0.001-1.0 m Na(+)) at 20 degrees C. The critical micellar concentrations were studied over a temperature range of 10 degrees C to 40 degrees C at one counterion concentration (0.001 m Na(+)), and from these data the standard thermo-dynamic functions of micellization were calculated. The ability of sodium fusidate solutions to solubilize the insoluble swelling amphiphiles, lecithin and monoolein, was investigated, and the results were compared with the solubilizing properties of sodium taurocholate. The critical micellar concentrations of sodium fusidate approximated those of sodium taurocholate. The values fell in the range of 1.44-4.56 mm, varying with the technique used, counterion concentration, and temperature. The percentage of counterions bound to fusidate micelles in water, calculated from the log critical micellar concentration-log Na(+) curve, was estimated to be negligible, which compares with sodium taurocholate micelles. The critical micellar concentration of sodium fusidate exhibited a minimum at 20 degrees C, a phenomenon observed with other ionic detergents and with bile salts. Micelle formation in sodium fusidate solutions was shown to be primarily entropy-driven at 10 degrees and 20 degrees C, whereas at 30 degrees and 40 degrees C the enthalpy factor predominated. From the surface tension measurements the molecular areas of sodium fusidate and sodium taurocholate were calculated. The mean molecular area of fusidate was 101 A(2), whereas sodium taurocholate possessed a molecular area of 88 A(2). It was demonstrated that the sodium fusidate molecule, like a bile salt molecule, lies with its longitudinal axis horizontal at an air-water interface. The apparent aggregation number of sodium fusidate micelles increased from 5 to 16 as the concentration of counterion increased from 0.01 to 0.60 m Na(+). These values are slightly larger than the corresponding aggregation numbers of sodium taurocholate micelles.
Bile↗
Sodium fusidate and the cytokine response in an experimental model of acute pancreatitis.
BACKGROUND: New therapies designed to downregulate the aberrant immune response associated with severe acute necrotizing pancreatitis (ANP) are being increasingly investigated in different experimental models of ANP. The aim of this study was to test the potential effects of sodium fusidate on the course of severe ANP in rabbits. METHODS: ANP was induced in 20 rabbits by retrograde injection of 5 per cent chenodeoxycholic acid into the pancreatic duct followed by duct ligation. The rabbits were allocated to pretreatment with intravenous physiological saline or sodium fusidate 80 mg/kg 30 min before the induction of ANP. Levels of serum amylase, lipase, tumour necrosis factor (TNF) alpha, interleukin (IL) 8, glucose and calcium, and leucocyte count were measured every 3 h for a total of 12 h. At the end of the experiment, ascitic fluid was collected and the pancreatic, lung and kidney tissues were obtained for histological examination. RESULTS: Pretreatment with sodium fusidate reduced the mortality rate from six of ten to three of ten (P < 005) and reduced the output of ascitic fluid from 5 2 to 2.0 ml/h (P < 0001). Serum levels of TNF-alpha and IL-8 were reduced significantly in the treated group from 5 min up to 9 h after induction of ANP. The leucopenia observed after 3 h in the untreated group was not significantly improved in the group treated with sodium fusidate (P = 0.055). By contrast, both treated and untreated rabbits had similar biochemical changes including levels of amylase, lipase, glucose and calcium as well as similar histological changes in the pancreas and lungs. CONCLUSION: Pretreatment with sodium fusidate resulted in a considerable reduction in mortality rate and ascitic fluid output in rabbits with bile-induced ANP, probably by lowering the TNF-alpha and IL-8 blood levels. However, pretreatment with sodium fusidate did not alter the local or systemic manifestations of ANP. Thus, cytokines other than TNF-alpha and IL-8 are likely to mediate the local and systemic symptoms of ANP.
Amylases↗
Cultured human fibroblasts as a model for evaluation of potential in vivo toxicity of membrane damaging antibiotics.
The toxic side effects of certain antimicrobial agents are probably related to their membrane damaging properties. Thus it should be possible to use measurement of membrane damage in vitro for evaluation of the potential toxicity in vivo of such antibiotics. We estimated the membrane damage induced in cultured human fibroblasts by anti-microbial agents, such as polyene antibiotics, sodium fusidate and polymyxin B as well as derivatives of some of these. Degree and character of membrane damage was determined on basis of leakage of three defined cytoplasmic markers from prelabelled cells after treatment with test substance. By comparing the minimal inhibitory concentrations against the target microbial cells (MIC) with the amounts needed to cause membrane damage of human cells (ED50) a 'therapeutic dose range' was obtained (ED50/MIC). The therapeutic dose range and the character of induced membrane damage were compared with the relative toxicities in vivo of each test substance. Highly toxic agents caused large functional 'holes' and/or showed a narrow therapeutic dose range, whereas less toxic substances induced smaller functional holes and/or had a larger therapeutic dose range. These parameters, evaluated in the presented model system, should be useful for an indication of potential toxicity in vivo.
Aminoisobutyric Acids↗
Antibiotic susceptibility of anaerobic bacteria with special reference to Bacteroides fragilis.
It was shown that recent Swedish clinical isolates of anaerobic bacteria are susceptible to many antibiotics by the agar dilution method with the exception of the Bacteroides group versus beta-lactam antibiotics or tetracyclines. Strains of B. fragilis were inhibited by 4--greater than 128 micrograms benzylpenicillin or cephalothin/ml, 1.0--64 micrograms cefoxitin/ml, 0.064--2 micrograms clindamycin or metronidazole/ml, 2--8 micrograms chloramphenicol/ml, 2--16 micrograms fusidic acid/ml and 0.032--32 micrograms doxycycline/ml. Resistance to beta-lactam antibiotics was partly due to the production of beta-lactamase. Growth of beta-lactamase producing strains in the presence of enzyme inhibitors such as clavulanic acid or CP-45899 together with cephaloridine lowered the MIC's manyfold. Cefoxitin with relative resistance to beta-lactamases inhibited the majority of the strains at 8 micrograms/ml. Cefoxitin-resistant strains (MIC greater than or equal to 16 micrograms/ml) were also resistant to the new cephalosporins BL-S786 and HR-756 as well as to the new cefamycins A, B, CL619-183, CS-1170 and Sq-14359 and to thienamycin. Cefamycin CL619-183, only showed a slightly higher in vitro activity than cefoxitin. Resistance to the cefamycins could not be correlated to the production of beta-lactamases.
Anti-Bacterial Agents↗
Effects of bile salts and aliphatic ionic surfactants on human lymphocyte proliferation.
BACKGROUND: The molecular mechanisms involved in the immunosuppressive properties of bile salts are partly unknown. METHODS: The aim of the study was to compare the effects of bile salts to those of various compounds with a steroid structure, or straight-chain hydrocarbons of different lengths and polar groups in the human mixed lymphocyte reaction. RESULTS: We showed a significant correlation between the effects of bile salts and a low critical micellar concentration, a high surface activity index, and the absence of conjugation. In addition to mixed lymphocyte reaction (MLR) inhibition, chenodeoxycholate (CDC) inhibit ConA-induced IL2 production without any effect on IL2 R expression. Fusidate, a negatively charged steroid, with physical properties comparable to those of deoxycholate, had similar effects. Cetyltrimethylammonium bromide (CTAB), which exhibited a very low critical micellar concentration, inhibited mixed lymphocyte reaction in an extent comparable to cyclosporin A. In contrast, aliphatic compounds with critical micellar concentrations in the same range as bile salts but with a lower molecular area had no effect. CONCLUSIONS: Amphiphilic negatively charged molecules inhibit T-cell proliferation to an extent that is dependent upon their hydrophobicity. These results may be explained, at least in part, by a modification in the cell membrane lipid bilayer structure.
Bile Acids and Salts↗
Immobilized artificial membrane chromatography: a rapid and accurate HPLC method for predicting bile salt-membrane interactions.
To predict bile salt-membrane interactions physiologically, we used an immobilized artificial membrane HPLC column that contains dimyristoyl-phosphatidylcholine molecules covalently linked to silica microspheres. Using a 90% aqueous (10% acetonitrile) mobile phase, 22 species of bile salts and 4 species of fusidates were eluted. Glycine conjugates displayed higher affinity for the column at pH 5.5, eluting later than their taurine-conjugated congeners, but this order was reversed at pH 6.5 and 7.4 as glycine conjugates became fully ionized. Capacity factors decreased logarithmically as functions of increasing temperature, permitting determinations of interaction enthalpies, which ranged from -2.86 to -7.67 kcal/mol. A standard curve was developed from which the enthalpy for an uncommon bile salt could be inferred from its capacity factor at room temperature. Bile salt interaction enthalpies were substantially better correlated than hydrophobic indices by octadecylsilane-HPLC (D. M. Heuman, J. Lipid Res. 1989. 30: 719-730) with equilibrium binding to small unilamellar vesicles and literature values reflecting bile salt-membrane interactions (e.g., biliary phosphatidylcholine secretion), but not with bile salt functions that do not require phospholipid (e.g., micellar cholesterol solubility). This new application should prove valuable for evaluating membrane-active physical-chemical properties as well as therapeutic potential of novel bile salts, particularly when they are available in quantities too small for study by conventional techniques.
Bile Acids and Salts↗