Influence of a Nigerian honey on CYP3A4 biotransformation of quinine in healthy volunteers.

WHAT IS KNOWN AND OBJECTIVES: Some studies, howbeit with conflicting reports, have suggested that consumption of honey has a potential to modulate drug metabolizing enzymes which may result in a honey-drug interaction. Numerous studies have established that honey varies in composition, influenced by the dominant floral, processing and environmental factors. Thus, variation in honey composition may be a contributing factor to the controversial results obtained. No previous drug interaction study has been carried out with any honey from Africa. CYP 3A4 is an important enzyme in drug metabolism studies as it is involved in the metabolism of over 50% of drugs in clinical use and quinine remains very relevant in malaria treatment in the tropics, and we therefore determined whether there is potential drug interaction between a Nigerian honey and quinine, a drug whose metabolism to 3-hydroxyquinine is mediated majorly by CYP3A4. METHODS: In a three-phase randomized crossover study with a washout period of 2 weeks between each treatment phase, ten (10) healthy volunteers received quinine sulphate tablet (600 mg single dose) alone (phase 1) or after administration of 10 ml of honey (Phase 2) and 20 mL of honey (Phase 3) twice daily for seven (7) days. Blood samples were collected at the 16th hour post-quinine administration in each phase, and quinine and its major metabolite, 3-hydroxyquinine, were analysed using a validated HPLC method. RESULTS: After scheduled doses of honey, the mean metabolic ratios of quinine (3-hydroxyquinine/quinine) increased by 24·4% (with 10 mL of honey) and reduced by 23·9% (with 20 mL of honey) when compared to baseline. These magnitudes of alteration in the mean metabolic ratios were not significant (P > 0·05; Friedman test). The geometric mean (95% CI) for the metabolic ratio of quinine before and after honey intake at the two dose levels studied was 0·82 (0·54, 1·23) and 1·29 (0·96, 1·72), respectively, and were also not significant (P = 0·296 and 0·081 respectively; Student's t-test). WHAT IS NEW AND CONCLUSION: This is a pioneer study on the effect of Nigerian/African honey on quinine metabolism. The findings indicated that low and high doses of honey did not significantly affect metabolism of quinine to 3-hydroxyquinine. This suggests that CYP3A4 activity is not significantly altered following low or high dose of honey, as CYP3A4 has been reported to be responsible for the conversion of quinine to 3-hydroxyquinine. In conclusion, the outcome of this study suggests that there may be no potential significant metabolic interaction between Nigerian honey and quinine administration.

Dissolution properties and characterization of halofantrine-2-hydroxypropyl-beta-cyclodextrin binary systems.

Halofantrine (HF) is a poorly water-soluble antimalarial drug with low bioavailability. Complex formation of HF.HCl and 2-hydroxypropyl-beta-cyclodextrin (HP-beta-CD) in aqueous solution and in solid state as well as the possibility of improving the solubility and dissolution rate of the drug though complexation with the cyclodextrin were investigated. Phase-solubility profile indicated that the solubility of the drug was significantly increased in the presence of HP-beta-CD and was classified as AL-type, indicating 1:1 stoichiometric inclusion complexes and an apparent stability constant value of 2300 M(-1). Solid inclusion complexes of HF, HCl and the cyclodextrin at 1:1 molar ratios were prepared by physical mixture, kneading, co-evaporation and freeze-drying methods and characterized by X-ray diffraction and Infra-red spectroscopy. The solubility and dissolution rates of HF.HCl from the complexes were determined and found to be dependent on the preparation method of the complexes. Dissolution profile of the drug was markedly enhanced by complex formation with the cyclodextrin and the product prepared by the freeze-drying method exhibited the most superior dissolution properties compared to the other methods used in this study. The results suggest that the complexation of HF.HCl with HP-beta-CD could improve therapeutic efficacy of the drug though enhanced absorption expected from increased drug dissolution.

Pharmacokinetic aspects of chloroquine-induced pruritus: influence of dose and evidence for varied extent of metabolism of the drug.

The significance of a pharmacokinetics basis in chloroquine (CQ)-induced pruritus was investigated by determining the disposition of the drug in two groups of volunteers; pruritus positive and pruritus negative. Single oral dose of 600 mg CQ was administered to each of 36 volunteers, 18 for each of the two groups. After a washout period of 9 months, 150 mg single oral dose of the drug was given to 12 of the same volunteers, six each from the two groups. Blood and urine samples were collected at predetermined times following administration of each dose. Concentrations of CQ and its major metabolite, desethylchloroquine (CQM), were measured in plasma and urine using an established HPLC method. Results showed that the ratio, AUC (CQ)/AUC (CQM), as well as AUC(0-48 h) and 24-h urinary CQ excretion were all significantly higher (P<0.05) in pruritus-positive compared to pruritus-negative volunteers, following administration of the 600-mg CQ dose. Also, urinary drug-metabolite ratios monitored over 0-48 h postdose were markedly higher in the pruritus positive group. However, after administration of the 150-mg dose, 24-h urinary CQ collection and urinary drug-metabolite ratios were highly comparable between the two groups (P>0.1). This study indicates that there might be a decreased metabolism of CQ in subjects susceptible to CQ-induced pruritus following ingestion of a therapeutic dose. It also suggests that the extent of metabolism of CQ in this group may be influenced by the dose of the drug. Comparatively higher CQ levels in pruritus susceptible subjects may possibly be responsible for the pruritus experienced by such individuals when given therapeutic regimen.

Effects of adjunctive treatment with combined cytokines in a neutropenic mouse model of multidrug-resistant Enterococcus faecalis septicemia.

STUDY OBJECTIVE: To examine whether the antienterococcal efficacy of a regimen of gentamicin plus vancomycin combined with granulocyte colony-stimulating factor (G-CSF) is enhanced by concurrent therapy with interferon-gamma (IFN-gamma). SETTING: Hospital laboratory. INTERVENTION: Mice rendered neutropenic by cyclophosphamide were intraperitoneally inoculated with a gentamicin- and vancomycin-resistant Enterococcus faecalis isolate. MEASUREMENTS AND MAIN RESULTS: Infected animals were randomized into treatment groups that received G-CSF alone or in combination with various dosages of IFN-gamma. Additional groups of animals received vancomycin; G-CSF, G-CSF plus vancomycin, IFN-gamma, and G-CSF; or vancomycin with both cytokines. Addition of IFN-gamma to G-CSF regimen resulted in no significant change (p>0.05) in survival, compared with treatment with G-CSF alone. Also, the antienterococcal efficacy of antibiotic plus G-CSF was not modified by coadministration of IFN-gamma. CONCLUSION: This study suggests that adjunctive application of combined cytokines may not be more beneficial than only G-CSF in combination with an antibiotic to treat multidrug-resistant enterococcal infection.

Modulation of efficacies and pharmacokinetics of antibiotics by granulocyte colony-stimulating factor in neutropenic mice with multidrug-resistant Enterococcus faecalis infection.

It has been demonstrated previously that, in non-neutropenic animals, interferon-gamma markedly enhances the efficacies of gentamicin and vancomycin against Enterococcus faecalis resistant to these antibiotics. The aim of our study was to determining whether granulocyte colony-stimulating factor (G-CSF) can be beneficial as an adjunct to gentamicin and vancomycin in the treatment of the same infection in neutropenic mice. After induction of neutropenia by cyclophosphamide, mice were inoculated ip with the organism. The infected animals received sc administrations of G-CSF, antibiotic or a combination of both agents at determined dosing regimens. Infected animals treated with G-CSF alone showed a dose-dependent increase in survival. The inoculum size used in establishing infection affected the effectiveness of the cytokine. Survival was significantly (P: < 0.01) better in the infected animals given gentamicin and vancomycin plus G-CSF than in those given antibiotics or G-CSF alone. The possibility of pharmacokinetic interaction between G-CSF and each of the antibiotics was examined. The cytokine significantly increased the plasma clearance of gentamicin, with a resultant decrease in the area under the concentration-time curve (AUC), while the disposition of vancomycin was not affected. This study suggests that G-CSF may be a useful adjunct to gentamicin and vancomycin for the treatment of multidrug-resistant E. faecalis infection in neutropenic patients.

Pharmacodynamic assessment of cefprozil against Streptococcus pneumoniae: implications for breakpoint determinations.

Cefprozil, an oral semisynthetic cephalosporin, is commonly utilized in the treatment of respiratory-tract infections in children. While this agent has provided acceptable clinical success over a number of years, this study was undertaken to better define its pharmacodynamic profile against Streptococcus pneumoniae. Nineteen clinical isolates of S. pneumoniae were utilized in the neutropenic murine thigh infection model. To simulate the pharmacokinetic profile of cefprozil in children, the renal function of mice was impaired with uranyl nitrate, and a commercially available cefprozil suspension (6 mg/kg of body weight) was administered orally every 12 h. Mice were infected with 10(6) to 10(7) CFU per thigh, and therapy was initiated 2 h later. At 0 and 24 h postinfection, thighs were harvested to determine bacterial density. Survival was assessed during 96 h of therapy. The magnitude of bacterial kill ranged from 0.5 to 4.4 log(10) CFU per thigh over 24 h, and the extent of microbial eradication was dependent on the MIC. Killing of more than 2.6 log(10) CFU per thigh was observed with MICs of < or =3 microg/ml, while either minimal killing or growth was detected with MICs of > or =4 microg/ml. Mortality in untreated control animals was 100%. Animals infected with strains for which the MICs were < or =2 microg/ml survived the infection, whereas MICs exceeding 2 microg/ml resulted in substantial mortality. These studies demonstrate the effectiveness of cefprozil against isolates of the pneumococcus for which the MICs are < or =2 microg/ml using a drug exposure typically observed in children. These data support a susceptibility breakpoint of < or =2 microg/ml for cefprozil.

Influence of adjunctive interferon-gamma on treatment of gentamicin- and vancomycin-resistant Enterococcus faecalis infection in mice.

Increasing antibiotic resistance and the development of multidrug-resistance in the enterococci has complicated the treatment of serious enterococcal infections. It has been demonstrated in vitro that interferon-gamma (IFN-gamma) significantly augments the activities of gentamicin and vancomycin against Enterococcus faecalis resistant to these antibiotics. The present study was aimed at determining whether this beneficial effect of IFN-gamma on antienterococcal antibiotic activity can be validated in vivo. Following intraperitoneal inoculation in mice with a gentamicin- and vancomycin-resistant E. faecalis clinical isolate, the animals received IFN-gamma, antibiotic or a combination of both agents, subcutaneously, at determined dosing regimens. Treatment with IFN-gamma alone significantly improved survival of infected animals in a dose-dependent manner. High dose IFN-gamma was not beneficial and the level of enterococcal infectious burden influenced the effectiveness of the cytokine. The addition of IFN-gamma to therapy with gentamicin or vancomycin, or a combination of both antibiotics was associated with a marked increase in survival of infected non-neutropenic mice compared to treatments with the agents alone. However, the same treatments made in infected neutropenic mice did not show an enhancement effect by IFN-gamma after a combination therapy with antibiotics. In a study to examine pharmacokinetic interactions, concurrent administration with IFN-gamma significantly modified the disposition of gentamicin but not that of vancomycin. The results of this study suggest that the use of IFN-gamma in combination with vancomycin or gentamicin is a new treatment option that might improve the outcome of therapy of multidrug-resistant E. faecalis infections.

Comparative efficacies of levofloxacin and ciprofloxacin against Streptococcus pneumoniae in a mouse model of experimental septicaemia.

The in vivo efficacies of levofloxacin and ciprofloxacin were compared against three clinical isolates of Streptococcus pneumoniae, using a mouse protection model. Two strains (SP 22 and SP 28) were penicillin-sensitive while one strain (SP 46) was penicillin-resistant. Each strain had identical susceptibility to both drugs. Using mice with renal impairment induced by uranyl nitrate injection, the elimination half-life of each antibiotic was prolonged to approximate human pharmacokinetic profiles of the drugs. The dosing regimen of each drug that yielded serum levels in mice which mimic human therapeutic concentrations of the drugs, were designed. One hour after intraperitoneal inoculation with minimum lethal dose of each strain, either levofloxacin at a dosing regimen of 10.6 mg/kg every 8 h or ciprofloxacin at 9.5 mg/kg every 8 h was subcutaneously administered for a total of six or 15 doses. In treatment, monitored daily for 5-8 days, levofloxacin resulted in higher survival compared with ciprofloxacin for the three strains. For example, percent survival following levofloxacin treatment recorded at day 4 postinfection with SP 22, SP 28 and SP 46 were 41, 90 and 30%, respectively, while the corresponding values after ciprofloxacin treatment were 27, 75 and 16%, respectively. However, statistical analysis did not reveal a significant difference (p > 0.05). The lack of significant difference observed in the efficacies of both drugs reflected the comparability of their 24-h AUC/MIC ratios. It is suggested that, with some strains of S. pneumoniae, the efficacy of levofloxacin may be equivalent to that of ciprofloxacin in the treatment of systemic pneumococcal infections caused by susceptible strains of the organism.

Pharmacodynamics of intermittent- and continuous-infusion cefepime alone and in combination with once-daily tobramycin against Pseudomonas aeruginosa in an in vitro infection model.

Cefepime, a fourth-generation cephalosporin, is currently one of the primary agents used in combination with an aminoglycoside when treating Pseudomonas aeruginosa infections. The bactericidal activity of cefepime administered as intermittent doses (IT) or continuous infusion (CI) both alone and in combination with once-daily tobramycin (ODT) against two clinical strains of P. aeruginosa was compared using an in vitro infection model. Cefepime concentrations simulated human pharmacokinetics after a 1-gram Q12 regimen, or a 1-gram loading dose followed by a 2-gram Q24 CI regimen; the ODT regimen mimicked peak concentrations of >/=10 x MIC. All regimen simulations were run in duplicate over 48 h and a growth control (no antimicrobials added) was run concurrently. Strains tested, PSA5 and PSA10, had MICs of 2 and 8 microg/ml to cefepime, respectively; both MICs to tobramycin were 1.0 microg/ml. CI regimens resulted in concentrations approximately 6x and 2x the MIC for PSA5 and PSA10, respectively. The change in log10 colony-forming units (CFU) per milliliter over time for both P. aeruginosa isolates was compared to initial inocula for all treatment regimens. Initial bolus doses of both IT and CI regimens resulted in a similar decrease in the log10 CFU/ml of both organisms over the first 12 h of the study. After subsequent doses, however, both IT regimens showed greatly diminished bactericidal activity, while both CI regimens were persistently bactericidal without the observation of significant regrowth. As a result, a statistical difference in log10 CFU/ml between both IT and CI regimens with and without ODT was realized at 24, 36 and 48 h for each isolate. Unlike IT dosing, CI cefepime alone or in combination with ODT optimizes bactericidal activity by maximizing the percent of the dosing interval that concentrations remained above the MIC resulting in undiminished bacterial inhibition when compared to IT regimens. These data further suggest that CI is the most efficient method of administration of beta-lactam antibiotics.

Pharmacokinetics of ticlopidine in the rabbit.

There is no information about the pharmacokinetics of ticlopidine in rabbits. Such information is valuable in designing appropriate dosing regimens for experimental studies of the drug with ultimate applications in man. The disposition kinetics of ticlopidine at three dose levels were evaluated in three groups of six rabbits which received 10, 50 or 100 mgkg(-1) drug once daily via the oral-gastric route. Blood samples were collected at predetermined times after the third dose. Plasma concentrations of the unchanged drug were determined by a validated liquid chromatography-mass spectrometry method with a limit of detection of 5 microg L(-1). There was a disproportionate increase in the mean maximum plasma concentration (Cmax) and the area under the plasma drug-concentration-time curve (AUC) for the 10 and 50 mgkg(-1) doses. The apparent terminal half-life (t1/2beta), apparent volume of distribution (Vdbeta/F), and total plasma clearance (CLp/F) of the drug were all dose-dependent. For example, t1/1beta for the 10, 50 and 100 mgkg(-1) doses were 1.04+/-0.10, 4+/-24+/-1.92 and 12.80+/-6.35 h, respectively, whereas the Vdbeta/F values for the corresponding doses were 214 31, 475 221 and 998+/-420 Lkg(-1), respectively. These results show that the 100-mgkg(-1) dose produces plasma ticlopidine concentrations similar to those found in man after administration of 250 mg of the drug. It is suggested that 100 mg kg(-1) might be the appropriate dose of ticlopidine for use in rabbit experimental studies with ultimate application to man.

Interferon-gamma effects on activities of gentamicin and vancomycin against Enterococcus faecalis resistant to the drugs: an in vitro study with human neutrophils.

The emergence of multidrug-resistant enterococci presents a major therapeutic challenge since there is currently no clearly effective antimicrobial therapy for these infections. The combinatorial effects of interferon-gamma (IFN-gamma) with gentamicin and/or vancomycin against a clinical isolate of drug-resistant Enterococcus faecalis, were evaluated in an in vitro system with human neutrophils. Following inoculation of cultures of human neutrophils with the organism, treatments were initiated immediately after the infection and the number of viable bacteria was determined at 12, 18 and 24 h. Antibiotics were applied at concentrations close to their clinically achievable serum trough and peak levels. Treatment with IFN-gamma alone induced a maximal growth inhibition of up to 40% at a concentration of 100 U/ml. Addition of the cytokine to either therapeutic trough or peak concentrations of gentamicin and vancomycin, or a combination of both antimicrobials, was associated with a significant (P < 0.01) enhancement of anti-enterococcal activity compared with the effects of the agents alone. Investigation of a potential underlying mechanism of anti-enterococcal action of IFN-gamma reveals that it is, most probably, largely due to an activated secretion of the microbicidal reactive oxygen intermediates by neutrophils. The results of this study show that there is a possibility that IFN-gamma could be a useful adjunct in the treatment of multidrug-resistant E. faecalis.

Effects of absorption enhancers in chloroquine suppository formulations: I. In vitro release characteristics.

The need to develop chloroquine suppository formulations that yield optimal bioavailability of the drug has been emphasized. This study demonstrates the effects of incorporation of known absorption-enhancing agents (nonionic surfactants and sodium salicylate) on the in vitro release characteristics of chloroquine from polyethylene glycol (1000:4000, 75:25%, w/w) suppositories. The release rates were determined using a modification of the continuous flow bead-bed dissolution apparatus for suppositories. Results showed that the extent of drug release from suppositories containing any of three surfactants (Tween 20, Tween 80 and Brij 35) was 100%, whereas 88% release was obtained with control formulation (without enhancer) (P<0.05). However, Tween 20 was more effective than Brij 35 and Tween 80 in improving the drug release rate. There was a concentration-dependent effect with Tween 20, and 4% (w/w) of this surfactant was associated with the highest increase in the rate of drug release from the suppositories. Sodium salicylate at a concentration of 25% (w/w) also significantly enhanced the drug release rate, but a higher concentration of the adjuvant markedly reduced both the rate and extent of drug release. Combined incorporation of Tween 20 and sodium salicylate did not significantly modify (P0.05) the rate of drug release when compared to the effect of the more effective single agent. Due to their effects in improving the drug release profiles coupled with their intrinsic absorption-promoting properties, it is suggested that incorporation of 4% (w/w) Tween 20 and/or 25% (w/w) sodium salicylate in the composite polyethylene glycol chloroquine suppository formulations, may result in enhancement of rectal absorption of the drug. This necessitates an in vivo validation.

Altered pharmacokinetics of halofantrine by an antacid, magnesium carbonate.

This study investigated the in vitro adsorption of halofantrine (Hf) by some antacids. Magnesium carbonate showed the highest adsorptive effect, the extent of adsorption being up to 83%. Only 4% of Hf adsorbed by the antacid could be eluted with 0.1 M HCl while no detectable elution occurred with water. Other antacids investigated were magnesium trisilicate and aluminium hydroxide and these had Hf-adsorption capacities of 23 and 43%, respectively. The effect of magnesium carbonate on the bioavailability of Hf was evaluated in seven healthy volunteers. The subjects were administered with 500 mg oral dose of Hf-HCl or the same dose of the drug in combination with 1 g of magnesium carbonate, in a crossover fashion. Blood samples were collected at predetermined time intervals and were analysed for Hf and its major metabolite, desbutylhalofantrine (Hfm), using high-performance liquid chromatography method. The results showed that magnesium carbonate significantly prolonged (P<0.05) the time to reach maximum plasma concentration (Tmax) of Hf. Also the maximum plasma concentrations (Cmax) of Hf and Hfm were significantly reduced (P<0.05). Furthermore, there was a reduction in the area under the curve (AUC) values of Hf and this was as high as 56% (range 1-56%). Results of this study suggest that it may not be advisable to concomitantly administer Hf with an antacid like magnesium carbonate.

Ion-pair reversed-phase high-performance liquid chromatographic analysis of halofantrine and desbutylhalofantrine in human plasma.

A new ion-pair reversed-phase high-performance liquid chromatographic (HPLC) method for the simultaneous measurements of halofantrine (HF) and its major metabolite, desbutylhalofantrine (Hfm), in human plasma is described. Sample treatment involved protein precipitation with acetonitrile followed by extraction with hexane-diethylether (ratio, 1:1; vol/vol) under alkaline condition. Chromatographic separation was achieved on a 10-microm particle size C-18 column (200 x 4.6 mm internal diameter) using a mobile phase consisting of methanol-0.05 M potassium dihydrogen phosphate (70:30, vol/vol) with 55 mmol/l perchloric acid (pH 3.1). Retention times for Hfm, Hf, and the internal standard were 5.3, 7.5, and 11.5 minutes, respectively. Detection limits of Hf and Hfm were 2.5 and 2.0 ng/ml, respectively (1 ng/ml = 2 nmol/l for Hf; 1 ng/ml = 2.25 nmol/l for Hfm). Intraassay and interassay coefficients of variation for both compounds were less than 7%, with an accuracy of no greater than 8% at concentrations of 40 and 400 ng/ml, respectively. The new HPLC method is sensitive, selective, and rapid. Relative to previous HPLC methods, it is simple and cost-effective. In addition, the internal standard is readily accessible. Application of this method in pharmacokinetic studies was demonstrated.

Time-dependent variability of chloroquine secretion into human saliva.

Chloroquine has been reported to be secreted into human saliva. This is a report of a study designed to underscore the importance of the finding. It involved the administration of 600 mg chloroquine per oral to seven volunteers and 150 mg by intramuscular route to six others. Blood and simultaneous saliva samples were collected and analyzed for the drug by an HPLC method. The results showed that chloroquine reaches peak concentration at the same time in both plasma and saliva after oral administration of the drug. A good correlation was obtained between the AUC values derived from saliva and plasma level data. Saliva to plasma concentration ratios obtained after administration of the drug by both routes were high (mean > 11) and exhibited a time-dependent variability. These results suggest that an active process, among other mechanisms, may be involved in the transfer of chloroquine into human saliva. Caution should be exercised in the use of saliva for therapeutic monitoring of chloroquine.

Pharmacokinetics and bioavailability of drotaverine in humans.

The pharmacokinetics and bioavailability of drotaverine was studied in 10 healthy volunteers after administration of single 80 mg oral and intravenous doses of the HCl salt of the drug, in a crossover fashion. Plasma and urine samples were analyzed for the unchanged drug by HPLC. The pharmacokinetic parameters, such as elimination half-life, plasma clearance, renal clearance and apparent volume of distribution, were not influenced by the route of drug administration. The drug was mainly eliminated by non-renal routes since renal clearance accounted for only 0.31 +/- 0.13% of the total plasma clearance. The absolute bioavailability was variable and ranged from 24.5-91% with a mean of 58.2 +/- 18.2% (mean +/- SD). It is suggested that the high variation in the bioavailability of drotaverine HCl after oral administration may result in significant interindividual differences in therapeutic response.

Activities of clarithromycin, azithromycin, and ofloxacin in combination with liposomal or unencapsulated granulocyte-macrophage colony-stimulating factor against intramacrophage Mycobacterium avium-Mycobacterium intracellulare.

The effects of ofloxacin, clarithromycin, and azithromycin in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF) against Mycobacterium avium-Mycobacterium intracellulare (MAI) were evaluated in an in vitro human macrophage infection model. Treatment of MAI-infected macrophages with GM-CSF alone induced a maximal killing effect at 1000 U/mL, and the potency was increased 100-fold by encapsulating the cytokine within liposomes. Antibiotics were applied at concentrations close to their clinically achievable serum trough and peak levels. Addition of GM-CSF to azithromycin and therapeutic trough concentrations of ofloxacin and clarithromycin was associated with significant (P < .01) augmentation of antimycobacterial activity compared with the effects of the agents alone. However, the enhancement effect by GM-CSF was not seen with therapeutic peak concentrations of ofloxacin and clarithromycin. Thus, GM-CSF may be a useful adjunct in the treatment of MAI infections with azithromycin, clarithromycin, and ofloxacin.

Disposition kinetics of aspirin in female New Zealand white rabbits.

Limited information exists on the disposition of aspirin in rabbits. Such information is of value not only for treatment but also for development of experimental protocols with human applications. We evaluated the pharmacokinetics of aspirin at different doses by monitoring serum concentrations of the major metabolite, salicylic acid (SA). Four groups of six female New Zealand white rabbits received 2.5, 10, 20, or 50 mg of aspirin/kg of body weight. Aspirin was given once daily via the oral-gastric route, and blood samples were obtained after the third dose. Samples were collected before the last dose, then at 0.25, 0.50, 0.75, 1.0, 1.5, 2, 3, 4, 6, 8, 12, and 24 h after dosing. Analysis of SA was completed by a validated assay on a high-performance liquid chromatography system. Mean maximal serum SA concentration was 7.54, 22.65, 43.2, and 70 micrograms/ml for the 2.5, 10, 20, and 50 mg/kg doses respectively. The total systemic clearance of SA was not altered by increasing doses of aspirin, but statistically significant differences were noted in the volume of distribution. The SA elimination half-life also increased proportionally with the aspirin dose. Bleeding tendency was associated with the highest dose of aspirin. Results of this study suggest that the 20 and 50 mg/kg dosages produced serum SA concentrations that simulate those observed in humans after 600-mg and 1.2-g aspirin doses respectively.

Enhanced killing of methicillin-resistant Staphylococcus aureus in human macrophages by liposome-entrapped vancomycin and teicoplanin.

The antibacterial effects of liposomal vancomycin and teicoplanin against intracellular methicillin-resistant Staphylococcus aureus (MRSA) were evaluated using a macrophage infection model. Human blood-derived monocytes were cultured for 7 days to obtain adherent macrophages. Uptake of each drug by macrophages was markedly enhanced by liposomal encapsulation. Following phagocytosis and removal of residual extracellular MRSA, the infected macrophages were exposed to clinically achievable concentrations of teicoplanin and vancomycin. The free (untrapped) and liposome-entrapped forms of each drug were used at the same concentration. The number of intracellular surviving bacteria was determined by colony counts after lysis of the macrophages at different time intervals following drug treatment. Intracellular antimicrobial effect of each drug was significantly (p < 0.001) increased by entrapment in liposomes. Also, the efficacies of the free and liposomal forms of both drugs were correspondingly comparable (p > 0.05). It is, therefore, concluded that liposomal encapsulation of vancomycin and teicoplanin results in an increased availability of the antibiotics for efficient elimination of intracellular MRSA infection.

Optimal times above MICs of ceftibuten and cefaclor in experimental intra-abdominal infections.

The duration of time that serum drug levels remain above the MIC (time above the MIC) for the pathogen has been shown to be the most significant parameter determining the efficacies of beta-lactam antibiotics. In the described study, we investigated the optimal time above the MIC of ceftibuten and cefaclor using a nonneutropenic mouse model of intra-abdominal infections caused by Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, and Streptococcus pneumoniae. The abilities of the drugs to protect mice against the organisms were determined in mouse protection tests, and the doses were fractionated to produce various dosing regimens with different times above the MIC. All drug-organism combinations showed a significant correlation (r > 0.9) between drug efficacy and the time above the MIC. Also, with ceftibuten treatment, the different dosing regimens that produced equal times above the MIC resulted in the same efficacy, whereas with cefaclor, an apparent dose-dependent effect was observed. These results showed that for a 100% recovery from K. pneumoniae and E. coli infections, the optimal times above the MIC with ceftibuten treatment were 2.2 and 1.6 h, respectively. Relatively high doses of both antibiotics were required to ensure recovery from S. pneumoniae infections. In vitro time-kill studies demonstrated that cefaclor exhibits a marked inoculum effect against the pathogens, and there was a concentration-dependent killing at a large inoculum size. On the other hand, ceftibuten showed no inoculum effect. It is suggested that optimization of both dose and time above the MIC appears to be necessary for the treatment of S. aureus infections with cefaclor, and this may apply to other beta-lactams tht exhibit marked inoculum effects.