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Background: Topical metronidazole is commonly used in the management of rosacea. No consensus on the optimal formulation, concentration, or dosing regimen exists., Purpose: To assess the relative efficacy of metronidazole cream, gel, and lotion at concentrations of 0.75% and 1%, in dosing regimens of once and twice daily., Methods: A meta-analysis of published metronidazole efficacy rates was performed., Results: In non-weighted analysis, the mean efficacy was 28.2% (95% confidence interval [CI], 22.0%-34.4%) for the cream, 38.4% (95% CI, 18.4%-58.4%) for the gel, and 35% for the lotion. Confidence intervals for QD versus BID dosing and 0.75% versus 1% concentrations also overlapped. In weighted analysis, the mean reduction was 31.3% for the cream, 22.1% for the gel, and 35% for the lotion., Conclusions: Metronidazole cream, gel, and lotion vehicles have similar efficacies. There were no substantial differences between concentrations of 0.75% and 1%, or between once daily and twice daily regimens.

The plasma pharmacokinetics of metronidazole (CAS 443-48-1) and its active OH-metabolite (CAS 4812-40-2) were investigated in 16 healthy volunteers after the oral administration of single oral doses of 500 mg metronidazole by means of a novel (test, T) and reference formulation (reference, R). The trial was conducted according to a randomised, controlled, open, within-subject cross-over design with two periods one week apart for wash-out. A single oral dose of 500 mg metronidazole by means of the test formulation T (Vagimid Dragees) resulted in a geometric mean C(max) of 10649 ng/ mL (CV: 0.21) for metronidazole after a median t(max) of 70 min (range: 40 to 120); the geometric mean of the AUC(0-t(z)) and AUC(0-infinity) were 107406 (CV: 0.25) and 109056 ng x h/mL (CV: 0.26); the arithmetic mean of the half-life (t1/2) and the mean residence time (MRT) were 7.28 h (CV: 0.12) and 11.62 h (CV: 0.10). For the OH-metabolite, the geometric mean C(max) was 1941 ng/mL (CV: 0.22) after a median t(max) of 480 min (range: 360 to 600) with a geometric mean AUC(0-tz) and AUC(0-infinity) of 48653 (CV: 0.21) and 52417 ng x h/mL (CV: 0.22), respectively; the arithmetic mean t1/2 and MRT were 10.60 h (CV: 0.21) and 21.14 h (CV: 0.13), respectively. The test formulation was bioequivalent with the reference formulation for both metronidazole (90% CI of the treatment ratio of 1.02 to 1.15 and 1.02 to 1.12 for C(max) and AUC) and its metabolite (90% CI of 0.92 to 1.05 and 0.98 to 1.06, respectively). The treatments were very well tolerated and there were no limiting safety-relevant findings.

This paper is the third in a series on the prescribing of medicines for children by dentists working in primary care. It deals with antibiotics, which may be prescribed for infections arising from teeth, and reviews current best practice.

Aims: To evaluate the effects of food and formulation on the pharmacokinetics of bismuth biskalcitrate, metronidazole and tetracycline when combined in a new 3-in-1 single capsule (BMT) for eradication of Helicobacter pylori., Methods: In a randomized, 3 x 3 cross-over design, 23 healthy males received one dose of BMT in the fed and fasting states and equivalent doses of the three drugs given together but as separate capsules while fasting. Bioequivalence was evaluated according to 90% confidence intervals (CIs) of ratios of geometric least square means for C(max), AUC(t), and AUC(infinity)., Results: With respect to food, none of the three drugs met bioequivalence guidelines. Bismuth had lower limit CIs ranging from 12% for C(max) to 25% for AUC(infinity). The corresponding values for tetracycline were 59% and 51%. Metronidazole had a lower limit CI of 74% for C(max). With respect to formulation, bismuth had lower limits of CIs ranging from 39% for C(max) to 50% for AUC(t) and higher limits of 146% for AUC(t), metronidazole met bioequivalence guidelines, and tetracycline had lower limits of CIs between 72% for AUC(t) and 74% for AUC(infinity)., Conclusions: Food significantly decreased the relative bioavailability of each drug but formulation was without effect. This decrease may be beneficial when a local gastric action is needed, as confirmed by a near 90% eradication rate when this combined capsule is administered with food to treat gastro-duodenal local infection by H. pylori.

Metronidazole (MTZ), a drug used for the treatment of protozoal infections caused by protozoa and anaerobic microorganisms, was conjugated to linear or branched poly(ethylene glycol) of 5,000, 10,000 and 20,000 Da. An ester linkage between polymer and drug was used in the coupling to yield a polymeric prodrug. The modification allowed overcoming the known MTZ solubility problem leading us to obtain a bioconjugate more suitable for parental administration. The conjugates of various molecular weight polymers have been tested in vitro toward chemical degradation and digestive enzymes. It was found that molecular weight and shape of PEG is critical for the prodrugs stability. Good resistance in the stomach acidic media was found and a slow release of the drug in the large intestinal fluid may take place. In vivo studies carried out following i.v. or s.c. administration to mice revealed improved pharmacokinetics properties upon conjugation.

Background: Acid suppression plus two antibiotics is currently considered the gold standard anti-Helicobacter pylori treatment, but the effective role of gastric antisecretory drugs is still poorly understood., Aims: To compare a 14-day ranitidine-based triple regimen against Helicobacter pylori with one based on omeprazole, and to study the influence of antisecretory drugs on metronidazole pharmacokinetics in human plasma., Methods: A total of 150 dyspeptic H. pylori-infected patients were randomized for ranitidine 300 mg b.d. (RCM group) or omeprazole 20 mg b.d. (OCM group) 14-day triple therapy, with clarithromycin 500 mg b.d. and metronidazole 500 mg b.d. On the eighth day of therapy, metronidazole pharmacokinetics was studied in plasma by high-performance liquid chromatography. The pharmacokinetic parameters (terminal half-life, area under the curve, peak-plasma level, peak time) of metronidazole were computed using standard non-compartmental methods. H. pylori status was monitored before and 4 weeks after the end of therapy by histology, serology and rapid urease test., Results: On an intention-to-treat basis, eradication rates were 91 and 76% for the RCM and OCM groups respectively (P < 0.02). Significantly different pharmacokinetic parameters of metronidazole were found between the groups: peak-plasma level (P < 0.01) and area under the curve (P < 0.02)., Conclusion: Our results show that the RCM regimen was more effective than that based on OCM and that the antisecretory drugs affected metronidazole availability, increasing the efficacy of ranitidine-based regimens.

A xanthate derivative (L) at the pendant hydroxy group of metronidazole, a nitroimidazole known to possess affinity for hypoxic tumors, has been used as the carrier molecule for targeted delivery of the gamma-emitting radioisotope 99mTc to tumors. The xanthate residues (S2(-)) from two molecules of this ligand (L) were used for chelation with the [99mTcN]2+ intermediate to form a square pyramidal and neutral [99mTcN/L2] complex in >95% yield using a low ligand concentration of 1 mg/mL (approximately 3 x 10(-3) M). Biodistribution studies carried out in Swiss mice bearing fibrosarcoma tumor showed selective accumulation of the injected activity in the tumor (1.44 +/- 0.26% per gram 1 h pi) with major clearance through hepatobiliary route. The complex showed high tumor/muscle ratio (2.15 and 3.35 at 1 and 3 h post-injection, respectively) and tumor/blood ratio, which were comparable to hypoxia targeting agents 99mTc-BMS181321 and 99mTc-BRU59-21 reported earlier.

Objective: To investigate whether the acid suppression therapy influences the absorption of bismuth from colloidal bismuth subcitrate (CBS); to locate the deposit position of bismuth in mice's organs and to detect the consequential change of cell functions in these deposited organs., Methods: 48 male SD rats weighing from 200-250 g were randomly divided into five groups: Group A(1), kill the rats on the cessation day of administration CBS; Group B(1), kill the rats on the day 8 weeks after the cessation of administration CBS; Group A(2) (CBS + amoxicillin + metronidazole + omeprazole), kill the rats on the cessation day of administration; Group B(2) (CBS + amoxicillin + metronidazole + omeprazole), kill the rats on the day 8 weeks after the cessation of administration; Control group. These medicines had been taken every day for 14 days. The issue sections (liver, brain and kidney) were counterstained after AMG development. The bismuth deposited in tissues was observed by microscopy. At the same time, the gray level of kidney tissue sections were measured and compared through image processing program. The deposition of bismuth and the degrees of cell organ's impairment were observed through electron microscopy. By the use of electron probe microanalysis, bismuth can be distinguished from chemical element., Results: The bismuth can be accumulated in cell bodies of proximal convoluted renal tubule, portal area, hypothalamus, and hypoglossal nuclei after its absorption. Under the light microscopy, heavy AMG staining granules were found in cell bodies of proximal convoluted renal tubule. It was discovered that the amounts of bismuth accumulation in kidney of quadruple therapy group were much more than that of single compound therapy group (P < 0.05). The amounts of bismuth accumulation in kidney on the cessation day of administration are more than that 8 weeks later (P < 0.01). What is more, under the electron microscopy, heavy AMG staining granules were found exclusively in lysosomes of proximal convoluted renal tubule cell. The electron microscopy found some cell impairment in quadruple therapy group: the impairment to these cells can be recovered 8 weeks after the cessation of administration., Conclusions: The acid suppression therapy causes an increase of bismuth absorption and accumulation from CBS in the rats' kidney. Finally, the absorbed bismuth can be discharged out of the body via kidney. Large amounts of bismuth accumulation in kidney can impair the functions of proximal convoluted renal tubule cell.

Emulsion gel (EMG) beads of calcium pectinate capable of floating in the gastric condition were developed using an emulsion-gelation method and their release properties were investigated. Attempts to modify the drug release were made by applying some additives into the starting solution prior to bead formation, by hardening with glutaraldehyde, and by coating with polymer. The metronidazole-loaded EMG beads were found to float on simulated gastric fluid. Increasing the drug to pectin ratio in the beads slowed the drug release from the conventional and the EMG beads. However, the drug release from these beads was rapid, i.e., about 80% of drug loading released within 20-80 min. The additives (PEG10000, glyceryl monostearate and Eudragit L) had a slight, insignificant, effect on the drug release. Using 2% glutaraldehyde as a hardening agent prolonged the drug release. Coating the beads with Eudragit RL significantly sustained the drug release while the beads remained buoyant. The results suggest that EMG beads are suitable as a carrier for intragastric floating drug delivery and that their release behaviour could be modified by hardening with glutaraldehyde or by coating with Eudragit RL.

Objectives: Previous studies have shown that metronidazole, alone or in combination with spiramycin (250 mg/1 500 000 units, three times/day), is an effective treatment for active periodontitis, although the dose of metronidazole currently used (750 mg/day) could provide concentrations in gingival crevice fluid that are too low for the MICs of the involved pathogens. This study tested the in vivo antibacterial efficacy of the currently used metronidazole dose (as contained in the fixed spiramycin/metronidazole combination) in patients with an active periodontitis, and of a high dose (1500 mg/day) of metronidazole alone., Methods: We measured the MICs of spiramycin and metronidazole for the recovered pathogens and the gingival crevice fluid antibiotic concentrations of both antibiotics, and attempted to correlate them with bacterial eradication., Results: The concentrations of metronidazole consistently exceeded the MICs for the pathogens isolated in the corresponding sites, even at the usual metronidazole (250 mg three times/day) dose. All the bacterial species were eradicated during treatment and at follow-up, although Fusobacterium spp. eradicated during treatment reappeared in a majority of the cases at follow-up, 30 days after treatment, in both groups., Conclusions: The results of antibiotic therapy with metronidazole or the spiramycin/metronidazole combination are consistent with their in vitro antibacterial activity and with the local antibiotic concentrations; they suggest that the currently used metronidazole dose (250 mg, three times/day) alone or as part of the spiramycin/metronidazole combination, could be sufficient for the treatment of active periodontitis.

Objectives: Studies investigating the target site concentration of antibiotics, such as beta-lactams and fluoroquinolones, have demonstrated differences between the drug concentrations in healthy volunteers and septic patients. The aims of this study were (i) to evaluate the muscle tissue concentration of metronidazole in patients with septic shock and (ii) to test the efficacy of metronidazole in an in vitro pharmacodynamic model at different single doses., Materials and Methods: Six patients admitted to the ICU of Tartu University Clinics with a diagnosis of septic shock were studied. Patients receiving metronidazole treatment within 48 h before the study or with a BMI > 35 were excluded. Metronidazole muscle tissue concentration was assessed by a microdialysis technique. Based on the microdialysis data, similar kinetics were simulated in in vitro experiments using Bacillus fragilis strains with MIC(90)s of 0.125 mg/L (BF125) and 1.0 mg/L (BF1)., Results: Metronidazole concentrations in plasma achieved a mean (s.d.) value of 11.4+/-2.0 mg/L at 30 min after administration of a single 500 mg intravenous dose, while in the muscle tissue, maximum concentrations of 8.2+/-4.5 mg/L were achieved at 140+/-92.3 min after the dose. When this metronidazole time course was simulated in vitro, the time to 99.9% kill ranged from 1.0 to 1.4 h for BF125 and from 1.8 to 3.5 h for BF1, while the eradication time ranged from 1.7 to 2.5 h and from 3.4 to 6.5 h, respectively. No regrowth was detected., Conclusion: Pharmacokinetic-pharmacodynamic simulation of metronidazole interstitial concentrations shows a high efficacy of the drug in septic patients.

The objective of this study was to investigate the effect of concurrent antibiotic administration on the disposition of mycophenolic acid (MPA) and mycophenolic acid glucuronide (MPAG) after oral administration of mycophenolate mofetil (MMF) in healthy subjects. Eleven healthy subjects were enrolled. The study was divided into 4 treatment periods. Subjects received MMF as a single oral 1-g dose alone and were then randomized to 3 antibiotic treatment periods. The 3 periods included norfloxacin, metronidazole, and a combination of norfloxacin and metronidazole. Antibiotic treatment was started 3 days prior to each MMF pharmacokinetic study day and was given for a total of 5 days. On day 4 of each antibiotic phase, subjects received a single 1-g oral dose of MMF. Plasma and urine samples were obtained over 48 hours after the MMF dose in all treatment periods and were quantitatively measured for MPA and MPAG. Pharmacokinetic parameters for MPA and MPAG were determined for all periods. Compared to MMF alone, the area under the plasma concentration versus time curve (AUC) of MPA was reduced by an average of 10%, 19%, and 33% when given with norfloxacin, metronidazole, and norfloxacin plus metronidazole, respectively. The AUC of MPAG was also reduced on average by 10%, 27%, and 41% in the corresponding periods. The combination of norfloxacin and metronidazole significantly reduced the AUC of MPA and MPAG in healthy subjects. This likely occurs as a result of reduced enterohepatic recirculation.

Moxifloxacin has been suggested as an option for monotherapy of intra-abdominal infections. Recent data support the use of a once-daily metronidazole regimen. The purpose of this study was to investigate the activity of levofloxacin (750 mg every 24 h [q24h]) plus metronidazole (1,500 mg q24h) compared with that of moxifloxacin (400 mg q24h) monotherapy in a mixed-infection model. By using an in vitro pharmacodynamic model in duplicate, Escherichia coli and Bacteroides fragilis were exposed to peak concentrations of 8.5 mg of levofloxacin/liter q24h, 32 mg of metronidazole/liter q24h, and 2 mg for moxifloxacin/liter q24h for 24 h. The activities of levofloxacin, metronidazole, moxifloxacin, and levofloxacin plus metronidazole were evaluated against E. coli, B. fragilis, and E. coli plus B. fragilis. The targeted half-lives of levofloxacin, metronidazole, and moxifloxacin were 8, 8, and 12 h, respectively. Time-kill curves were analyzed for time to 3-log killing, slope, and regrowth. Pre- and postexposure MICs were determined. The preexposure levofloxacin, metronidazole, and moxifloxacin MICs for E. coli and B. fragilis were 0.5 and 1, >64 and 0.5, and 1 and 0.25 mg/liter, respectively. Levofloxacin and moxifloxacin achieved a 3-log killing against E. coli and B. fragilis in all experiments, as did metronidazole against B. fragilis. Metronidazole did not decrease the starting inoculum of E. coli. The area under the concentration-time curve/MIC ratios for E. coli and B. fragilis were 171.7 and 85.9, respectively, for levofloxacin and 26 and 103.9, respectively, for moxifloxacin. Levofloxacin plus metronidazole exhibited the fastest rates of killing. The levofloxacin and moxifloxacin MICs for B. fragilis increased 8- to 16-fold after the organism was exposed to moxifloxacin. No other changes in the postexposure MICs were found. Levofloxacin plus metronidazole administered once daily exhibited activity similar to that of moxifloxacin against the mixed E. coli and B. fragilis infection. A once-daily regimen of levofloxacin plus metronidazole looks promising for the treatment of intra-abdominal infections.

Objective: To investigate whether acid suppression therapy influences the absorption of bismuth from colloidal bismuth pectin (CBP)., Methods: 48 male SD rats were randomly divided into five groups to be administer with different medicines once a day for 14 days: group A1 (administered with CBP only and killed on the cessation day of administration), group B1 (administered with CBP only and killed 8 weeks after the cessation of administration), group A2 [administered with CBP + amoxicillin (AMO) + metronidazole (MTR) + losec and killed on the cessation day of administration], group B2 (administered with CBP + AMO + MTR + losec and killed 8 weeks after the cessation of administration), and control group (administered with distilled water). The kidney issue sections were counterstained after AMG development. The bismuth deposited in tissues was observed by microscopy. The gray level of kidney tissue sections were measured and compared through image processing program. The deposition of bismuth and the degrees of cell organ's impairment were observed by electron microscopy. By using electron probe microanalysis bismuth was identified from the chemical elements in the specimens., Results: Under the light microscopy, black-brown granules were discovered in the cell bodies of the proximal convoluted renal tubule. The amounts of bismuth accumulated in kidney of the 2 quadruple therapy groups were much more than those of the 2 single compound therapy groups (all P < 0.05). The amount of bismuth accumulated in kidney on the cessation day of administration was more than that eight weeks later (both P < 0.01). Under electron microscopy, black-brown granules were observed exclusively in the lysosomes of the proximal convoluted renal tubule cell. Electron microscopy found cell impairment in the quadruple therapy groups. Impairment of these cells could be recovered 8 weeks after the cessation of administration., Conclusion: Acid suppression therapy causes an increase of absorption and accumulation of bismuth from CBP in the kidney. Bismuth can be accumulated in the cell bodies of proximal convoluted renal tubule after its absorption. The absorbed bismuth can be discharged out of the body via kidney. Large amounts of bismuth accumulation in kidney can impair the functions of proximal convoluted renal tubule cells.

Prophylactic and therapeutic management of portosystemic encephalopathies is based on protein restriction in the diet, and the use of lactulose and antibiotics such as metronidazole. These actions intend to reduce the main source of intestinal ammonia production and release into the systemic circulation. The aim of this study was to evaluate the medium-term effects of mesocaval shunt on the pharmacokinetics of metronidazole in rats with healthy livers. Male Lewis rats were divided into two groups. The first group was subjected to mesocaval shunt (MCS) and the other employed as a control. The following tests were carried out in both groups: metronidazole pharmacokinetics, determination of ALT, AST, albumin, urea and ammonium, liver weight and histomorphology. A loss in body and liver weight was registered in rats subjected to MCS. AST levels also increased compared to controls. Significant differences in almost all pharmacokinetic parameters were detected between MCS and control rats, especially in Kel, AUC and Cmax. Modifications in metronidazole pharmacokinetics and liver weight changes without microstructural modification secondary to MCS were found. We suggest that individual drug-monitoring and pharmacokinetic analysis must be carried out in metronidazole medicated patients with modifications in portal circulation with or with out macro or micro liver structural alterations.

The purpose of this investigation was to evaluate the steady-state pharmacokinetics, pharmacodynamics, and safety of intravenous levofloxacin at 750 mg administered once daily combined with three different dosages of intravenous metronidazole (500 mg every 8 h [q8h], 1,000 mg q24h, and 1,500 mg q24h). Eighteen healthy adult subjects received all three combinations in a randomized, crossover fashion. Serial blood and urine samples were collected on the third day of each study period. The 24-h areas under the inhibitory (AUIC(0-24)) and bactericidal (AUBC(0-24)) curves of these three combination regimens were determined against clinical isolates of Bacteroides fragilis, Bacteroides thetaiotaomicron, Peptostreptococcus asaccharolyticus, and Escherichia coli. The mean concentrations of levofloxacin were not different between study periods and were similar to those previously published. The mean (+/- standard deviation) areas under the metronidazole plasma concentration-time curve (AUC(0-24)) for 1,500-mg q24h (338 +/- 105 mg.h/liter) and 500-mg q8h (356 +/- 68 mg.h/liter) regimens were not different (P > 0.05), but both were significantly higher than the 1,000-mg q24h AUC(0-24) (P < 0.05, 227 +/- 57 mg.h/liter). Mean (+/- standard deviation) total body clearance and renal clearance values were similar among the 500-mg q8h, 1,000-mg q24, and 1,500-mg q24h regimens (62 +/- 7, 67 +/- 13, and 67 +/- 14 and 11 +/- 3, 12 +/- 2, and 12 +/- 5 ml/min/1.73 m2, respectively). Levofloxacin at 750 mg q24h plus metronidazole at 500 mg q8h or 1,500 mg q24h resulted in similar AUIC(0-24) and AUBC(0-24) values with one exception: the AUIC(0-24) for the 1,500-mg q24h regimen against B. thetaiotamicron was significantly higher (P < 0.05) than those of the other regimens. Overall, the combination of levofloxacin at 750 mg once daily and metronidazole at 500 mg q8h or 1,500 mg q24h appeared to have greater AUIC(0-24) and AUBC(0-24) values than did the 1,000-mg q24h regimen. All combination regimens of levofloxacin and metronidazole were well tolerated, and no serious drug-related adverse effects were reported. The pharmacokinetic, safety, and pharmacodynamic data from our study suggest that a once-daily regimen of intravenous levofloxacin at 750 mg and metronidazole at 1,500 mg warrants further clinical investigation.

Pulse dosing is a novel approach to dosing that produces escalating antibiotic levels early in the dosing interval followed by a prolonged dose-free period. Antibiotic is frontloaded by means of four sequential bolus injections, after which antibiotic levels are allowed to diminish until the next dose. This study compares standard thrice-daily dosing and pulse dosing of metronidazole against Bacteroides spp. in an in vitro model. Two American Type Culture Collection Bacteroides fragilis isolates (metronidazole MIC for each organism = 1 mg/liter) were exposed to metronidazole for 48 or 96 h. Human pharmacokinetics were simulated for an oral 500-mg dose given every 8 h (maximum concentration of drug [C(max)] = 12 mg/liter; half-life = 8 h; area under the curve [AUC] = 294 mg . h/liter) and for pulse dosing. Pulses, each producing an increase in metronidazole concentration of 9 mg/liter, were administered at times 0, 2, 4, and 6 h of each 24-h cycle, with a targeted half-life of 8 h (AUC = 347 mg . h/liter). A metronidazole-resistant B. fragilis strain (metronidazole MIC = 32 mg/liter) was exposed to both dosing regimens and, additionally, to a regimen of 1,500 mg administered once daily (C(max) = 36 mg/liter; AUC = 364 mg . h/liter). Furthermore, regimens against one B. fragilis isolate and one B. thetaiotaomicron isolate corresponding to one-fourth and one-eighth of the thrice-daily and pulse dosing regimens, mimicking peak metronidazole concentrations achieved in abscesses, were simulated in 48-h experiments (metronidazole MIC = 1 mg/liter). Time-kill curves were generated for each experiment and analyzed for bactericidal activity, defined as a bacterial burden reduction >/= 3 log(10) CFU/ml. The results of paired (Wilcoxon matched-pair signed-rank test) and nonpaired (Mann-Whitney test) statistical analyses conducted on time to 3 log(10) kill data and area under the kill curve data from each of the thrice-daily dosing experiments versus each of the pulse dosing experiments were considered not significant for a given isolate-dosing regimen combination. The thrice-daily dosing, pulse dosing, and once-daily dosing regimens all exhibited bactericidal activity. Metronidazole administered in standard or pulse dosing fashion was highly active against both susceptible and resistant strains of Bacteroides spp.

Metronidazole has been suggested as an adjunct in the treatment of Acanthamoeba keratitis. This study involves the permeation of metronidazole from topically applied solutions and gels through human and rabbit corneas. The permeation of metronidazole, from the solutions and gels through the corneas, was determined using a flow-through diffusion apparatus. Human (32) and rabbit (54) corneas were obtained from an eye bank and animal nursery farm, respectively. Experiments were conducted at 20 degrees C and over a time period of 24 hours. High-performance liquid chromatography (HPLC) analysis was used as a detection method. Statistical tests used included an Analysis of Variance (ANOVA) and Duncan's multiple range test, for a determination of the steady state, and a nonlinear regression analysis, using an F test, was used to compare entire curves. Flux rates for 0.5% and 1% metronidazole solutions across human corneas were found to be 14% and 30% higher, respectively, than for rabbit corneas. However, the flux rates of the 0.5% and 0.8% metronidazole gels across rabbit corneas were found to be 7% and 25% higher than those for human corneas. The flux rates measured for at least the first 10 hours were not, statistically, significantly different between the metronidazole released from aqueous solutions and from the gel. Steady-state flux rates of the 0.5% metronidazole aqueous and gel formulations were approximately half those of the 0.8% and 1% preparations. Because of the longer corneal contact times, it may be therapeutically advantageous to use 0.8% metronidazole concentrations in gels for treating Acanthamoeba keratitis infestations. Further in vivo studies on the ocular compatibility of these formulations need to be performed. The use of rabbit corneas as an in vitro permeability model for human corneas is supported by these studies.

Background and Purpose: Hypoxia of clonogenic tumor cells is a major reason for radioresistance and hence local failure in radiotherapy. The objective of the present study was to test the efficacy of the hypoxic cell sensitizer isometronidazole (ISO) during fractionated irradiation in two different human squamous cell carcinomas., Material and Methods: Local control was evaluated for FaDu (radiobiological hypoxic fraction [rHF] 7%) and GL tumors (rHF 0.1%) after single-dose (SD) irradiation under ambient conditions and after 30 fractions within 6 weeks (30 f/6 w). ISO was applied 60 min before SD irradiation at a concentration of 100 mg/kg body weight (b.w.) or 750 mg/kg b.w. in both tumors. During fractionated irradiation, ISO was applied daily 60 min before each fraction (100 mg/kg b.w., in FaDu also 750 mg/kg b.w.)., Results: 100 mg/kg b. w. ISO did not improve local control after SD irradiation or 30 f/6 w in both tumor models. Application of 750 mg/kg b. w. ISO significantly decreased the SD-TCD(50) in FaDu tumors (dose-modifying factor [DMF] = 1.2; p = 0.01) but not in the better oxygenated GL tumor. ISO at 750 mg/kg b.w. also significantly improved local control of FaDu tumors after 30 fractions in 6 weeks (DMF = 1.2; p = 0.01), indicating that hypoxic clonogenic cells in FaDu tumors are not only present before start of irradiation but also limit the efficacy of treatment during a fractionated course of radiotherapy., Conclusion: ISO at a concentration of 750 mg/kg b.w. shows an efficacy as a hypoxic cell sensitizer in severely hypoxic FaDu tumors but not in less hypoxic GL tumors. This supports the principle of hypoxic cell sensitization and improvement of local control of hypoxic tumors by nitroimidazole derivatives. However, doses of 750 mg/kg b. w. before each fraction may be difficult to achieve in the clinical situation. This, in light of the fact that other well-tolerable hypoxic cell sensitizers such as nimorazole with clinically proven efficacy at daily oral doses of < 3 g are available, limits the potential usefulness of ISO for radiation oncology.

Metronidazole (MTZ) and other nitroimidazole derivatives have been extensively used to treat infections caused by protozoa and anaerobic bacteria. However, the need for new derivatives with similar therapeutic activity but lower toxicity to human beings prevails. On this purpose, three metronidazole analogues were synthesized, namely: 1-(p-methylphenacyl)-2-methyl-4-nitro imidazole (CPMe), 1-(p-methoxyphenacyl)-2-methyl-4-nitroimidazole (CPMeO), and 1-(p-fluorphenacyl)-2-methyl-4-nitroimidazole (CPF), which at low concentrations (0.5-2 microg/ml) showed a higher activity against Entamoeba histolytica than MTZ (3-6 microg/ml). The aim of this work was to investigate the cytogenetic effect of the three MTZ analogues on human lymphocyte cultures with and without metabolic activation in vitro, using the sister chromatid exchange test (SCE), comparatively with MTZ. The effect of the compounds on the cell proliferation kinetics (CPK) measured by the replication index (RI) and the cytotoxic effect in the mitotic index (MI) was evaluated as well. The SCE frequencies with and without S9 metabolic activation in treated and control lymphocytes showed no significant statistical differences. However when metabolic activation was involved a significant increase in the amount of third division metaphases provoked the CPK increased significantly with all the tested compounds. The RI showed similar behaviour, except for compound CPF.

Purpose: To investigate the in vitro permeation of metronidazole through rabbit and human corneas in the presence and absence of 0.01% benzalkonium chloride and to suggest its use as adjunct therapy in the treatment of Acanthamoeba keratitis., Methods: Metronidazole permeation through rabbit and human corneas, the latter being unsuitable for transplantation, were used for all permeability experiments. Flux rates for metronidazole from 0.5% and 1.0% aqueous solutions in the presence and absence of 0.01% benzalkonium chloride (BZCL) were determined. ANOVA and the Duncan multiple range test were used to test for steady state and an unpaired t test with the Welch correction was used to test for differences between the mean flux values at each time point. A significance level of 5% was used for all the statistical tests. In the clinical cases described, 0.5% aqueous solution was used., Results: Steady-state flux rates for metronidazole from 0.5% and 1.0% solutions across both rabbit and human corneas were achieved after 6 and 4 hours, respectively. No statistically significant differences were obtained in the presence and absence of 0.01% BZCl (P < 0.05) between the steady state flux values at both concentrations of metronidazole of human and rabbit corneas, except for 0.5% metronidazole across rabbit corneas. Flux rates of metronidazole across human corneas were 12%-33% higher than those across rabbit corneas. For both rabbit and human corneas, flux rates of metronidazole from 0.5% and 1.0% solutions were reduced by between 4% and 11%, respectively, in the presence of 0.01% benzalkonium chloride., Conclusions: Although statistically significant differences in flux values were obtained between human and rabbit corneas, the study supports the suitability of the in vitro rabbit cornea as a model for investigating permeation of drugs through human corneas. However, direct extrapolation of animal data to humans must be approached cautiously. The metronidazole from a 1% solution had a steady-state flux rate approximately double that from the 0.5% solution. Higher concentrations of up to 1% may be considered for clinical use for treating Acanthamoeba keratitis infections. It would appear to be prudent to omit benzalkonium chloride as a preservative from preparations of metronidazole formulated for topical ophthalmologic use. Early clinical experience with the topical solution as adjunct therapy in the treatment of Acanthamoeba keratitis is encouraging.

The bioavailability of metronidazole in rabbits was studied using plasma concentration measurements after the administration of the drug in a hydrophilic (glycerogelatin) suppository form. The peak in the plasma concentration time curve occurred about 1 hour after administration, indicating that the rate of absorption is fast and equivalent to that observed in humans after oral administration. There was rapid elimination of the drug, as indicated by a relatively high elimination rate constant and low plasma half-life. The in vitro dissolution profile of the suppositories further confirms rapid absorption of the drug from the suppositories in the rectum. The presence of Tween 80 enhanced the in vitro release of metronidazole, but the presence of a hydrogenated vegetable oil lubricant (Lubritab) caused retardation in the drug release from the suppositories.

A multiparticulate system combining pH-sensitive property and specific biodegradability for colon-targeted delivery of metronidazole has been investigated. Cross-linked chitosan microspheres were prepared from an emulsion system using liquid paraffin as the external phase and solution of chitosan in acetic acid as the disperse phase. The multiparticulate system was prepared by coating cross-linked chitosan microspheres exploiting Eudragit L-100 and S-100 as pH-sensitive polymers. Morphology and surface characteristics of the formulations were determined by scanning electron microscopy. Particle size of the chitosan microspheres was determined by optical microscopy while that of coated microspheres was determined by particle size analyzer. In vitro drug-release studies were performed in conditions simulating stomach-to-colon transit in presence and absence of rat caecal contents. The size of the microspheres was small and they were efficiently microencapsulated within Eudragit microspheres, forming a multireservoir system. By coating the microspheres with Eudragit pH-dependant release profiles were obtained. No release was observed at acidic pH; however, when it reached the pH where Eudragit starts solublizing there was continuous release of drug from the formulation. Further, the release of drug was found to be higher in the presence of rat caecal contents, indicating the susceptibility of chitosan matrix to colonic enzymes released from rat caecal contents.

A clinical study was undertaken in 12 healthy volunteers. At first, subjects received metronidazole (CAS 443-48-1; a substrate for cytochrome CYP3A4 and CYP2C9) alone at a dose of 400 mg every 8 h for 3 days. On day 4, blood and urine were collected at different time points and metronidazole levels were measured. After a washout period (> 10 half-lives) of one week silymarin (CAS 22888-70-6) was given at a daily dose of 140 mg for 9 days. From day 7 both silymarin (140 mg/day) and metronidazole (3 x 400 mg/day) were given till the 9th day. On day 10, blood and urine were collected as above and the levels of metronidazole and its metabolite were measured by HPLC. Administration of silymarin increased the clearence of metronidazole and its major metabolite, hydroxy-metronidazole (HM) by 29.51% and 31.90%, respectively, with a concomitant decrease in half-life, Cmax and AUC(0-48). Urinary excretions of acid-metronidazole (AM), HM as well as metronidazole in 48 h were decreased. The results indicate that silymarin might induce both intestinal P-glycoprotein and CYP3A4 upon multiple dose administration.

Various approaches for colon targeted drug delivery have been studied over the last decade including, pro-drugs, timed-released systems, coating of pH-dependant polymer and the use of polysaccharides. In the present work, a novel formulation consisting of cross-linked microspheres of guar gum has been investigated for colon-targeted delivery of metronidazole. An emulsification method involving the dispersion of aqueous solution of guar gum in castor oil was used to prepare spherical microspheres. Process parameters were analyzed in order to optimize the formulation. Shape and surface morphology of the microspheres were examined using scanning electron microscopy. Placebo microspheres exhibited a smooth surface while the incorporation of drug imparted a slight roughness to the surface texture. Particle size of the microspheres was determined using laser diffraction particle size analyzer. The in vitro drug release studies were performed in simulated gastric fluid for 2 h and intestinal fluid for 3 h, which revealed that the drug was retained comfortably inside the microspheres and that only 15.27+/-0.56% of the drug was released in 5 h. In vitro release rate studies were also carried out in simulated colonic fluid (SCF) in the presence of rat cecal contents, which showed improved drug release. Moreover, to induce the enzymes that specifically act on guar gum, the rats were treated with 1 ml of 1% w/v dispersion of guar gum for 2, 4 and 6 days and release rate studies were repeated in SCF in the presence of 2 and 4% w/v of cecal matter. A marked improvement in the drug release was observed in presence of cecal matter obtained after induction when compared to those without induction. In vitro release studies exhibited 31.23+/-1.49% drug release in 24 h in dissolution medium without rat cecal matter. However, the incorporation of 4% w/v cecal matter obtained after 6 days of enzymes induction increased the drug release to 96.24+/-4.77%.

Objective: To evaluate the concentration of metronidazole in muscle tissue using microdialysis and to compare it with plasma concentration and in vitro-defined MIC(90) (minimal inhibiting concentration) for the most frequent anaerobic bacteria isolated in our hospital., Materials and Methods: Six female patients scheduled for elective gynaecological surgery were included. Exclusion criteria were active inflammatory process and being overweight (BMI more than 30). Microdialysis catheters (CMA 60 catheters with 20 kDa cut-off membrane) were placed into the m. vastus lateralis. The microdialysis perfusion rate was 2 microl/min. To assess in vivo recovery of the drug, retrodialysis with a 5-mg/l solution of metronidazole was performed. Microdialysis and blood samples were collected simultaneously 10 h after metronidazole administration. MIC(90) data were obtained from the database of the microbiology laboratory of the local hospital., Results: Data from five patients were included in analysis. The metronidazole concentration in blood achieved a value of 16.5+/-4.6 mg/l at 30 min (first available data), while in muscle a maximum level of 7.8+/-1.5 mg/l was achieved at 114 min. The mean MIC(90) for the Bacteroides fragilis group was 0.25+/-0.26 mg/l. Data from mean plasma concentrations were fitted into the two-compartmental model and time over MIC(90) and time over four times MIC(90) were calculated, which were 52.1+/-13.5 h and 33.2+/-8.7 h, respectively. The C(max)/MIC(90) ratio was 65.8+/-18.5 for plasma and 31.1+/-6.2 for muscle., Conclusion: The present data demonstrate that metronidazole penetrates well into muscle tissue. Muscle tissue concentrations reach values far greater than MIC(90) for the Bacteroides fragilis group and persist at such high levels for at least 10 h.

Objective: To measure the concentration of metronidazole and its hydroxymetabolite in plasma and cutaneous microdialysates and to compare metronidazole penetration into cutaneous microdialysates against theoretical predicted penetration in a peripheral compartment., Method: A single oral dose of 2 g of the parent drug was administered to 10 healthy male volunteers. Microdialysis probes with 2 kDa molecular weight cut-off were inserted intradermally and were perfused with Ringer solution up to 8 h after drug ingestion. Drug and metabolite concentrations were measured by high performance liquid chromatography., Results: Mean maximum concentration in plasma, cutaneous microdialysates and theoretical peripheral compartment were 214 +/- 49, 151 +/- 52 and 146 +/- 38 micromol/L, respectively, and were achieved after about 2.1 +/- 0.8, 2.8 +/- 1.0 and 6.0 +/- 2.9 h. The extent of penetration into cutaneous microdialysates and theoretical peripheral compartment relative to plasma were 0.672 +/- 0.196 and 0.675 +/-0.207, respectively, and did not differ significantly. Moreover, maximum concentration as well as area under concentration-time curve in these compartments also did not differ significantly., Conclusion: Use of cutaneous microdialysis technique permits the characterization of true systemic drug disposition, for optimizing drug treatment strategies.

The present study was carried out to find the in vivo performance of guar gum-based colon-targeted tablets of metronidazole as compared to an immediate release tablets in human volunteers. Six healthy volunteers participated in the study and a crossover design was used. Blood samples were obtained at different time intervals and the plasma concentration of metronidazole was estimated by reverse phase HPLC. The immediate release tablets of metronidazole produced peak plasma concentration (Cmax of 2990 +/- 574.6 ng/mL) within 2.8 +/- 0.6 h. On oral administration of colon-targeted tablets, metronidazole started appearing in the plasma between 5 h and 8 h, and reached the peak concentration (Cmax of 1940.0 +/- 528.4 ng/mL) at 11.1 +/- 2.1 h (Tmax). The AUC(0-infinity) and t(1/2) of metronidazole were unaltered on administering the drug as a colon-targeted tablet indicating that the extent of absorption and elimination were not affected by targeting the drug to the colon. However, colon-targeted tablets showed delayed tmax and absorption time (ta), decreased Cmax and decreased absorption rate constant as compared to immediate release tablets. This in turn indicated that metronidazole was delivered to the colon resulting in a slow absorption of the drug and making it available for local action in the colon.

Objective: To prepare the controlled-release delivery gutta-percha points containing metronidazole compound (CDGMC) and to determine its release rate in vitro., Methods: The drug points were made by using compound drugs and gutta-percha as a carrier, and CDGMC were prepared followed by enveloping a release membrane outward. The best formula was selected according to the release parameters of the drugs extracted in the release experiments in vitro. The CDGMC were placed into the extracted teeth after root canals were routinely prepared. The non-drug CDGMC was used as the control. The absorbency of the drugs in normal saline (37 degrees C, pH 7.4) was determined timely. The percentage of release and cumulated release of the drugs were calculated according to the concentrations of drugs in medium., Results: The in vitro experiments showed that this system contained 1,880 micrograms of metronidazole and 267 micrograms of ciprofloxacin. The experiments in healthy single root canal showed that the drug release amounts around the perioapical area were metronidazole 88.54 micrograms/ml and ciprofloxacin 9.05 micrograms/ml in 10 days., Conclusion: CDGMC can continuously release effective drug concentrations more than 10 days and could be considered as an ideal method for clinical application.

The levels of metronidazole and pefloxacin in plasma and tissue penetration of both drugs were studied after prophylactic administration to 7 patients undergoing colorectal surgery. Metronidazole (1,500 mg) and pefloxacin (800 mg) were administered as an intravenous infusion 1 hour before surgery. Mean plasma levels of pefloxacin decreased from 12.92 +/- 4.10 microg/ml at the end of the infusion to 2.18 +/- 1.03 microg/ml at 36 h. These values were above the MIC90 for E. coli (0.125 microg/ml) and E. faecalis (0.5 microg/ml), microorganisms responsible for abdominal infections. Tissue pefloxacin levels were also measured with a range from 0.72 - 7.78 microg/g in subcutaneous cell tissue, from 1.94 - 17.55 microg/g in peritoneum and from 2.76 - 21.99 microg/g in colon wall. Mean plasma concentrations of metronidazole decreased from 39.89 +/- 17.08 microg/ml at the end of the infusion to 2.63 +/- 1.11 microg/ml at 36 h. During this period, concentrations were higher than 2 microg/ml, the MIC90 value for B. fragilis, the anaerobic pathogen more frequently involved in postoperative infections after rectal and colonic surgery. Tissue metronidazole levels ranged from 3.64 - 13.37 microg/g in subcutaneous cell tissue, from 3.26 - 41.66 microg/g in peritoneum and from 6.72 - 43.12 microg/g in colon wall. The AUC/MIC values (efficacy parameter for concentration-dependent killing antibiotics such as pefloxacin and metronidazole) obtained were the following: metronidazole AUC/MIC value for B. fragilis was 173; pefloxacin AUC/MIC values for E. coli and E. faecalis were 941 and 235, respectively. The values of these parameters are higher than the recommended values to ensure efficacy, which means good exposure of the antimicrobials to the microorganisms. In conclusion, the combination of pefloxacin and metronidazole as prophylactic agents to prevent infections in patients undergoing colorectal surgery produce plasma and tissue levels above the MIC values of the main pathogens responsible for this kind of infections.

Objective: To characterize the elution and bioactivity of metronidazole and gentamicin sulfate polymerized, individually and in combination, with polymethylmethacrylate (PMMA)., Study Design: In vitro experimental study., Methods: PMMA beads containing metronidazole (3 concentrations), gentamicin sulfate, or metronidazole and gentamicin sulfate were immersed in 5 mL of phosphate-buffered saline in triplicate. Eluent was replaced at specified time intervals for 1 or 21 days, and antibiotic concentrations were measured by high-performance liquid chromatography. Changes in antibiotic bioactivity attributable to polymerization or copolymerization of the antibiotics with PMMA, ethylene oxide sterilization, and storage of AIPMMA beads containing metronidazole were evaluated., Results: Antibiotic elution patterns were similar for all groups. Day 1 elution for groups containing metronidazole or gentamicin individually represented a mean 63%-66% and 79%, respectively, of the 21-day total. Approximately 50% of the day 1 elution occurred during the first hour. The elution of metronidazole was dose dependent. The elution of metronidazole (day 3-21) and gentamicin (all days) was significantly greater when metronidazole and gentamicin were combined (P <.05). The addition of metronidazole delayed polymerization of PMMA. Neither polymerization nor copolymerization of metronidazole and gentamicin with PMMA, gas sterilization, or 2-month storage of beads containing metronidazole significantly affected antimicrobial bioactivity., Conclusions: Metronidazole elution from PMMA was dose dependent. Copolymerization of metronidazole and gentamicin sulfate in PMMA resulted in increased rates of elution. Intraoperative preparation of metronidazole-impregnated PMMA beads is not practical, but sterilization and storage for 2 months should not affect efficacy., Clinical Relevance: The local delivery of biologically active metronidazole and gentamicin by elution from PMMA is feasible., (Copyright 2003 by The American College of Veterinary Surgeons)

Objective: To screen for inhibitory effects of diosmin on cytochrome P(450)-mediated metabolism of metronidazole in healthy volunteers., Design: Before/after non-blinded investigation conducted in healthy male volunteers., Methods: After an overnight fast, metronidazole (two 400-mg tablets) was administered to 12 volunteers, either alone or after a 9-day pretreatment period with a once-daily dose of diosmin 500-mg tablets under direct observation. Serum concentrations of metronidazole up to 48 h postdose and urinary concentrations of metronidazole and its two major metabolites up to 24 h postdose were measured using reversed-phase high-performance liquid chromatography., Results: Metronicazole plasma AUC((0- infinity )) and C(max) were significantly higher after diosmin pretreatment by (mean) 27% and 24%, respectively. However, time to reach peak concentration (t(max)) was not affected significantly. Urinary excretion of acid and hydroxy metabolites in urine was decreased significantly, while excretion of unchanged metronidazole was increased., Conclusion: Diosmin pretreatment significantly altered the metabolism of metronidazole, as demonstrated by changes in plasma pharmacokinetics as well as by urinary recovery of both parent drug and its major metabolites. This may be caused by the inhibition of cytochrome P(450) enzymes.

Vaginal suppository formulations of metronidazole were prepared using six different bases as Witepsol H15, Cremao, Ovucire WL2944, Ovucire WL3264, PEG 1500, PEG 6000. Three different dissolution methods were used to evaluate the in vitro drug release from the suppositories. The diffusion studies were performed through synthetic (cellophane) and natural membrane (rabbit vagina), but the drug did not show good permeation characteristics from natural membrane. Ovucire WL3264 suppositories of metronidazole labeled with 99mTc (Tecnetium-99m) were used for the vaginal absorption and biodistribution studies in the rabbits. Scintigraphic images were collected after vaginal administration of the labeled suppositories using SPECT gamma fitted with a low energy, high-resolution parallel hole collimator. The labeled drug showed high biodistribution in urine beside vaginal site. The results of this study suggested that the Ovucire WL3264 suppository of metronidazole prepared for vaginal infections could also be effective in the urinary infections.

Metronidazole is a synthetic nitroimidazole-derived antibacterial and antiprotozoal agent used for the treatment of infections involving gram-negative anaerobes. The aim of this study is to develop an in vivo microdialysis with microbore high-performance liquid chromatographic system for the pharmacokinetic study of metronidazole in rat blood, brain and bile. In addition, to investigate the disposition mechanism of metronidazole, the P-glycoprotein modulator and cytochrome P450 inhibitor were concomitantly administered. Separation of metronidazole from various biological fluids was applied to a microbore reversed-phase ODS 5 microm (150 x 1 mm I.D.) column. Its mobile phase consists of an acetonitrile-50 mM monosodium phosphate buffer (pH 3.0) containing 0.1% triethylamine (10:90, v/v) with a flow-rate of 0.05 ml/min. The UV detector wavelength was set at 317 nm. The results suggest that metronidazole penetrates the blood-brain barrier (BBB) and goes through hepatobiliary excretion. However, these pathways of BBB penetration and hepatobiliary excretion of metronidazole may not be related to the P-glycoprotein.

A cysteine-based bifunctional chelating agent viz. N-(2'-hydroxybenzyl)-cysteine with a free carboxylic acid group (CAA) was synthesized. Bearing in mind the affinity of localization of nitroimidazoles in hypoxic tissues, this bifunctional chelating agent was coupled to metronidazole (MNZ). The (99m)Tc labeling studies of the novel agent (MNZCAA) thus obtained, was carried out and the radiolabeled product was subsequently purified. The complexation yield under optimized condition was approximately 85%. Biodistribution studies carried out in Swiss mice bearing 'barcl-95' tumors showed selective accumulation of the injected activity in the tumor (1.70%/g at 30 min p.i.) with renal as well as hepatobiliary clearance. High tumor/muscle ratio (14.7 at 3 h post-injection) of the novel agent indicates considerable promise towards further evaluation.

Alginate gel beads containing ethylcellulose (ALECs) were prepared and investigated with regard to buoyancy, in vitro and in vivo drug release profiles, and drug targeting specificity in the gastric mucosa. When the ethylcellulose (EC) content of ALECs containing metronidazole (MZ) was higher than 3%, the beads floated in all test solutions with a specific gravity of approx. 1.01. ALECs containing 5% EC released MZ gradually and floated throughout the experimental period in simulated gastric juice (pH 1.2), and all of the drug had been released after 90 min. When we orally administered ALECs to guinea pigs, about 85% of the incorporated MZ was released at 1 h. The MZ concentration of the gastric mucosa after administration of ALECs was greater than that observed with administration of MZ solution, despite lower serum concentrations. Furthermore, the similar data were obtained for ALECs with 7% EC. These results suggest that ALECs may become a practical vehicle for delivering drugs to the gastric mucosa.

The aim of the study was to evaluate initially the applicability of certain natural polymers, as metronidazole binding agents in the treatment of ulcerative lesions in the gastric mucous membrane. The investigation involved systems containing metronidazole in combination with sodium alginate, citrus pectin and citrus-apple pectin. The rate of metronidazole release from the investigated preparations was evaluated after acidification to pH in gastric environment. Constant rates were determined, which were from 0.25 h-1 to 0.58 h-1 as well as half-release time, which were from 1.20 h to 2.82 h. Also, dynamic viscosity of the investigated systems was assessed--the dynamic viscosity of the gelatinous form with 2% content of sodium alginate increased by three orders of magnitude under the influence of acid pH, i.e. from about 160 cPa.s to about 30,000 cPa.s. Similarly, the viscosity of the preparation containing 4% of citrus-apple pectin increased after acidification from about 140 cPa.s to almost 40,0000 cPa.s. The use of sodium alginate and citrus-apple pectin as metronidazole carriers may prolong the time of action of the drug on pathologically changed gastric mucosa. The fraction of metronidazole which is in immediate contact with the pathologically changed surface is in concentration exceeding significantly MIC and MBC at usual oral doses.

Background and Aims: The success of Helicobacter pylori eradication regimens depends on gastric pH, inflammation, and mucus thickness. Our aim was to investigate the effects of acid secretion, inflammation, and mucolysis on gastric antibiotic transfer., Subjects and Methods: A total of 134 anaesthetised rats were given metronidazole, amoxicillin, or clarithromycin intravenously and gastric contents were aspirated via an indwelling cannula. Acid secretion was controlled by either omeprazole or pentagastrin while gastritis was induced by infection with H pylori or dosing with iodoacetamide. Mucolysis was achieved by instilling pronase into the gastric lumen., Results: Metronidazole transfer increased with acid secretion and fell with omeprazole, independently of gastric pH. Clarithromycin was also transferred with acid but was then rapidly degraded. Omeprazole prevented this degradation, raising gastric luminal concentrations. Omeprazole did not alter amoxicillin transfer. Gastritis induced by H pylori did not alter gastric transfer of metronidazole and amoxicillin but that of clarithromycin was increased by 23%. However, gastritis induced by iodoacetamide reduced clarithromycin transfer without any effect on metronidazole or amoxicillin transfer. Pronase treatment increased amoxicillin transfer fourfold and metronidazole by 66% but reduced clarithromycin transfer by 35%., Conclusions: Metronidazole and clarithromycin are predominantly transferred with gastric acid rather than by an acid trapping mechanism. Pronase increases the appearance of amoxicillin and metronidazole in gastric secretions.

Metronidazole (MTZ, 1-[2-hydroxyethyl]-2-methyl-5-nitroimidazole), an antiparasitic and antibacterial compound, is one of the world's most used drugs. MTZ is potentially carcinogenic to humans due to the following facts: it is a proven mutagen in bacterial systems, it is genotoxic to human cells and also, it is carcinogenic to animals. However, due to inadequate epidemiological evidence, it is not considered as a risk factor for cancer in humans. As it will be discussed here, the existing population studies are deficient since they have not included sufficient sample size, the follow-up time has not been long enough, and the individual sensitivity to the drug might have been acting as a confounding factor. Due to the increasing use of this drug, more and improved studies are needed to elucidate its mechanism of genotoxicity and its carcinogenic potential.

The aim of the present study is to develop colon targeted drug delivery systems for metronidazole using guar gum as a carrier. Matrix, multilayer and compression coated tablets of metronidazole containing various proportions of guar gum were prepared. All the formulations were evaluated for the hardness, drug content uniformity, and were subjected to in vitro drug release studies. The amount of metronidazole released from tablets at different time intervals was estimated by high performance liquid chromatography method. Matrix tablets and multilayer tablets of metronidazole released 43-52% and 25-44% of the metronidazole, respectively, in the physiological environment of stomach and small intestine depending on the proportion of guar gum used in the formulation. Both the formulations failed to control the drug release within 5 h of the dissolution study in the physiological environment of stomach and small intestine. The compression coated formulations released less than 1% of metronidazole in the physiological environment of stomach and small intestine. When the dissolution study was continued in simulated colonic fluids, the compression coated tablet with 275 mg of guar gum coat released another 61% of metronidazole after degradation by colonic bacteria at the end of 24 h of the dissolution study. The compression coated tablets with 350 and 435 mg of guar gum coat released about 45 and 20% of metronidazole, respectively, in simulated colonic fluids indicating the susceptibility of the guar gum formulations to the rat caecal contents. The results of the study show that compression coated metronidazole tablets with either 275 or 350 mg of guar gum coat is most likely to provide targeting of metronidazole for local action in the colon owing to its minimal release of the drug in the first 5 h. The metronidazole compression coated tablets showed no change either in physical appearance, drug content or in dissolution pattern after storage at 40 degrees C/75% RH for 6 months.

To develop a localized drug delivery system that offers prolonged administration of metronidazole into the periodontal pocket, muccoadhesive gel formulations containing 5% w/w metronidazole were prepared using the bioadhesive polymers: carboxymethylcellulose, methylcellulose, hydroxyethylcellulose, polyvinylpirrolidone, and carbopol. Increased concentrations of the polymers decreased the drug release rate and enhanced syringeability, yield value, and adhesiveness but decreased the spreadability. The bioadhesive properties of the gels were affected by pH and Ca(2+) concentration. The gel containing 20% hydroxyethylcellulose, 20% polyvinylpirrolidone, and 1% carbopol exhibited zero-order drug release kinetics and suitable physical properties for drug delivery to the periodontal pocket.

Metronidazole was formulated in mucoadhesive vaginal tablets by directly compressing the natural cationic polymer chitosan, loosely cross-linked with glutaraldehyde, together with sodium alginate with or without microcrystalline cellulose (MCC). Sodium carboxymethylcellulose (CMC) was added to some of the formulations. The drug content in tablets was 20%. Drug dissolution rate studies from tablets were carried out in buffer pH 4.8 and distilled water. Swelling indices and adhesion forces were also measured for all formulations. The formula (FIII) containing 6% chitosan, 24% sodium alginate, 30% sodium CMC, and 20% MCC showed adequate release properties in both media and gave lower values of swelling index compared with the other examined formulations. FIII also proved to have good adhesion properties with minimum applied weights. Moreover, its release properties (% dissolution efficiency, DE) in buffer pH 4.8, as well as release mechanism (n values), were negligibly affected by aging. Thus, this formula may be considered a good candidate for vaginal mucoadhesive dosage forms.

The influence of synthetic drugs prescribed for peptic ulcer on the pharmacokinetic fate of glycyrrhizin (GL) from Shaoyao-Gancao-tang (SGT, a traditional Chinese formulation, Shakuyaku-Kanzo-to in Japanese) was investigated in rats. Co-administration of histamine H2-receptor antagonist (cimetidine) and anticholinergic drug (scopolamine butyl bromide) with SGT didn't influence the area under the plasma concentration-time curves (AUC) of glycyrrhetic acid (GA), an active metabolite derived from GL in SGT. The AUC of GA from SGT were significantly reduced by co-administration of synthetic drugs commonly used for peptic ulcer in a triple therapy (OAM), a combination of a proton pump inhibitor (omeprazole) and two antibiotics (amoxicillin and metronidazole). We found that the reduction of AUC in OAM treatment was due to the antibacterial effect of amoxicillin and metronidazole on intestinal bacteria in rat which lead to the decrease of GL-hydrolysis activity. The present study suggests that it may not be a proper way to use triple therapy containing antibiotics simultaneously with SGT for healing of chronic ulcers.

A rapid, selective and sensitive HPLC assay has been developed for the routine analysis of metronidazole in small volumes of rat plasma, gastric aspirate and gastric tissue. The extraction procedure involves liquid-liquid extraction and a protein precipitation step. A microbore Hypersil ODS 3 microm (150 x 2.1 mm I.D.) column was used with a mobile phase consisting of acetonitrile-aqueous 0.05 M potassium phosphate buffer (pH 7) containing 0.1% triethylamine (10:90). The column temperature was at 25 degrees C and the detection was by UV absorbance at 317 nm. The limit of detection was 0.015 microg ml(-1) for gastric juice aspirate and plasma and 0.010 microg g(-1) for gastric tissue (equivalent to 0.75 ng on-column). The method was linear up to a concentration of 200 microg ml(-1) for plasma and gastric juice aspirate and up to 40 microg g(-1) for tissue, with inter- and intra-day relative standard deviations less than 14%. The measured recovery was at least 78% in all sample matrices. The method proved robust and reliable when applied to the measurement of metronidazole in rat plasma, gastric juice aspirate and gastric tissue for pharmacokinetic studies in individual rats.

Background: Perioperative prophylaxis is recommended to be administered intravenously which, compared to oral prophylaxis, is more expensive. However, pharmacokinetic data on oral perioperative prophylaxis in patients with preoperative surgical and anesthesiological preparation are not available., Patients and Methods: 40 patients with open hernial repair or cholecystectomy (low-risk group), colonic or pancreatic resection (high-risk group) received a standard single-dose perioperative prophylaxis with 4.5 g mezlocillin and 0.5 g metronidazole intravenously in addition to 400 mg ofloxacin orally 2 h prior to surgery. Antibiotic concentrations were measured perioperatively and pharmacokinetic data calculated., Results: Serum and tissue concentrations of ofloxacin were above the MIC90 of the potential bacterial spectrum for surgical infection throughout the entire operation. Pharmacokinetic data were not influenced by preoperative surgical or anesthesiological preparation., Conclusion: Tissue and serum concentrations and the antibacterial spectrum of orally administered ofloxacin suggest effective protection against perioperative infection. Pharmacokinetic data confirm that oral ofloxacin may be used effectively as single-dose perioperative antibiotic prophylaxis. Since there are no clinical data comparing oral and intravenous singLe-dose prophylaxis, a prospective randomized clinical trial should be performed.

A series of amino acid esters (3a-e) have been synthesized and evaluated as potential prodrugs of metronidazole with the aim of improving aqueous solubility and therapeutic efficacy. The aqueous solubility and the lipophilicity (expressed as the log P value) of metronidazole and its esters were investigated. In general the prodrugs revealed enhanced water solubility compared with metronidazole. N,N-diethylglycinate hydrochloride (3a) and 4-ethylpiperazinoacetate (3e) derivatives displayed higher aqueous solubility, which exceeded that of the parent drug by factors of approximately 140 and 100, respectively. All the esters revealed lower log P values than metronidazole except for the 4-phenylpiperazinoacetate derivative (3f), which was 6.5-times more lipophilic than metronidazole. The hydrolysis kinetics of the esters were studied in aqueous phosphate buffer (pH 7.4) and 80% human plasma at 37 degrees C. In all cases the hydrolysis followed pseudo-first-order kinetics and resulted in a quantitative reversion to metronidazole as evidenced by HPLC analysis. The prodrugs exhibited adequate chemical stability (half-life, t1/2, 4-16 h) in aqueous phosphate solution of pH 7.4. In 80% human plasma they were hydrolysed within a few minutesto metronidazole. The esters 3d (methylpiperazinoacetate derivative) and 3f were exempted since their t1/2 values were approximately 2.5 and 8.5 h, respectively. A comparative pH-rate profile study of N,N-diethylglycinate hydrochloride (3a) and 4-ethyl-piperazinoacetate (3e) derivatives in aqueous buffer solution over the pH range 2.2-10 was investigated. The results indicated that 3a showed marked stability at pH 2-6 followed by accelerated hydrolysis at pH 7.4. The basic ester 3e was found to be less stable at lower pH values but exhibited comparative stability at physiological pH. Moreover, in-vivo experiments in rabbits revealed a higher metronidazole plasma level with sustained release characteristics within the prodrug-treated animals (10- and 2.5-fold) as compared with the parent drug-treated group. In conclusion, the designed amino acid esters 3a and 3c-e might be considered as good candidates for water-soluble prodrug forms of metronidazole.

Objective: Gender is usually considered to be one of the factors influencing disposition of drugs, but the evidence available is sometimes conflicting and information for a large number of frequently used drugs is lacking. An evaluation of sex differences in the disposition ofmetronidazole was carried out during a bioequivalence study., Subjects and Methods: Twenty-four volunteers (12 males and 12 females) were included in an open, single-dose, two-sequence, crossover randomized trial with a one-week washout interval. All volunteers received in each period, a single 250 mg dose of one of the two study formulations of metronidazole. Venous blood samples were collected immediately before and at 15 time points in an 48-hour interval after drug administration; metronidazole concentrations were determined by HPLC. Non-compartmental pharmacokinetic analysis was performed and log-transformed AUC(0-infinity) and Cmax were tested for bioequivalence. Sex differences were evaluated by means of a 4-factor (sex, sequence, treatment and period) ANOVA., Results: The studied formulations were found bioequivalent according to international standards: average 90% confidence interval for AUC(0-infinity) was 98 to 104 and for Cmax 93 to 115. After correction for the administered dose/kg, AUC was about 12% lower in females than in males (p = 0.0388) and, therefore, a higher calculated oral Cl/kg was found in females. Apparent distribution volume, after correction for weight, was significantly higher in males (p = 0.0019). Metronidazole half-life and MRT were shorter in females than in males (p - 0.0014 and p = 0.0002, respectively)., Conclusions: Data obtained in this study suggest that metronidazole clearance in females is about 12% higher than in males although these differences are probably of no clinical relevance.

Objective: To evaluate oral single dose prophylaxis in colorectal surgery., Design: Prospective study., Setting: University hospital, Sweden., Subjects: 24 patients (13 women; 11 men; mean age 57 years, range 27-81) listed for elective colorectal operations., Intervention: At 0630 on the day of the operation all patients were given an oral dose of trimethoprim-sulphamethoxazole (TMP 160 mg and SMZ 800 mg) and metronidazole (2 g). The serum concentrations of TMP and SMZ were analysed in venous samples taken at the start and end of each operation., Results: The earliest operation started at 0830 and the last finished at 1700. The median (range) serum concentrations of TMP were 1.4 (0.7-2.6) mg/L (start) and 1.3 (1.0-2.8) mg/L (end), and of SMZ 35 (15-65) mg/L (start) and 33 mg (13-70) mg/L (end). The individual values were above or equal to the minimal inhibitory concentration (TMP 0.8 mg/L; SMZ 15.2 mg/L) for relevant gram-negative species., Conclusion: Oral TMP/SMZ in the morning gives satisfactory serum concentrations independently of when the operation is done during the day. The regimen is simple and has the potential for being an effective alternative to intravenous prophylaxis.