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Objectives: To develop and validate procedures that may be suitable for assessment of competency of two groups of non-pharmacist staff (pharmacy students and trainee support staff) in extemporaneous dispensing. This is important given the prospect of remote supervision of community pharmacies in the UK., Methods: Analytical methods were validated according to International Conference on Harmonisation specifications and procedures were optimized to allow efficient drug extraction. This permitted straightforward determination of drug content in extemporaneously prepared lidocaine hydrochloride mouthwashes and norfloxacin creams and suspensions prepared by 10 participants recruited to represent the two groups of non-pharmacist staff., Key Findings: All 10 participants had completed the extemporaneous dispensing of all three products within 90 min. Extraction and analysis took approximately 15 min for each lidocaine hydrochloride mouthwash and 30 min for each diluted norfloxacin cream and norfloxacin suspension. The mean drug concentrations in lidocaine hydrochloride mouthwashes and diluted norfloxacin creams were within what are generally accepted as being pharmaceutically acceptable limits for drug content (100 +/- 5%) for both groups of participants. There was no significant difference in the mean drug concentration of norfloxacin suspensions prepared by the participant groups. However, it was notable that only one participant prepared a suspension containing a norfloxacin concentration that was within pharmaceutically acceptable limits (101.51%)., Conclusions: A laboratory possessing suitable equipment and appropriately trained staff could cope readily with the large number of products prepared, for example, by a cohort of pre-registration students. Consequently, the validated procedures developed here could usefully be incorporated into the pre-registration examination for pharmacy students and a final qualifying examination for dispensers and pharmacy technicians. We believe that this is essential if the public and the profession are to have confidence in extemporaneous dispensing carried out in the absence of a pharmacist.

Objectives: To explore the urine bactericidal activity of co-amoxiclav and norfloxacin against Escherichia coli in an in vitro pharmacodynamic model simulating the human urinary concentrations observed after administration of a single oral dose of 2000/125 mg sustained-release co-amoxiclav and 400 mg norfloxacin., Methods: Six E. coli isolates exhibiting amoxicillin/clavulanic acid MICs of 4/2 (two strains), 8/4, 16/8, 32/16 and 64/32 mg/L and norfloxacin MICs of < or =0.25 mg/L (three strains), 32, 64 and 256 mg/L were used. Colony counts were determined over 12 h and differences between the bacterial counts of initial inocula and the bacterial counts at each sampling time-point were calculated., Results: With co-amoxiclav, bactericidal activity (>3 log(10) reduction) was obtained against the susceptible (MIC < or = 8/4 mg/L) and intermediate (MIC = 16/8 mg/L) strains from 3 to 12 h, and from 3 to 10 h against the resistant strains (MIC > or = 32/16 mg/L), which exhibited a 2 log(10) reduction at 12 h. With norfloxacin, bactericidal activity was obtained against the susceptible strains from 4 to 12 h and from 8 to 12 h against the resistant strain with an MIC of 32 mg/L. Regrowth, with respect to initial inocula, occurred from 8 h onwards with the strain with MIC = 64 mg/L and from 3 h onwards with the strain with MIC = 256 mg/L., Conclusions: While regrowth occurs after exposure of high norfloxacin-resistant E. coli to urine physiological concentrations of norfloxacin, this study suggests that clavulanic acid can be given twice daily (to protect amoxicillin activity) with respect to uncomplicated cystitis due to E. coli exhibiting amoxicillin/clavulanic acid MICs up to 64/32 mg/L.

Objective: To compare the bacteriological and clinical efficacy of three treatments for uncomplicated cystitis in ambulatory pre-menopausal women: ciprofloxacin 250 mg orally twice daily for 3 days, trimethoprim/sulfamethoxazole 160/800 mg orally twice daily for 7 days, and norfloxacin 400 mg orally twice daily for 7 days., Materials and Methods: A total of 455 women were randomly assigned to three treatment groups: 151 received ciprofloxacin, 150 received trimethoprim/sulfamethoxazole, and 154 received norfloxacin. Bacteriological cure and clinical resolution were evaluated 5-9 days and 4-6 weeks after completion of treatment., Results: There was no significant difference among the three treatment groups: overall efficacy ranged from 78.5% for the trimethoprim/sulfamethoxazole group, to 84.5% for the ciprofloxacin group. The highest overall incidence of drug-related adverse effects occurred in the trimethoprim/sulfamethoxazole patients., Conclusions: These data indicate that a 3 day treatment with ciprofloxacin is at least as clinically and bacteriologically effective as 7 day treatments with trimethoprim/sulfamethoxazole and norfloxacin for uncomplicated lower urinary tract infections.

An attempt has been made to design suitable niosome-encapsulated drug delivery system for ciprofloxacin and norfloxacin. Encapsulation of ciprofloxacin and norfloxacin in niosomes was investigated and the nasal and intestinal absorption of the products studied. More than 80% of the drugs were successfully encapsulated to give products with sustained release characteristics. Encapsulation in niosomes also improved the stability of the antibacterial compounds. Although the systemic availability of these niosome-encapsulated antibacterial compounds was not increased after nasal administration, intestinal absorption was significantly higher in comparison with that of plain inclusion complexes.

The effectiveness of norfloxacin as an antibacterial agent in ophthalmology is limited by poor drug delivery and limited ocular bioavailability. Liposomes containing norfloxacin have been prepared from different phospholipids using a novel technique with an encapsulation efficiency sixteen times greater than that of a conventional film method. The in-vitro release of the norfloxacin and the transcorneal characteristics of the liposomes have been evaluated. Differential scanning calorimetry was used to determine the interaction occurring between liposomes and cornea. The release of liposome-entrapped norfloxacin was affected by the pH of the environment. In the in-vitro corneal perfusion studies, norfloxacin-loaded liposome was transferred through the cornea at a slower rate than was the free drug. Norfloxacin-loaded liposomes were accumulated primarily in the cornea. The drug corneal retention of the lipids increased in the order dimyristoyl-L-alpha-phosphatidylcholine < dipalmitoyl-L-alpha -phosphatidylcholine < distearoyl-L-alpha-phosphatidylcholine. In the corneal drug-elimination study, liposomal norfloxacin increased the loading of the drug in cornea; the maximum value of the loading occurred 5 h after dosing. The drainage of liposomes from the cornea was somewhat slower than the solution form. Accumulation of norfloxacin in the cornea was greater for the liposome-entrapped drug. The results suggest that norfloxacin-loaded liposomes are absorbed by the cornea via endocytosis.

In a double-blind four-block randomized trial the efficacy and tolerance of a single dose of pefloxacin 800 mg was compared with a five day treatment with norfloxacin 400 mg twice daily in the treatment of uncomplicated urinary tract infections in general practice. The 222 patients included were all healthy non-pregnant women, aged between 18 and 65 years, with dysuria, urinary frequency or urgency, who visited their general practitioner. Outcome parameters were the rates of resolution of symptoms after eight to ten days (T2) and after six weeks (T3), the bacteriological response at T2 and T3, and the tolerance of pefloxacin and norfloxacin. Only slight differences were demonstrated at any stage and after six weeks the success rates in the pefloxacin group were not different from those in the norfloxacin group. Tolerance in both groups was rated as satisfactory, although the higher dose of pefloxacin caused more gastrointestinal side effects.

The pharmacokinetic properties of the new fluoroquinolones are characterized by a high volume of distribution, long biological half-life, low serum protein binding, elimination by renal and extrarenal mechanisms with high total and renal clearances, limited biotransformation and moderate to excellent bioavailability after oral administration. However, each quinolone derivative (ciprofloxacin, enoxacin, fleroxacin, norfloxacin, ofloxacin and pefloxacin) possesses individual pharmacokinetic parameters, which should be considered in the treatment of patients, especially when liver or renal dysfunction exists.

The pharmacokinetics and tissue penetration of five quinolones were studied in volunteers. The compounds were norfloxacin (400 mg po), enoxacin (400 mg iv and 600 mg po), ciprofloxacin (100 mg iv and 500 mg po), ofloxacin (600 mg po) and pefloxacin (400 mg iv). Of the oral agents studied ofloxacin and ciprofloxacin were the most rapidly absorbed (Tmax = 1.2 h) and enoxacin the least (Tmax = 1.9 h). The serum levels attained were highest in the case of ofloxacin (after allowing for the higher dose administered). The serum half-lives were norfloxacin 3.75 h, ciprofloxacin 3.9 h (po), 4.0 h (iv), ofloxacin 7.0 h, enoxacin 6.2 h (po), 5.1 h (iv) and pefloxacin 10.5 h. All agents penetrated blister fluid readily. The 24 h urine recovery was 62% for oral enoxacin, 46.4% for iv enoxacin (plus 12.2% for oxo-enoxacin), 27% for norfloxacin, 30.6% for oral ciprofloxacin, 75.7% for iv ciprofloxacin, 73% for ofloxacin and 4.9% for pefloxacin (plus 9.2% for the norfloxacin metabolite and 17.8% for pefloxacin N-oxide).

Pefloxacin (Pef) is a new quinolone which has been shown to have good in-vitro activity against Staphylococcus aureus, and to reach high tissue concentrations. Its efficacy was compared to that of 2 quinolone derivatives, norfloxacin (Nor) and ciprofloxacin (Cip) and to that of methicillin (Meth), cephalothin (Cep), pristinamycin (Pri) and vancomycin (Van), in an experimental model of S. aureus abscesses. Mice challenged with an intramuscular thigh injection of a calibrated inoculum developed local abscesses. Three S. aureus strains (with different antibiotic resistance profiles (Pase-, Pase+, MethR)) were used. In this model, the antibiotics showing the best ED50 following oral administration, against all three strains were Pef greater than Cip greater than Pri greater than Nor, by subcutaneous administration for the Pase- strain Pef = Cip greater than Cep greater than Van; for the Pase+ strain Pef = Cip greater than Van greater than Meth and for the Pase+ MethR strain: Pef = Cip greater than Van greater than Cep. These data indicate that pefloxacin and ciprofloxacin are highly active in vivo against various strains of S. aureus, and appear to be more potent than norfloxacin, vancomycin, cephalothin and methicillin.

Multiple-dose kinetics of pefloxacin was determined in 12 normal male subjects given 400 mg pefloxacin by iv 1 h-infusion every 12 h for 16 doses. Twelve other subjects (6 men and 6 women) were given 400 mg pefloxacin by mouth every 12 h for 18 doses. Plasma and urine concentrations of pefloxacin and its main metabolites (N-desmethyl pefloxacin or norfloxacin and pefloxacin N-oxide) were measured by high performance liquid chromatography. The bioavailability of pefloxacin was complete and plasma concentrations after iv or oral administration were similar. Pefloxacin was rapidly absorbed from the gastrointestinal tract and reached maximum plasma concentrations about 1 h after dosing. Pefloxacin elimination (T 1/2 beta) increased from 11.00 +/- 2.64 h after the first iv dose to 13.93 +/- 3.58 h after the last iv dose (P less than 0.01). Apparent total body clearance decreased from 148.5 +/- 47.6 to 106.9 +/- 39.2 ml/min (P less than 0.01) because of decreased non-renal clearance (apparent volume of distribution did not significantly change over the repeated pefloxacin administration). Similar results were obtained after repeated oral dosing. Renal clearance of pefloxacin was low (7.47 +/- 2.28 ml/min) indicating that non-renal clearance represents the major route of elimination of this quinolone. Urinary excretion of pefloxacin and N-desmethyl and N-oxide metabolites was approximately 31% of the pefloxacin dose and beta-elimination half-lives of these metabolites were very close to that of pefloxacin (13.34 +/- 2.72 h and 11.95 +/- 2.64 h respectively). Due to a possible saturable process in the metabolic pathway, some accumulation occurred during repeated iv or oral treatment (accumulation ratio = 1.37 +/- 0.20). These results show that concentrations of pefloxacin in excess of the minimum inhibitory concentrations for many important pathogens can be rapidly achieved in plasma and urine with the 400 mg bid regimen with both iv and oral routes.

Nine subjects (5 women) aged between 17-66 years, with hydrocephalus were studied. An external ventricular drain was introduced for diagnostic purposes. Cerebro-spinal fluid (CSF) and plasma samples were obtained at suitable intervals after 1 h infusion of 400 mg pefloxacin. In plasma, pefloxacin Cmax was 8.54 +/- 1.53 (mean +/- S.E.M.) mg/l, at the end of infusion, whereas N-desmethyl pefloxacin concentration was 0.17 +/- 0.03 mg/l. The metabolite accounted for only 2% of plasma levels of pefloxacin. In CSF, pefloxacin Cmax was 2.97 +/- 0.32 mg/l, 5-6 h after the start of infusion, whereas N-desmethyl pefloxacin Cmax varied between 0.1-0.2 mg/l. Apart from the 1 h sample, the CSF/plasma ratio of pefloxacin was 60% which is similar to the unbound fraction of pefloxacin in plasma. The apparent half-life (T1/2) of transfer of pefloxacin from plasma to CSF was 1.26 +/- 0.18 h, assuming a first order process, while the apparent elimination T1/2 in CSF was 13.40 +/- 1.76 h, which is similar to the elimination T1/2 found previously in plasma, thus accumulation of pefloxacin in CSF is unlikely. With the present dosage regimen, CSF quickly attains therapeutic levels of pefloxacin.