Active Ingredient: Norfloxacin
Study design The four clinical studies were prospective, randomized, single-blind patient blinded, multicenter, and comparative in parallel groups.
The aim of the studies was to compare the efficacy and safety of nitroxoline versus cotrimoxazole and norfloxacin in female patients with acute uncomplicated sporadic cystitis NWNF 10, 11, 13 or with acute episode of recurrent uncomplicated cystitis NWNF 15.
Table 5 Study design of the four meta-analysed prospective, open, randomised clinical studies in female patients with acute uncomplicated and recurrent cystitis treated with nitroxoline NTX versus a control antibiotic, cotrimoxazole CTX or norfloxacin NFX Full size table Selection of patients After medical history including kind and duration of symptoms, pretreatment and concurrent medication, physical examination including body temperature, urinalysis and confirmation of the clinical diagnosis including additional tests needed, eligible patients were informed about aim, performance, possible adverse events and their right to terminate the study without giving any reasons.
If written informed consent was documented, patients were included into the study after inclusion and exclusion criteria had been checked.
In three studies NWNF 10, 11, 13 female patients with clinical signs and symptoms of acute sporadic uncomplicated cystitis and in one study NWNF 15 those with acute episode of recurrent uncomplicated cystitis were included.
Because an objective outcome eradication of bacteriuria was the primary aim of the study, a double-blind design was not considered necessary at that time.
The control visits were one day end of treatment and 7—13 days test of cure after end of therapy.Explanation 2. Biological data 2.
In the ten day treatment study NWNF 15 an additional visit during therapy at day 6 was scheduled.
The thirty-eighth Committee concluded that the most relevant parameter in vitro for assessing the risk to human intestinal flora is the geometric mean MIC against the most sensitive intestinal microorganism Annex 1, reference 97.
Flumequine is a fluoroquinolone and thus has a broad spectrum of activity against aerobic gram-negative bacteria.
In humans, this class of antimicrobial agents is used clinically for selective elimination of potential aerobic and facultative anaerobic pathogens from the gastrointestinal tract while preserving the predominant anaerobic bacterial gut flora.
Anaerobic bacteria such as Bifidobacterium, Bacteroides, Eubacterium, Fusobacterium, and Peptostreptococcus spp.
Since the obligate anaerobic bacteria that are predominantly isolated from the gastrointestinal tract are relatively insensitive to fluoroquinolones, disturbance of the human gut ecosystem by residues of flumequine is unlikely.
COMMENTS The Committee considered additional information on the induction of arthropathy in young dogs, the hepatotoxic and liver enzyme-inducing effects of flumequine in mice, the possible mechanism of the hepatocarcinogenicity of flumequine, and its effect on human gut microflora.
The studies were carried out according to appropriate standards for study protocol and conduct. The animals showed no overt clinical signs of arthropathy.
Gross necropsy revealed erosions of the joint surfaces in two of 10 dogs at the highest dose and in one of 10 animals at the lowest dose. The severity of the lesions was similar at three and 13 weeks.
The Committee considered that the gross lesions in the one animal at the lowest dose were not compound-related, since no histopathological alterations were found and no gross lesions were observed at the next two higher doses.
Histopathological examination of the liver revealed dose-dependent hypertrophy, degenerative alterations, and centrilobular hepatocellular necrosis.
Increased mitosis was observed only in males at the highest dose. At its forty-second meeting, the Committee noted that there was evidence of compound-related tumorigenic effects in the livers of CD-1 mice.
The hepatotumorigenic activity of flumequine was more pronounced in male mice, which are known to be sensitive to liver tumour induction.