Norfloxacin, development

Over 10000 quinolone antibacterial agents have now been synthesized. Nalidixic acid is regarded as the progenitor of the new quinolones. It has been used for several years as a clinically important drug in the treatment of urinary tract infections. Since its clinical introduction, other 4-quinolone antibacterials have been synthesized, some of which show considerably greater antibacterial potency. Furthermore, this means that many types of bacteria not susceptible to nahdixic acid therapy m be sensihve to the newer derivahves. The most important development was the introduction of a fluorine substituent at C-6, which led to a considerable increase in potency and spectrum of activity compared with nalidixic add. These second-generation quinolones are known as fluoroquinolones, examples of which are ciprofloxacin and norfloxacin (Fig. 5.19). 

The synthesis and antibacterial properties of norfloxacin (2a) were described in 1980 [65]. In this key paper in the evolution of quinolone antibacterial agents, a series of 6,7,8-polysubstituted-l-ethyl-l,4-dihydro-4-oxoquinoline-3-carb-oxylic acids (13) was synthesized, employing previously developed quantitative structure-activity relationships (QSAR) for the corresponding 6-, 7- and 8-monosubstituted derivatives versus Escherichia coli. The QSAR analysis... 

A wide variety of organotin compounds developed by Carraher, Sabir, Roner, and others based on known antiviral drugs such as acyclovir and known antibacterial agents such as ciprofloxacin, norfloxacin, cephalexin (structure 11.21), and ampicillin inhibit a wide variety of viruses including ones responsible for many of the common colds, chicken pox, small pox, shingles, and herpes simplex. 

In lower UTI it is essential to choose an agent that achieves a high concentration in urine, e.g. nitrofurantoin or norfloxacin. In a patient with fever, an upper UTI can be expected (pyelonephritis bacteremia) and therefore an agent with adequate concentrations in blood and urine should be given, e.g. the second generation cephalosporin cefurox-ime. When urosepsis develops (high fever, chills... 

A chemiluminescence method was developed for determination of pazufloxacin mesylate (08MI85). Pazufloxacin was determined in formulation using water-soluble quantum dots as fluorescent probe (08MI86). A molecularly imprinted polymer was developed, and it exhibits higher affinity and selectivity for pazufloxacin than for norfloxacin and ofloxacin (05MI31). 

Wang et al. reported the simultaneous determination of trace amounts of ciprofloxacin, pefloxacin, and norfloxacin in serum and urine by TLC-fluorescence spectrodensitometry [24]. The drug substances were applied to the silica gel plates, and developed to 9 cm with CHC13/ methanol/toluene/CH2Cl2/aqueous NH3 (27 46 17 5 5). Fluorescence spots were observed upon excitation at 254 nm, while the fluorescence spectrodensitometric measurements were performed at 400 nm (excitation at 278 nm). The calibration graph was linear upto 75 ng/spot for ciprofloxacin, with an RSD that was less than 8.6%. The recovery was 96-108%. 

The breakthrough in the development of quinolones came with the appearance of norfloxacin 6 [19], a second-generation quinolone which combined a 6-fluorine substituent with a piperazine ring in the 7-position of the basic compound. Additional quinolones then followed in rapid succession pefloxacin [20], enoxacin [21] and fleroxacin [22] (Fig. 14.5). Particular mention must be made of ciprofloxacin 8 [23-25], ofloxacin 5 [26,27] and its active enantiomer levofloxacin 7 [28]. These quinolones have a broad spectrum of activity, which also includes Gram-positive bacteria and Pseudomonas aeruginosa, as well as favorable pharmacokinetics. The rapid absorption of these compounds from the gastrointestinal tract and their effective tissue penetration also allows them to be used for the treatment of systemic infections. 

A 38-year-old woman took norfloxacin (300 mg/day) and tiaramide hydrochloride (300 mg tds) for an infection with Mycoplasma pneumoniae. One day after the start of treatment, her symptoms of cough and fever worsened and she developed lumbago and hematuria. The diagnosis was confirmed by percutaneous renal biopsy. She slowly improved without specific treatment. Lymphocyte stimulation tests were negative, but rechallenge with norfloxacin was followed by bilateral lumbago. 

A 33-year-old man developed myalgia and rhabdomyo-lysis while taking norfloxacin for cystitis. He complained of general muscle fatigue, tendon disorders, and articular pain. When norfloxacin was withdrawn, his symptoms abated, with persistence of shght myalgia for 10 days. 

More recently Brochot et al. [89] reported an extension of the isobolographic approach to interaction studies for convulsant interaction among pelloxacin, norfloxacin, and theophylline in rats. Their contribution is unique in that they started out by explaining pharmacodynamic interactions for two drugs, but then extended the approach to derive an isobol for three drug interaction. In addition they included Bayesian analysis and developed a population model with Markov chain Monte Carlo methods. 

Since the development in 1980 of norfloxacin as a nsefnl antibacterial agent, a large nnmber of analogs have been synthesized. Among them, the conjnnctive approach led to highly potent tetracyclic analogs (Fignre 16.39). ... 

The palladium-catalyzed amination reaction is developed for the preparation of fluoroanilines from fluorohaloarenes (82 - 98 % yields) and the synthesis of fluoroquinolone antibaeterials including Norfloxacin (58 — 75 % yields). For both sets of substrates, the fluoro-substituent remains intact, thus, the chemoselectivity is quantitative. 

No clinically significant changes in theophylline levels occurred in a patient given norfloxacin who subsequently had marked changes when given ciprofloxacin. This report and the studies in Table 33.4 , (p.ll93) contrast with the records of the FDA in the US, which describe 3 patients (up to 1989)" and 9 patients (up to 1991) who experienced marked increases in theophylline levels ranging from 64 to 171% (mean 103%). Three patients developed seizures, and one died. ... 

The simultaneous and pH-assisted spectrofluorimetric determination of Norfloxacin (NFLX) and Gatifloxacin (GFLX) in the same sample in pharmaceutical preparations was developed. The method implies the formation of coordination complexes between Tb and Eu + and NFLX or GFLX in sol-gel matrix. The luminescence intensity of Tb and Eu + for these complexes in their mixtures is quite sensitive to two variant sets of pH and thus a dual-controlled luminescence is achieved and a reversible on/off switchable emission of one system was observed by timing its optimal values of... 

Some bacteria, yeast, and other pathogens have developed a mechanism to pump out tetracycline and other antibiotics. This is their way of defending against the antibiotics. Some drugs have been developed to block this pump, so that the antibiotics administered will do its work unimpeded. Recently, such a compound, 5 -methoxyhy-drocarpin (5 -MHC), was isolated from barberry plants. When the antibiotics barberine was administered with 5 -MHC, it was found to inactivate the strain of S. aureus that was resistant to antibiotics such as norfloxacin. 

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