The flouroquinolones constitute good number of antimicrobial agents which have been useful against community-acquired infection and hospital acquired infection. The newer released flouroquinolones which includes levofloxacin have been reported to display excellent pharmacokinetic properties which include good penetration into the tissues and improved once daily administration of the antimicrobial. Some of these flouroquinolones including levofloxacin are available for oral and intravenous administration and their mode of action is such that it rapidly inhibits the translation and transcription process of the DNA by inhibiting the DNA gyrase or the topoisomerase IV enzymes, ( Frederick et al 2009) of the bacterial cell and eventually leads to the death of the bacteria.
Although due to mutation, some bacteria have developed resistant to some flouroquinolones.( Steven et al 1998).but considering the safety profile, low resistant level and excellent action against some gram-positive bacteria like S.pneumonia, levofloxacin in
particular have been made first choice in the treatment of hospital acquired pneumonia.( Daryl et al 2003).
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Fluoroquinolones in general are antibacterial agents that have proven to have a broad spectrum of activity against gram-positive and gram-negative bacteria which has made their use for the treatment of infectious disease be very effective. Although we have some flouroquinolones that have adverse side effects for instance we have enoxacin, lomefloxacin, norfloxacin, ofloxacin, levofloxacin and gatifloxacin have been reported to induce hypoglycaemia and they do this by stimulating the production of insulin which is achieved by blocking the ATP sensitive potassium channels of the pancreatic Î²-cells.( Ishiwata et al 2006). Side effects such as knee rupture, renal failures, tendinitis, organ transplantation have also been associated with the use of flouroquinolones. ( Frederick et al 2009).
Levofloxacin which is an isomer of the racemix structure ofloxacin like the rest of the flouroquinolones have good activity against most gram positive bacteria and it is being used to treat skin and skin structure infection and also urinary tract infection or sepsis (Siewert 2006).
In this essay, I shall be evaluating the properties and pharmaceutical characteristics of the Levaquin which is a drug produced from the flouroquinolone levofloxacin. This essay will look at the chemical and industrial preparation of the drug, it will also evaluate its pharmacokinetic and pharmacodynamic properties including the clinical trials and side effects.
To fully understand the mechanism of action of levofloxacin, we need to understand the mode of actions of the bacteria which makes use of the DNA gyrase. This enzyme which has two A subunits and two B subunits is responsible for the winding of the double strands of the bacterial DNA to minimize the length and maximize efficient packing of the cell. The A subunits introduces disturbance to the two strands of the DNA which makes the supercoiling occur in the B subunit. Levofloxacin then acts on the topoimerase II on the
gram negative bacteria and topoimerase IV in gram positive bacteria (Bernardetta et al 2000) by inhibiting the DNA gyrase subunit A and also prevents the resealing of the broken strand which eventually kills the bacteria cell. Some bacteria cells have developed some mechanism of resistance to the flouroquinolones by developing chromosomal mutation on the the DNA
gyrase which reduces its binding affinity ,so the drug is unable to bind to the receptor.( Steven et al 1998). When compared to other flouroquinolones, levofloxacin has the lowest resistant to bacteria. (Daryl et al 2003).
Production of Levaquin (Patents)
Levaquin is a chiral fluorinated carboxyquinolone drug ( Jorgee et al 2010). But before I go into the chemistry of levaquin, I would talk briefly on chirality. To get the full gist on chirality, take the human hand as an example, the hands are both mirror images of each other but they cannot be imposed on each other which means the left hand cannot be rotated to look exactly like the right hand. Chirality can then be said to be a property of asymmetry related to three dimensional structure. (Miles 2003) This can also be called stereoisomer which implies having the same molecular formula or even atomic composition but different spatial arrangement. A good example of stereoisomer is an enantiomer. Just like the definition of a stereoisomer, an enantiomer has the same number of atoms connected in the same order but different arrangement in space of the atoms to its racemic structure and most pharmaceutical companies have gained from the enantiometric pharmaceuticals because as the racemix patent is about to expire,they begin to publicise the single enantiomer of this racemix drug to extend the product life and market monopoly. This phenomenon is called chiral switch. (Miles 2003).
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Synthesis of levaquin (Levofloxacin): Levaquin was first patented in 1987 by Daiichi Seiyaku Co., Ltd. Japan and was approved by the United States Food and Drugs administration in 1996 to be used in the treatment of life threatening bacterial infections. The only difference between levofloxacin and ofloxacin according to the United States Food and Drugs administration is the increased potency of levofloxacin against mycobacterium
whereas ofloxacin has less activity against mycobacterium. The synthesis of levofloxacin is such that has the convergent route and good yield of the pure product.
The original patent is Daiichi Seiyaku Co., Ltd. Japan with patent no (U.S. Patent No 4,382,892) which is directed toward pyrido[1,2,3-de][1,4]benzoxazine derivatives and methods of preparing them.
U.S. Patent No. 5,051,505 is directed toward the processes involved in preparing piperazinyl quinolone derivatives. The process comprises reacting dihaloquinolones with piperazine derivatives and tetra alkyl ammonium halides in the presence of a polar solvent
such as acetonitrile, dimethylformamide, pyridine, sulfolane and dimethyl sulfoxide. (Park, et al.1991).
U.S. Patent No. 5,155,223 is directed toward the preparation of quinolinecarboxylic acids.
U.S. Patent No. 5,545,737 discloses selectively producing a levofloxacin hemihydrate or monohydrate by controlling the water content of an aqueous solvent in which levofloxacin is dissolved during a crystallization.
The original patent Daiichi Seiyaku Co., Ltd. Claims that 9-fluoro-2,3-dihydro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid ethyl ester is esterified with 3,5-dinitrobenzoyl chloride to give the racemix ester which is then resolved into its optical isomers by HPLC over a sumipax OA4200 column using hexane-1,2-dichloroethane-ethanol as carrier solvent. The -(-) optical isomer is hydrolized with ethanolic aqueous NaHCO3 to afford the (-)-alcohol which is treated with triphenylphosphite methiodide in DMF giving the corresponding (-)-iodomethyl derivative . The reduction and simultaneous hydrolysis of (-)-iodomethyl derivative with tributyltin hydride in ethanol yields (-)-9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid (VII), which is finally treated with N-methylpiperazine (VIII) to give (-)-ofloxacin which is levofloxacin. (Hayakawa ,et al.1983)
Structure of Levofloxacin
Industrially, the reaction may be performed by heating the starting compound with an amine at a temperature of about 700C to 1500C. This is best done in the prescence of a polar organic solvent likedimethylsulfoxide, sulfolane, dimethylformamide, dimethylacetamide or water. This reaction is best performed in the prescence of an acid acceptor such as triethylamine, dimethylaniline, potassium carbonate. The product from the reaction can then
be obtained and purified by conventional techniques such as evaporation, filtration, extraction, chromatography, recrystallization and a combination thereof but because the industry deals with a large amount crystallization technique is suitable. For instance if the product is precipitated by cooling ,filteration will be used for collection but if after filteration the precipitate cannot be found, the reaction mixture will be shaken with either chloroform or water and after which the product is obtained by concentrating the chloroform layer if the product then contains some by-products or impurities, further purification can be done using silica gel chromatography and recrystallization. (Hayakawa ,et al.1991)
U.S. Patent No. 5,053,407 is directed toward optically active pyridobenzoxazine derivatives, novel processes for preparing the same, and intermediates useful for preparing such derivatives. The inventors also discovered that the S(-)- ofloxacin (levofloxacin) has an antibacterial property which doubles that of the structure ofloxacin (.+-.). At the same time they found out that even the other isomer of ofloxacin i.e. R(+) ofloxacin exhibits
antibacterial activity that is about 1/10 - 1/100 times that of the structure but posseses the same toxicity with ofloxacin, but S(-)- ofloxacin (levofloxacin) has increased activity against microbes with little or no acute toxicity. All these facts were discovered using mice as the case study and administration is intravenous. The inventor also developed a novel means of obtaining the racemix compound(levofloxacin) from the substrate(ofloxacin) by hydrolyzing with with an enzyme like lipase which gives the S(-)- ofloxacin ,R(+) ofloxacin. Hence it can be concluded that the optically active compound can be obtained by utilizing asymmetric hydrolysis with lipase enzyme obtained from Pseudomonas aeruginosa. (Hayakawa, et al.1991)
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U.S. patent No. 5,142,046 was aimed at inventing an object which is useful for synthesizing optically active Ofloxacin and other pyridobenzoxazine derivatives. Also to provide a novel process for preparing optically active Ofloxacin and its analogs by the use of the above-described intermediate.
Environmental impact of Levaquin: According to the centre for drug evaluation and research, based on the national environmental policy act of 1969(NEPA) which requires pharmaceutical companies to assess the impact of their drugs which must be considered by the Food and Drug Administration before giving approval to any drug product application.
This body carefully considered the environmental impact of levaquin (levofloxacin) in the treatment of hospital-acquired pneumonia, community acquired pneumonia, acute pylenonephritis, complicated urinary tract infection, complicated and uncomplicated skin and skin structure infection, and chronic bacteritis and eventually came to a conclusion that if the drug enters the aquatic and terrestrial environment via the patient, it is readily degraded on exposure to light and this was seen in the result of the toxicity characterization of the drug on environmental organisms which came out to be non toxic when exposed at the right concentration. Therefore levofloxacin (Levaquin) does not have any significant harmful effect on the human environment.
Pharmaceutical product testing
Pharmacology: A pharmaceutical product test was carried out on levofloxacin to check its bioequivalence and bioanalytical method using HPLC(High Performance Liquid Chromatography) and albino rat as a case study and at the end of the test the values for the AUC, Tmax, Cmax, T1/2, Kel,(Area under curve, Maximum time, Maximum concentration, Half life, Elimination rate constant) when compared with a standard drug;levoflox(reference drug),showed not much difference( Jorgee et al 2010). Compared to its racemix structure, levofloxacin has been reported to have improved invitro activity against some gram positive bacteria strains for example levofloxacin has better activity against Staphylococcus aureus, Staphylococcus epidermidis, Enterococcus faecalis and Enterococcus faecium when compared with ciprofloxacin, levofloxacin has improved in vitro activity against S pneumonia. It also has excellent activity against some strains of gram negative bacteria which includes P aeruginosa, Neisseria gonorrhoeae and M catarrhalis.it also has improved
activities against some strains of anaerobic organisms for example Bacteroides fragilis, Clostridium perfringens. .( Steven et al 1998).
This will be divided into four different categories which has to do with its absorption, distribution ,metabolism and excretion. levofloxacin displays favourable pharmacokinetics when compared to other flouroquinolones except from ofloxacin which has almost the same pharmacokinetic properties.
Absorption: This is the rate at which a drug molecule is absorbed in the body. Levofloxacin is readily absorbed by the gastrointestinal tract when taken orally and both the oral and intravenous dose are readily interchangeable because they have almost the same plasma concentration profile. Administration of levofloxacin with food slows down its absorption and prolongs peak serum concentration by 1 hr which then reduces peak serum concentration by 14percent. When taken orally, absolute bioavailability is 99percent.( Steven et al 1998).
The bioavailability was observed in a study carried out on some healthy, fast Mexican adults who were given a 500-mg dose of oral levofloxacin. At the end of the study, these ones met the regulatory requirements to assume absolute bioavailability based on the rate and extent of absorption. (Juan Francisco et al 2009)
Distribution: This indicated the concentration rates of the drug molecule in different parts of the body over a certain period of time. Levofloxacin concentrations in lung tissue has been reported to be higher than serum because it has a mean volume of distribution ranging from 1.09 to 1.26L/Kg after single and multiple doses of 500-mg which indicates wide tissue penetration. Because of its minimal penetration into the central nervous systems, levofloxacin is not very efficient in the treatment of meningitis and other CNS infections. .( Steven et al 1998). Further studies have shown that liposomal-encapsulated levofloxacin increases its
concentration in serum. This was observed in the pharmaceutical study carried out by Martin et al (2003) where ciprofloxacin delivered by liposomes was compared to the conventional type and the result shows that the liposomal encapsulated ciprofloxacin had higher concentration in serum, white blood cells and lung lavage fluid of a rat model of pneumococcal pneumonia .
Elimination: This involves the rate and form in which the drug molecule is cleared from the body. Because it undergoes minimal metabolism, elimination of levofloxacin is unchanged in the urine. It is cleared mainly by the kidney in humans. Differences in pharmacokinetics in male and female, young and old patients when adjustment is made for decreased renal function. As a result of its stereochemical stability, when in plasma or urine, levofloxacin does not convert back to its active isomer D-Ofloxacin (Steven et al 1998).
Levoflox (reference product)
Generic (test product)
AUC 0 - t(ng. h/ml)
AUC 0 - âˆž(ng. h/ml)
C max(ng /ml)
Table showing the pharmacokinetic properties of levaquin in albino rat plasma concentration when compared to a standard. (Jorgee et al 2010).
Clinical trials and uses
A clinical trial was carried out by Onyeji et al (1998) to check for the efficacies of levofloxacin and ciprofloxacin against S. pneumoniae in a mouse model of septicaemia using three isolates of different strains two of which are penicillin sensitive and one penicillin resistant. after four days of post infection with the different strains of SP, the percentage survival following levofloxacin treated mice was more than ciprofloxacin treated mice. Also in a study carried out by Bernardetta et al (1999) to check the bactericidal properties of levofloxacin compared with ciprofloxacin on clinical isolates on different types of Pseudomonas aeruginosa, it was observed that levofloxacin showed more bactericidal properties that ciprofloxacin. In order to determine the mechanism of flouroquinolone induced abnormalities in blood glucose, a clinical trial was carried out in rats that receive intravenous doses of levofloxacin and their arterial blood was sampled periodically. It was discovered that levofloxacin can induce hypoglycaemia and hyperglycaemia in rats. (Ishiwata et al 2006).
Levofloxacin is currently approved in the use of community acquired pneumonia, acute maxillary sinusitis, complicated urinary tract infection, acute bacterial excaberations of chronic bronchitis, acute pyelenonephritis. .( Steven et al 1998). The study conducted by Pierluigi et al (2006) to check the major role of levofloxacin in the treatment of a case of Listeria monocytogenes meningitis, it was concluded that levofloxacin unlike some other flouroquinolones may be a good option for the treatment of meningitis caused by the acute bacteria Listeria monocytogenes. 1109 patients were enrolled in a study to compare levofloxacin 750 mg once-daily for five days with ciprofloxacin 400/500 mg twice-daily for 10 Days for the treatment of complicated urinary tract infections and acute pyelonephritis, and the result shows that both drugs are very effective and a 5 day course of levofloxacin is non inferior to the 10 days course of ciprofloxacin (Janet et al 2008).
To buttress that study as well Richard et al as cited by Steven et al also performed a combined test to check the effectiveness of levofloxacin in the treatment of acute pyelenonephritis by comparing the effect when administred alongside ciprofloxacin, and lomefloxacin to 259 patients suffering from acute pyelonephritis and the results also
confirmed that levofloxacin was as effective as ciprofloxacin and lomefloxacin in the treatment of acute pyelonephritis.
A 750mg dose of levofloxacin was also tested against the 500mg dose in the treatment of acute maxillary sinusitis in a study carried out by Jack et al (2006) and it was observed that the higher dose had a short course in killing the pathogen. The safety and tolerability of levofloxacin was also observed using rat and mice as a case study and it was reported that no animal drug-drug interaction, and it is not toxic in animals, it also causes no impairment of fertility in animals and finally no indication to carcinogenic potential was seen in a two year study(Tuberculosis).
Market share of levaquin
The cost of levaquin highly depends on the form and strength. The tablet forms comes in 250mg, 500mg, and 750mg which costs $41, $71, and $85 respectively for 30
tablets(http://www.adrugrecall.com) The oral form produced by Ortho McNeil pharmaceutical inc. comes only in 25mg/mL and cost varies.
Sales of levaquin overtook sales of cipro as a result of the initiative taken by Johnson& Johnson sales forced with Omnicare between the periods covering 1999-2004. Omnicare inc. being the largest independent provider of pharmaceutical products represents about 30% of the market share and it has quickly taken control of its business unit purchasing functions. An example is the success it achieved in the sales of levaquin. Levaquin moved from 12% market share in January 1999 to 41% in June 1999 and at the end of 2001, market share of levaquin had jumped to 66.1% whereas the market share of cipro had plunged to 28% from 80% as at that time. So it was alleged by the authorities/government that Johnson & Johnson paid kickbacks to Omnicare in the form of rebates, grants and educational funding.
Levaquin has proven to be a hit drug for Johnson & Johnson/ Ortho McNeil generating billions of dollars in additional revenue. For instance just in 2007, Johnson &
Johnson generated about $1.6 billion just from the sales of levaquin which is about 6.5% of their total revenue that year and an 8% increase over the previous year. In that same year it was rated 37th in the top 200 most prescribed drugs and 19th in the world sales. At the end of the year, levaquin sales were in an excess of $1.6 billion becoming the most prescribed flouroquinolone drug in that year. Post marketing surveillance was difficult because levaquin was sold with different brand names.
Dosage form of levaquin
Levaquin is available in different dosage form ranging from tablets, oral solution and intravenous in form of injection. The tablet form is available in 250mg, 500mg, and 750mg. The oral solution is available at 25mg/mL which is a multi-use self preserving solution. The U.S Food and Drug administration approved the new oral formulation of levaquin in 2004 for patients who have some difficulty in swallowing and despite new, it's as effective as the tablet and intravenous formulation in its antimicrobial activity and it provides continued dosing for renally impaired patients (Raritan N.J 2004). The intravenous form in the form of injection may appear clear- yellow to clear greenish colour but this does not affect its potency and activity.
The most commonly observed adverse effect of levofloxacin is vomiting, dizziness, pain at the injection site, headache, altered state, nausea, diarrhoea; levofloxacin also appears to be responsible for few CNS disturbances. .( Steven et al 1998). Also to buttress the effect of levofloxacin on the CNS, Boonsong et al (2008) raised an awareness of a serious but rare side effect of levofloxacin which is levofloxacin-induced delirium (also known as acute confusional state) with psychotic features in a relatively young female. During the clinical trials of flouroquinolones, a study was conducted to see the effect of flouroquinolones on diplopia in which a total of 171 cases was reported after a median of 9.6days following drug therapy ( Fredrick et al 2009) which indicates that levofloxacin may cause diplopia-which is a defect where two images are perceived as one.