Pharmaceutical Evaluation Of Levaquin Biology

Table of Content

The flouroquinolones constitute good figure of antimicrobic agents which have been utile against community-acquired infection and infirmary acquired infection. The newer released flouroquinolones which includes levofloxacin have been reported to expose first-class pharmacokinetic belongingss which include good incursion into the tissues and improved one time day-to-day disposal of the disinfectant. Some of these flouroquinolones including levofloxacin are available for unwritten and endovenous disposal and their manner of action is such that it quickly inhibits the interlingual rendition and written text procedure of the Deoxyribonucleic acid by suppressing the Deoxyribonucleic acid gyrase or the topoisomerase IV enzymes, ( Frederick et al 2009 ) of the bacterial cell and finally leads to the decease of the bacteriums.

Although due to mutant, some bacteriums have developed resistant to some flouroquinolones. ( Steven et al 1998 ) .but sing the safety profile, low immune degree and first-class action against some Gram-positive bacteriums like S.pneumonia, levofloxacin in peculiar have been made first pick in the intervention of infirmary acquired pneumonia. ( Daryl et al 2003 ) .

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Fluoroquinolones in general are antibacterial agents that have proven to hold a wide spectrum of activity against Gram-positive and Gram-negative bacterium which has made their usage for the intervention of infective disease be really effectual. Although we have some flouroquinolones that have inauspicious side effects for case we have enoxacin, lomefloxacin, norfloxacin, ofloxacin, levofloxacin and gatifloxacin have been reported to bring on hypoglycemia and they do this by exciting the production of insulin which is achieved by barricading the ATP sensitive K channels of the pancreatic I?-cells. ( Ishiwata et al 2006 ) . Side effects such as articulatio genus rupture, nephritic failures, tendonitis, organ organ transplant have besides been associated with the usage of flouroquinolones. ( Frederick et al 2009 ) .

Levofloxacin which is an isomer of the racemix construction ofloxacin like the remainder of the flouroquinolones have good activity against most gram positive bacteriums and it is being used to handle tegument and tegument construction infection and besides urinary piece of land infection or sepsis ( Siewert 2006 ) .

In this essay, I shall be measuring the belongingss and pharmaceutical features of the Levaquin which is a drug produced from the flouroquinolone levofloxacin. This essay will look at the chemical and industrial readying of the drug, it will besides measure its pharmacokinetic and pharmacodynamic belongingss including the clinical tests and side effects.

To to the full understand the mechanism of action of levofloxacin, we need to understand the manner of actions of the bacteriums which makes usage of the DNA gyrase. This enzyme which has two A fractional monetary units and two B fractional monetary units is responsible for the twist of the dual strands of the bacterial Deoxyribonucleic acid to minimise the length and maximise efficient wadding of the cell. The A fractional monetary units introduces perturbation to the two strands of the DNA which makes the supercoiling occur in the B fractional monetary unit. Levofloxacin so acts on the topoimerase II on the 200575299 BIOL5244

gm negative bacteriums and topoimerase IV in gm positive bacteriums ( Bernardetta et al 2000 ) by suppressing the Deoxyribonucleic acid gyrase subunit A and besides prevents the resealing of the broken strand which finally kills the bacterium cell. Some bacteriums cells have developed some mechanism of opposition to the flouroquinolones by developing chromosomal mutant on the the Deoxyribonucleic acid

gyrase which reduces its binding affinity, so the drug is unable to adhere to the receptor. ( Steven et al 1998 ) . When compared to other flouroquinolones, levofloxacin has the lowest resistant to bacteriums. ( 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 chemical science of levaquin, I would speak briefly on chirality. To acquire the full effect on chirality, take the human manus as an illustration, the custodies are both mirror images of each other but they can non be imposed on each other which means the left manus can non be rotated to look precisely like the right manus. Chirality can so be said to be a belongings of dissymmetry related to three dimensional construction. ( Miles 2003 )

This can besides be called stereoisomer which implies holding the same molecular expression or even atomic composing but different spacial agreement. A good illustration of stereoisomer is an enantiomorph. Just like the definition of a stereoisomer, an enantiomorph has the same figure of atoms connected in the same order but different agreement in infinite of the atoms to its racemic construction and most pharmaceutical companies have gained from the enantiometric pharmaceuticals because as the racemix patent is about to run out, they begin to advertise the individual enantiomorph of this racemix drug to widen the merchandise life and market monopoly. This phenomenon is called chiral switch. ( Miles 2003 ) .

Synthesis of levaquin ( Levofloxacin ) : Levaquin was foremost patented in 1987 by Daiichi Seiyaku Co. , Ltd. Japan and was approved by the United States Food and Drugs disposal in 1996 to be used in the intervention of life endangering bacterial infections. The lone difference between levofloxacin and ofloxacin harmonizing to the United States Food and Drugs disposal is the increased authority of levofloxacin against mycobacteria 200575299 BIOL5244 whereas ofloxacin has less activity against mycobacteria. The synthesis of levofloxacin is such that has the convergent path and good output of the pure merchandise.

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 derived functions and methods of fixing them. U.S. Patent No. 5,051,505 is directed toward the procedures involved in fixing piperazinyl quinolone derived functions. The procedure comprises responding dihaloquinolones with piperazine derived functions and tetra alkyl ammonium halides in the presence of a polar dissolver such as acetonitrile, dimethylformamide, pyridine, sulfolane and dimethyl sulfoxide. ( Park, et al.1991 ) .

U.S. Patent No. 5,155,223 is directed toward the readying of quinolinecarboxylic acids. U.S. Patent No. 5,545,737 discloses selectively bring forthing a levofloxacin hemihydrate or monohydrate by commanding the H2O content of an aqueous dissolver in which levofloxacin is dissolved during a crystallisation.

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 so resolved into its optical isomers by HPLC over a sumipax OA4200 column utilizing hexane-1,2-dichloroethane-ethanol as bearer dissolver. 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 decrease and coincident hydrolysis of ( – ) -iodomethyl derivative with tributyltin hydride in ethanol outputs ( – ) -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 eventually 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 get downing compound with an aminoalkane at a temperature of approximately 700C to 1500C. This is best done in the prescence of a polar organic dissolver likedimethylsulfoxide, sulfolane, dimethylformamide, dimethylacetamide or H2O. This reaction is best performed in the prescence of an acerb acceptor such as triethylamine, dimethylaniline, K carbonate.

The merchandise from the reaction can so be obtained and purified by conventional techniques such as vaporization, filtration, extraction, chromatography, recrystallization and a combination thereof but because the industry deals with a big sum crystallisation technique is suited. For case if the merchandise is precipitated by chilling, filteration will be used for aggregation but if after filteration the precipitate can non be found, the reaction mixture will be shaken with either trichloromethane or H2O and after which the merchandise is obtained by concentrating the trichloromethane bed if the merchandise so contains some byproducts or drosss, farther purification can be done utilizing silicon oxide gel chromatography and recrystallization. ( Hayakawa, et al.1991 )

U.S. Patent No. 5,053,407 is directed toward optically active pyridobenzoxazine derived functions, fresh procedures for fixing the same, and intermediates utile for fixing such derived functions. The discoverers besides discovered that the S ( – ) – ofloxacin ( levofloxacin ) has an antibacterial belongings which doubles that of the construction ofloxacin ( .+-. ) . At the same clip they found out that even the other isomer of ofloxacin i.e. R ( + ) ofloxacin exhibits 200575299 BIOL5244

antibacterial activity that is about 1/10 – 1/100 times that of the construction but posseses the same toxicity with ofloxacin, but S ( – ) – ofloxacin ( levofloxacin ) has increased activity against bugs with small or no acute toxicity. All these facts were discovered utilizing mice as the instance survey and disposal is endovenous. The discoverer besides developed a fresh agencies of obtaining the racemix compound ( levofloxacin ) from the substrate ( ofloxacin ) by hydrolysing 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 using asymmetric hydrolysis with lipase enzyme obtained from Pseudomonas aeruginosa. ( Hayakawa, et al.1991 )

U.S. patent No. 5,142,046 was aimed at contriving an object which is utile for synthesising optically active Ofloxacin and other pyridobenzoxazine derived functions. Besides to supply a fresh procedure for fixing optically active Ofloxacin and its parallels by the usage of the above-described intermediate 200575299 BIOL5244

Environmental impact of Levaquin: Harmonizing to the Centre for drug rating and research, based on the national environmental policy act of 1969 ( NEPA ) which requires pharmaceutical companies to measure the impact of their drugs which must be considered by the Food and Drug Administration before giving blessing to any drug merchandise application.

This organic structure carefully considered the environmental impact of levaquin ( levofloxacin ) in the intervention of hospital-acquired pneumonia, community acquired pneumonia, acute pylenonephritis, complicated urinary piece of land infection, complicated and unsophisticated tegument and tegument construction infection, and chronic bacteritis and finally came to a decision that if the drug enters the aquatic and tellurian environment via the patient, it is readily degraded on exposure to visible radiation and this was seen in the consequence of the toxicity word picture of the drug on environmental beings which came out to be non toxic when exposed at the right concentration. Therefore levofloxacin ( Levaquin ) does non hold any important harmful consequence on the human environment.

Pharmaceutical merchandise proving

Pharmacology: A pharmaceutical merchandise trial was carried out on levofloxacin to look into its bioequivalence and bioanalytical method utilizing HPLC ( High Performance Liquid Chromatography ) and albino rat as a instance survey and at the terminal of the trial the values for the AUC, Tmax, Cmax, T1/2, Kel, ( Area under curve, Maximum clip, Maximum concentration, Half life, Elimination rate invariable ) when compared with a standard drug ; levoflox ( reference drug ) , showed non much difference ( Jorgee et al 2010 ) .

Compared to its racemix construction, levofloxacin has been reported to hold improved invitro activity against some gram positive bacteriums strains for illustration levofloxacin has better activity against Staphylococcus aureus, Staphylococcus epidermidis, Enterococcus faecalis and Enterococcus faecium when compared with Cipro, levofloxacin has improved in vitro activity against S pneumonia. It besides has first-class activity against some strains of gm negative bacteriums which includes P aeruginosa, Neisseria gonorrhoeae and M besides has improved 200575299 BIOL5244 activities against some strains of anaerobiotic beings for illustration Bacteroides fragilis, Clostridium perfringens. . ( Steven et al 1998 ) .


This will be divided into four different classs which has to make with its soaking up, distribution, metamorphosis and elimination. levofloxacin shows favorable pharmacokinetics when compared to other flouroquinolones except from ofloxacin which has about the same pharmacokinetic belongingss.

Absorption: This is the rate at which a drug molecule is absorbed in the organic structure. Levofloxacin is readily absorbed by the GI piece of land when taken orally and both the unwritten and endovenous dosage are readily interchangeable because they have about the same plasma concentration profile. Administration of levofloxacin with nutrient slows down its soaking up and prolongs peak serum concentration by 1 hour which so reduces peak serum concentration by 14percent. When taken orally, absolute bioavailability is 99percent. ( Steven et al 1998 ) .

The bioavailability was observed in a survey carried out on some healthy, fast Mexican grownups who were given a 500-mg dosage of unwritten levofloxacin. At the terminal of the survey, these 1s met the regulative demands to presume absolute bioavailability based on the rate and extent of soaking up. ( Juan Francisco et Al 2009 )

Distribution: This indicated the concentration rates of the drug molecule in different parts of the organic structure over a certain period of clip. Levofloxacin concentrations in lung tissue has been reported to be higher than serum because it has a average volume of distribution runing from 1.09 to 1.26L/Kg after individual and multiple doses of 500-mg which indicates broad tissue incursion. Because of its minimum incursion into the cardinal nervous systems, levofloxacin is non really efficient in the intervention of meningitis and other CNS infections. . ( Steven et al 1998 ) . Further surveies have shown that liposomal-encapsulated levofloxacin increases its 200575299 BIOL5244

concentration in serum. This was observed in the pharmaceutical survey carried out by Martin et Al ( 2003 ) where Cipro delivered by liposomes was compared to the conventional type and the consequence shows that the liposomal encapsulated Cipro had higher concentration in serum, white blood cells and lung lavage fluid of a rat theoretical account of pneumococcal pneumonia.

Elimination: This involves the rate and signifier in which the drug molecule is cleared from the organic structure. Because it undergoes minimum metamorphosis, riddance of levofloxacin is unchanged in the piss. It is cleared chiefly by the kidney in worlds. Differences in pharmacokinetics in male and female, immature and old patients when accommodation is made for reduced nephritic map. As a consequence of its stereochemical stableness, when in plasma or piss, levofloxacin does non change over back to its active isomer D-Ofloxacin ( Steven et al 1998 ) .

Clinical tests and utilizations

A clinical test was carried out by Onyeji et Al ( 1998 ) to look into for the efficaciousnesss of levofloxacin and Cipro against S. pneumoniae in a mouse theoretical account of blood poisoning utilizing three isolates of different strains two of which are penicillin sensitive and one penicillin resistant. after four yearss of station infection with the different strains of SP, the per centum endurance following levofloxacin treated mice was more than Cipro treated mice.

Besides in a survey carried out by Bernardetta et Al ( 1999 ) to look into the bactericidal belongingss of levofloxacin compared with Cipro on clinical isolates on different types of Pseudomonas aeruginosa, it was observed that levofloxacin showed more disinfectant belongingss that Cipro. In order to find the mechanism of flouroquinolone induced abnormalcies in blood glucose, a clinical test was carried out in rats that receive endovenous doses of levofloxacin and their arterial blood was sampled sporadically. It was discovered that levofloxacin can bring on hypoglycemia and hyperglycemia in rats. ( Ishiwata et al 2006 ) .

Levofloxacin is presently approved in the usage of community acquired pneumonia, acute maxillary sinusitis, complicated urinary piece of land infection, acute bacterial excaberations of chronic bronchitis, acute pyelenonephritis. . ( Steven et al 1998 ) . The survey conducted by Pierluigi et Al ( 2006 ) to look into the major function of levofloxacin in the intervention of a instance of Listeria monocytogenes meningitis, it was concluded that levofloxacin unlike some other flouroquinolones may be a good option for the intervention of meningitis caused by the ague bacterium Listeria monocytogenes. 1109 patients were enrolled in a survey to compare levofloxacin 750 mg once-daily for five yearss with ciprofloxacin 400/500 mg twice-daily for 10 Dayss for the intervention of complicated urinary piece of land infections and acute pyelonephritis, and the consequence shows that both drugs are really effectual and a 5 twenty-four hours class of levofloxacin is non inferior to the 10 yearss class of Cipro ( Janet et al 2008 ) .

To buttress that survey every bit good Richard et al as cited by Steven et Al besides performed a combined trial to look into the effectivity of levofloxacin in the intervention of acute pyelenonephritis by comparing the consequence when administred aboard Cipro, and lomefloxacin to 259 patients enduring from acute pyelonephritis and the consequences besides 200575299 BIOL5244 confirmed that levofloxacin was every bit effectual as Cipro and lomefloxacin in the intervention of acute pyelonephritis.

A 750mg dosage of levofloxacin was besides tested against the 500mg dosage in the intervention of acute maxillary sinusitis in a survey carried out by Jack et Al ( 2006 ) and it was observed that the higher dosage had a short class in killing the pathogen. The safety and tolerability of levofloxacin was besides observed utilizing rat and mice as a instance survey and it was reported that no carnal drug-drug interaction, and it is non toxic in animate beings, it besides causes no damage of birthrate in animate beings and eventually no indicant to carcinogenic potency was seen in a two twelvemonth survey ( Tuberculosis ) .

Market portion of levaquin

The cost of levaquin extremely depends on the signifier and strength. The tablet signifiers comes in 250mg, 500mg, and 750mg which costs $ 41, $ 71, and $ 85 severally for 30.

Gross saless of levaquin overtook gross revenues of Cipro as a consequence of the enterprise taken by Johnson & A ; Johnson gross revenues forced with Omnicare between the periods covering 1999-2004. Omnicare inc. being the largest independent supplier of pharmaceutical merchandises represents about 30 % of the market portion and it has rapidly taken control of its concern unit buying maps. An illustration is the success it achieved in the gross revenues of levaquin. Levaquin moved from 12 % market portion in January 1999 to 41 % in June 1999 and at the terminal of 2001, market portion of levaquin had jumped to 66.1 % whereas the market portion of Cipro had plunged to 28 % from 80 % as at that clip. So it was alleged by the authorities/government that Johnson & A ; Johnson paid kickbacks to Omnicare in the signifier of discounts, grants and educational support.

Johnson generated about $ 1.6 billion merely from the gross revenues of levaquin which is about 6.5 % of their entire gross that twelvemonth and an 8 % addition over the old twelvemonth. In that same twelvemonth it was rated 37th in the top 200 most prescribed drugs and 19th in the universe gross revenues. At the terminal of the twelvemonth, levaquin gross revenues were in an surplus of $ 1.6 billion going the most prescribed flouroquinolone drug in that twelvemonth. Post selling surveillance was hard because levaquin was sold with different trade name names.

Dosage signifier of levaquin

Levaquin is available in different dose signifier runing from tablets, unwritten solution and endovenous in signifier of injection. The tablet signifier is available in 250mg, 500mg, and 750mg. The unwritten solution is available at 25mg/mL which is a multi-use ego continuing solution. The U.S Food and Drug disposal approved the new unwritten preparation of levaquin in 2004 for patients who have some trouble in get downing and despite new, it ‘s every bit effectual as the tablet and endovenous preparation in its antimicrobic activity and it provides continued dosing for renally impaired patients ( Raritan N.J 2004 ) . The endovenous signifier in the signifier of injection may look clear- xanthous to clear light-green coloring material but this does non impact its authority and activity.

Adverse effects

The most normally ascertained inauspicious consequence of levofloxacin is purging, giddiness, hurting at the injection site, concern, altered province, sickness, diarrhea ; levofloxacin besides appears to be responsible for few CNS perturbations. . ( Steven et al 1998 ) . Besides to buttress the consequence of levofloxacin on the CNS, Boonsong et Al ( 2008 ) raised an consciousness of a serious but rare side consequence of levofloxacin which is levofloxacin-induced craze ( besides known as acute confusional province ) with psychotic characteristics in a comparatively immature female. During the clinical tests of flouroquinolones, a survey was conducted to see the consequence of flouroquinolones on double vision in which a sum of 171 instances was reported after a median of 9.6days following drug therapy ( Fredrick et al 2009 ) which indicates that levofloxacin may do diplopia-which is a defect where two images are perceived as one.

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