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Clavulanic Acid
Jeremie Tapiero Montreal,Canada
ã2008Elvier Inc.All rights rerved.
Introduction
Clavulanic acid is ud with beta-lactama nsitive penicillins to protect them against
the hydrolysis of their beta-lactam ring and so rendering them effective against beta-lactama producing bacteria.Clavulanic acid was discovered in a microbiological screen
of fermentation broths intended to identify compounds that protect benzylpenicillin
against beta-lactama-producing bacteria Reading and Cole(1997).Beta-Lactamas hydrolyze the critical four-membered ring of penicillins Baggaley et al(1997)and cepha-losporins Marsh et al(1992),producing penicilloic acid derivatives and in the ca of cephalosporins,analogous degradation products,rendering them powerless as antibacter-
ials.Although clavulanic acid has only weak antibiotic properties,as potent beta-lactama inhibitor,it enhances the activity of beta-lactam antibiotics against many resistant Gram-positive and Gram-negative bacterial infections that resist penicillin mono-therapy by beta-lactama production Haginaka et al(1981).Clavulanic acid is then most often formulated
辞退证明in combination with antibiotics such as amoxycillin Brown et al(1976).
Nomenclature
Name of the Clinical Form Clavulanic acid
Related Names Source:EMTREE Clavulanic Acid;brl14151;clavulanate;clavulanic
acids;3(2hydroxyethylidene)7oxo4oxa1aza-
bicyclo[3.2.0]heptane2carboxylic acid;3(2hy-
droxyethylidene)7oxo4oxa1azabicyclo[3.2.0]
heptane2carboxylic acid;brl14151;3(2hydro-
xyethylidene)7oxo4oxa1azabicyclo[3.2.0]he-
ptane2carboxylic acid
Chemical Names Clavulanic acid:(3-(2-hydroxyethyldiene)-7-oxo-4-
oxa-1-azabicyclo[3.2.0]heptane-2-carboxylic
CAS Number58001-44-8
Basic Chemistry
Chemical Structure
Structure
Chemical Formula C8H9N O5
Properties
1
Physical Properties
The CA structure is very unstable,and
degrades rapidly under normal processing
conditions (3–4hours in solution after extraction).The influence of temperature on the adsorption process was investigated involving equilibrium and kinetic studies and carrying out batch shake experiments at four different temperatures with the
ion exchanger resin Amberlite IRA 400Barboza et al (2003).Molecular Weight 199.161
Solubility
Soluble in water
Human Pharmacokinetics
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Clavulanic acid is very water soluble,unstable and conquently difficult to extract from plasma.Samples can be stored at-80 C for no more than 3months and correct storage and handling of samples are esntial for accurate results.Plasma samples were first deprotei-nized with acetonitrile that was removed by extraction with dichloromethane.Several HPLC methods for the determination of clavulanic acid have been described after ultrafil-tration of plasma including precolumn derivatization and ion-pairing technology Ellis et al (2000).Recently,HPLC paration followed by lective mass spectrometric detection has been developed for simultaneous determination of amoxycillin and clavulanic acid in human plasma Yoon et al (2004).However,the instability of CA in the injection medium and long chromatography times made a high sample throughput by HPLC impossible and a simple and fast method for the determination of clavulanic acid in human plasma using a combination of different methods has been reported Ellis et al (2000).Pharmacokinetic Properties
Value
Units Prep.and Route of Admin.
Reference Comments
Absorption
The pharmacokinetics of amoxycillin /clavulanic acid (4:1)combination (Augmentin)was studied after i.v.,i.m.and oral administration Escudero et al (1998),Hoizey et al (2002).Following oral administration of
Augmentin,the absorption of amoxicillin and
clavulanic acid do not vary.However,the absorption of clavulanic acid
incread significantly when administered at the beginning of meals.Bioavailability
The bioavailability of
amoxicillin and clavulanic acid was 85%and 75%respectively.
Clavulanic Acid
2
Clavulanic Acid3 Distribution The mean ratio of amoxicillin
and clavulanic acids levels
distributed in cutaneous
tissue and rum was33%
and26%respectively;in
bile86and50%
洗衣机结构
respectively and in pleural
liquid71%and91%
respectively.Amoxicillin
and clavulanic acid were
also detected in peritoneal
liquid.Both drugs cross
the placenta barrier.While
amoxicillin is found in the
maternal milk,no data are
available for clavulanic
acid.
Volume of Distribution In adult after oral
administration of1000mg
amoxicillin and125mg
clavulanic acid,the peak
concentration of
amoxicillin in rum after
60–90minutes was13–15
mg/l and3–5mg/l for
无氧耐力
clavulanic acid,in50–60
minutes.In children after
五颜六色的意思
oral administration of
26.67mg/kg amoxicillin
and3.33mg/kg clavulanic
acid,the peak
concentrations are11.4
mg/l for amoxicillin and2.5
mg/l for clavulanic acid in
30–40minutes.In infants
after oral administration of
20mg/kg amoxicillin and
2.5mg/kg clavulanic acid,
the peak concentrations in
rum are7.5mg/l for
amoxicillin,and1.5mg/l
for clavulanic acid,in
30–60minutes.
Plasma Protein Binding As determined by
ultrafiltration17%for
amoxicillin,and22%for
clavulanic acid bind to
plasma protein.
Metabolism
Plasma Half-Life
Bio Half-Life
Clearance Following simultaneous
administration of1000mg
amoxicillin and125mg
clavulanic acid,the half life
elimination is60–70
minutes and55–65
minutes,respectively.It
was respectively55–100
minutes and55–80
minutes following
街舞达人administration of500mg
amoxicillin and 62.5mg clavulanic acid.
Routes of Elimination
The elimination of amoxicillin and clavulanic acid is
mainly through renal route.Each compound was
found in active form.After oral administration of 500mg amoxicillin and 125mg clavulanic acid,the
藤县中学
amount collected in urine during the first 6hours was 65%of the amoxicillin administered do and 30–45%of the clavulanic acid administered do.
Targets-Pharmacodynamics
Clavulanic acid rapidly and irreversibly inhibits most of beta-lactamas produced by Gram positive and Gram negative bacteria.It can bind irreversibly at the active center of beta-lactama to the hydroxyl group of rine to produce a stable acylated intermediate leading to the inactivation of the enzyme Aharonowitz and Demain (1978).Thus the association of amoxicillin and clavulanic acid is active against a great number of bacteria including tho that are resistant due to beta-lactamas cretion,particularly of peni-cillina type.This association is active in bacteria that are naturally resistant to amoxi-cillin such as Klebsiella ,Proteus vulgaris ,Bacteroides fragilis or in bacteria with acquired resistance such as Staphylococcus ,gonococcus,Haemophilus influenzae ,Escherichia coli ,and Proteus mirabilis .Target Name(s):
Beta-Lactama
Gram-positive and Gram-negative bacteria nsitive or resistant to beta-lactam antibiotics
Therapeutics
Many pathogenic bacteria crete beta-lactamas as defen mechanisms against the widely ud beta-lactam antibiotics.Most of the antibiotics can penetrate the mycobac-terial cell wall and have affinity for penicillin binding proteins (PBP)Casals et al (1986),W ong et al (1998).Thus,Mycobacteria tuberculosis was found susceptible to some beta-lactam antibiotics and penetration of macrophage had been at suitable levels Chambers et al (1995).According to the W orld Health Organization (WHO)reports,8million people are infected with tuberculosis and 3million people die each year due to the increasing number of Multi Drug Resistance (MDR)strains Cohn et al (1997).The ri in the incidence of tuberculosis and the problem of MDR strains to beta-lactam antibiotics Sorg and Cynamon (1987),Medeiros (1997)was related to beta-lactama production and the impermeability to beta-lactams due to the lipid rich outer cell wall Zhang et al (1992).The in vitro efficacy of various beta-lactam and beta-lactama inhibitor combinations against M.tuberculosis particularly the isoniazid and rifampicin multidrug resistant
Clavulanic Acid
4
Clavulanic Acid5 clinical isolates has been shown Dinc¸er et al(2004).Penicillin G,amoxicillin,ampicilli
n, cefazolin,cephalothin,cefaclor,cefuroxime,ceftazidime,cefotaxime,cefepime,and meropenem were ud in combination with the beta-lactama inhibitors(clavulanic
acid,tazobactam,and sulbactam).The minimum inhibitory concentration(MIC)of
beta-lactam antibiotics for M.tuberculosis was reduced when combined with beta-lactama inhibitors Dinc¸er et al(2004).Therefore,beta-lactama inhibitors are of potential clinical importance.Clavulanic acid(CA),a condary metabolite of Streptomyces clavuligerus is a potent beta-lactama inhibitor and its application in conjunction with penicillin has proved to be a successful in countering the problem of resistance to antibiotics Baggaley et al(1997).
Indications
Value Units Prep.and Route of Admin.Reference Comments
Dosage
Adver Effects
Allergic reaction to Clavulanic acid with good tolerance to other beta-lactam antibiotics Fernandez-Rivas et al(1995).
Other Rearch Information
The biosynthesis of clavulanic acid involves many more steps than the penicillin forma-
tion.Non-heme iron oxygenas are the only step common to both pathways,but,they
appear to have little evolutionary relationship Marsh et al(1992).In the cour of clavulanic acid formation,clavaminate syntha(CS),a member of the non-heme iron
alpha-ketoglutarate(alpha-KG)-dependent oxygenas,catalyzes three distinct and non-quential oxidations Solomon et al(2000),Ryle and Hausinger(2002).Moreover,the formation of the beta-lactam ring of clavulanic acid takes place early in the pathway through the action of a new kind of enzyme,a beta-lactam syntheta(beta-LS)Bachman
et al(1998),McNaughton et al(1998).The primary quences of the proteins show
clear evolutionary relation to asparagine synthetas.The first committed step in clavu-
lanic acid biosynthesis gathers two intermediates from primary metabolism in the pres-
ence of thiamine diphosphate(TDP)to carry out transformation to initiate the biosynthetic pathway.
Journal Citations
Aharonowitz,Y.,Demain,A.L.,1978.Carbon catabolite regulation of cephalosporin production in
Streptomyces clavuligerus.Antimicrob.Agents Chemother.,14,159–164.
Bachmann,B.O.,Li,R.,Townnd,C.A.,1998.-Lactam syntheta:a new biosynthetic enzyme.Proc.Natl.
Acad.Sci.USA,95(16),9082–9086.
Baggaley,K.H.,Brown,A.G.,Schofield,C.J.,1997.Chemistry and biosynthesis of clavulanic acid and other
clavams.Nat.Prod.Rep.,14(4),309–333.
99宿舍四级查分Barboza,M.,Almeida,R.M.R.G.,Hokka,C.O.,2003.Influence of temperature on the kinetics of adsorption
and desorption of clavulanic acid by ionic exchange.Biochem.Engineeing J.,14(1),19–26.
Brown,A.G.,Butterworth,D.,Cole,M.,Hanscomb,G.,Hood,J.D.,Reading,C.,Rolinson,G.N.,1976.
Naturally-occurring beta-lactama inhibitors with antibacterial activity.J.Antibiot.,29,668–669.

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