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plasma lev els (usu ally fol low ing rapid IV bolus) (MW 225.2; as sodium salt for IV infusion MW 247.2) and pre-ex ist ing re nal dis ease. Note: Crys tal li - Syn onyms: Acyclovir, Acycloguanosine.
za tion oc curs ex clu sively af ter (rapid) IV ad - Usual dos age: Size of dose and dos age in ter - min is tra tion (re nal ac cu mu la tion of the drug).
val de pend on route of ad min is tra tion, age These fea tures are re vers ible or pre vent able with ad e quate fluid re ple tion, re duced acy -clovir dose and slow in fu sion rates (at least 1 hr). In rare cases, fo cal in ter sti tial in flam ma - GI fate: Fol low ing oral ad min is tra tion, ab sorp - tion with out tu bu lar ne cro sis, con sist ing of in - ter sti tial hem or rhages, con ges tion of lym pho - bioavailability is about 20% (range 15 – 30%).
cytes and plasma cells has been ob served See also valaciclovir. PPB range 9 – 22% Neurotoxic (neu ro psy chi at ric) symp toms ap - Dis tri bu tion and me tab o lism: At steady-state, pear ing dur ing aciclovir (and valaciclovir) ther - aVD is ~ 0.8 l/kg; dis tri bu tion to all tis sues apy have re peat edly been rec og nized [294, 412, 830] and are re ported in pa tients with (conc. 10 times that in plasma). Only a small acute or chronic re nal fail ure [31, 345, 643, amount (15% of a dose) is con verted to the in ac - 733, 741, 827]. These un usual ad verse ef - tive 9-carboxymethoxymethylguanine (CMMG), the only sig nif i cant me tab o lite in man.
Elim i na tion: Pre dom i nantly ex creted in the Dos age in re nal in suf fi ciency and di al y sis urine via glo mer u lar fil tra tion and tu bu lar se - cre tion; more than 80% of a dose is ex creted è Dos age ad just ments are rec om mended! un changed, only lit tle (9 – 14%) is found as in -ac tive, ox i dized me tab o lite CMMG; re In se vere re nal im pair ment (CKD Stage 5GFR < clear ance is about 75 – 80% of to tal body clear ance and al most 3 times greater than times elim i na tion t1/2 in nor mal sub jects; aVD CrCl (250 ml/min). Up to 2% of a dose is ex - was de creased by 20% and to tal body clear - ance was only 10%, which rep re sents non-re - short (2 – 3 hrs). The ther a peu tic ac tion of aciclovir in in fected cells de pends on con ver - func tion de creases, a unique sit u a tion de vel - ops where a greater part of the drug is con - monophosphate to ac ti vated aciclovir tri phos - verted to the me tab o lite. In ESRD the drug is prob a bly elim i nated en tirely by hepatic trans -for ma tion to the me tab o lite but the elim i na - tion of the me tab o lite in the urine is lim ited. It would, there fore, be ex pected to ac cu mu late.
12 – 79% [707]. Aciclovir is rap idly ex creted in How ever the clin i cal sig nif i cance of such ac cu - mu la tion is not known. In all cases of re nal im - Its con cen tra tions in re nal tis sue can ex ceed pair ment, dos age ad just ment is nec es sary.
10 times that in plasma. The con cen tra tion of Dur ing parenteral ad min is tra tion, ad just dos - the drug in re nal col lect ing ducts may ex ceed the drug’s sol u bil ity lead ing to crys tal li za tion l In CKD Stage 3GFR 59–30, give usual dose ev - in re nal tu bules (ob struc tive crys tal nephro - l in CKD Stage 4GFR 29–15, give usual dose ev - may rise, typ i cally within 24 – 48 hrs af ter on - l in CKD Stage 5GFR <15, give half the usual set of treat ment. Ma jor risk fac tors for tran - dose ev ery 24 hrs or usual dose ev ery 48 hrs. Al ter na tive: Keep the dos age in ter val the same (8 hrs) and re duce the dose per in - ter val; an ini tial load ing dose (usual dose or half of usual dose) may be use ful. The ad - Usual dos age: Dif fers, ac cord ing to the route van tage of this sched ule is that it min i mizes sim i lar mean plasma con cen tra tions.
Oral doses (against varicella-zoster in GI fate: Readily ab sorbed; fol low ing sublingual tions) may be re duced to the fol low ing: ad min is tra tion, ab sorp tion is rel a tively slow, l In CKD Stage 4GFR 29–15, give 800 mg 3 plasma lev els peak within 3 – 4 hrs; sub stan - tial first-pass me tab o lism al ready in the gut l in CKD Stage 5GFR <15, give 800 mg ev ery 12 hrs, and for her pes sim plex 200 mg ev ery availability 16% of the dose af ter oral and 55% of the dose af ter sublingual in take; PPB 95 – Hemodialysis: Aciclovir is readily re moved by 98% (very high); very short plasma t1/2, a few 6 hrs, di al y sis clear ance 820 – 113 ml/min Me tab o lism: Partly me tab o lized via CYP3A4 (with con ven tional mem branes), and re duc - to form norbuprenorphin (less ac tive than the tion of plasma lev els dur ing one HD was about glucuronic acid (par ent drug and me tab o lites). uBe tween di al y ses, half the usual dose ev ery Buprenorphine is highly lipophilic. In an es the - 24 hrs and re place ment of 60 – 100% of tized pa tients, lower plasma lev els and a lower the load ing dose af ter each HD. In the event clear ance by ~30% have there fore been re - of se vere neurotoxicity and nephro toxicity ported, im ply ing lower ini tial vol ume of dis tri - due to over dose, re moval by one or sev eral Elim i na tion: Fol low ing oral ad min is tra tion, CAPD: The clear ance by PD and CAPD is low, mostly ex creted in the fe ces (~ 70% of an oral CAPD clear ances of 3 – 8 ml/min and elim i na - dose), mainly un changed; ~ 15% of the dose tion t1/2 of 15 – 17 hrs have been ob served can be found in the urine, as me tab o lites. Af - [710, 1271, 1352]. Fol low ing IV in fu sion, the ter parenteral ad min is tra tion, 68% of the dose peritoneal dialysate re cov ery was 6 – 11% of a is found un changed in the fe ces and about dose de pend ing on the con cen tra tion of glu - 27% in the urine as me tab o lites. Elim i na tion t1/2 3 hrs. Be cause the drug is mostly ex creted l Dos age in CAPD pa tients as in pa tients with in fe ces, an entero-hepatic cir cu la tion is likely.
se rum creatinine > 7 mg/dl (CrCl 15ml/min); no sub sti tu tion nec es sary [1433].
Dos age in re nal in suf fi ciency and di al y sis In view of the pos si ble ef fi cient trans fer of è No dos age ad just ments nec es sary! peritoneal ad min is tra tion has been pro -posed [169, 233].
Since the agent is cleared mainly by hepatic l For pre ven tion of cytomegalovirus dis ease ex trac tion (via bile in the fe ces) and me tab o - lism, elim i na tion is not de pend ent on re nal func tion, al though me tab o lites are ex creted [90, 912]. These drugs should how ever be partly in the urine. In a clin i cal study [601], buprenorphine ki net ics were sim i lar in an es - with drawn at the first sign of re nal tox ic ity.
the tized healthy pa tients and those with re nalim pair ment re gard ing half-lives, aVD andclear ances, but plasma lev els of the me tab o -lites were el e vated in pa tients with re nal im - pair ment (norbuprenorphin 4 times and the Fe cal elim i na tion may orig i nate from three sources. Fol low ing oral ad min is tra tion, about l Usual doses may be given in all de grees of half of the amount in fe ces orig i nates from the re nal in suf fi ciency [601, 1452].
non-ab sorbed drug (not fol low ing IV ad min is - No data avail able re gard ing re moval by HD tra tion). Some drug ex cre tion via bile is to be and PD, but re moval is un likely be cause of ex pected. A third and con tro ver sial route of elim i na tion is the transluminal ex cre tion of No sub sti tu tion re quired dur ing and af ter di al - ciprofloxacin across the bowel mu cosa into Dos age in re nal in suf fi ciency and di al y sispa tients: è Dos age ad just ments are rec om mended! Ciprofloxacin is elim i nated pri mar ily by re nal ex cre tion; how ever, the drug is also me tab o - Usual dos age: 250 – 750 mg twice daily by lized and partly cleared through the biliary sys - mouth or 200 – 400 mg IV 2 – 3 times daily, re sult ing in peak plasma lev els in the range of These al ter na tive path ways of drug elim i na - 3 – 5 mg/l (the peak plasma lev els re quired to tion ap pear to com pen sate for the re duced re - achieve the tar get AUC are 2.5 – 3.5 mg/l). In nal ex cre tion in re nal pa tients. As a con se - crit i cally ill pa tients with se vere sep sis 400 mg quence, el e vated elim i na tion t1/2 of up to 12 IV 3 times daily has been used [898].
hrs have only been ob served in pa tients withCKD stage 3 to 4GFR 59–15. It is sug gested that in pa tients with im paired re nal func tion there GI fate: About 75% of an oral dose is ab may be a vari able in crease in elim i na tion of sorbed, mainly from the in tes tine; plasma lev - els peak within 30 – 90 min; PPB 20 – 40%; above: Elim i na tion). This vari abil ity in the most of the ab sorbed drug can dif fuse into the route of elim i na tion leads to some un cer tainty extravascular space; aVD un der steady-state con di tion 2 – 3 l/kg (very high), con cen tra - ciprofloxacin in re nal pa tients, es pe cially for tions in tis sues and body flu ids higher than in those pa tients with life-threat en ing in fec tions plasma; be cause of ini tial first-pass ef fect in the liver oral bioavailability is ~65% (range 45– 84%).
Rec om mended dos age guide linesl In pa tients with CKD stage 2 to 3 Me tab o lism: 12 – 20% of the dose is con - min is ter usual doses with cau tion.
verted to a min i mum of 4 me tab o lites, 3 pos - sess lower ac tiv ity than the par ent drug, one is half a usual oral dose twice daily or a usual oral dose (500 mg) ev ery 18 hrs or an IV dose up to 400 mg ev ery 18 – 24 hrs.
>10% as me tab o lites) or 75% of an IV dose life-threat en ing in fec tions ad min is ter a (63% un changed and >10% as me tab o lites),via glo mer u lar fil tra tion and re nal tu bu lar se -cre tion; re nal ex cre tion greatly ex ceeds CrCl. A smaller quan tity ap pears in the fe ces (39% ofan oral dose, or 14% of an IV dose); most ofthe drug is ex creted un changed, only 12 –20% as me tab o lites (see above); elim i na tiont usual ini tial dose, sub se quent doses (twice In pa tients with CKD stage 5GFR <15 (ESRD) un - uGolper et al. [1689] stud ied ciprofloxacin der di al y sis, elim i na tion by HD and PD is sub - be hav ior in sta ble CAPD pa tients (oral dose of 750 mg ev ery 12 hrs for 4 doses. Peakplasma lev els ranged from 2.9 – 6.4 mg/l; Hemodialysis: Even though the HD clear ance clear ance by CAPD was 2% of the to tal body is ~40 ml/min, nor mal elim i na tion t1/2 has (sys temic) clear ance; si mul ta neous ra tios been re ported on day of di al y sis. Thus, l ad min is ter usual oral dos age on day of di al - 0.57 within a dwell time of 4 hrs and 0.75 y sis (2 doses, one dose af ter di al y sis) but re - within a dwell time of 8 hrs. Long-dwell ex - duce oral dos age be tween di al y ses to 250 – changes may be nec es sary to achieve rea - son able dialysate con cen tra tions of oral CAPD pa tients: Ciprofloxacin is ac tive against var i ous strains of aer o bic gram-pos i tive mi cro - or gan isms and against most strains of aer o bic use of oral ciprofloxacin for the first-line gram-neg a tive mi cro or gan isms. Be cause the treat ment of CAPD peri to ni tis. Fif teen in fec - pre dom i nant prob lem in CAPD pa tients is peri - tious ep i sodes im proved within the first 48 hrs and a cure rate of 70% was re corded by patho gens, the drug has fre quently been used in peri to ni tis. Due to its high ef fi cacy it be - came a first-line an ti bi otic against CAPD peri - kinetics of oral ciprofloxacin (750 mg twice to ni tis. It is ap plied orally, by IV in jec tion or IP within 12 hrs) in CCPD pa tients with peri to - (in the dialysate of the bags). How ever, pub - ni tis. Mean ter mi nal t1/2 was 10 hrs, mean lished data are con tro ver sial, es pe cially re - gard ing route of ad min is tra tion and pen e tra - the mean cal cu lated to tal body clear ance.
brane. Dos age guide lines are not well de fined and there fore in this ar ti cle re sults from clin i - to be use ful for em pir i cal gram-neg a tive cal tri als are used to eval u ate treat ment mo - cov er age of CCPD peri to ni tis (sen si tive E.
uIn a re cent study [1702], 95 ep i sodes of peri to ni tis in 54 pa tients on CAPD or CCPD uFol low ing a sin gle dose of 750 mg, Shalit et al. [1665] found in CAPD pa tients with peri - ciprofloxacin and IP cefazolin. The cure rate to ni tis a pro longed mean ter mi nal t1/2 of was al most 90% of pos i tive cul tures.
uIn a multicenter study by Goffin et al.
though the peritoneal fluid con tained 64% [1706], the ef fi ciency of a si mul ta neous ad - of the plasma con cen tra tion of the drug, in - min is tra tion of IV vancomycin 15 mg/kg, and oral ciprofloxacin 250 mg twice daily drug was re moved con tin u ously via CAPD above 3 ml/min) was eval u ated in PD pa - peak ef flu ent peritoneal fluid 1.3 mg/l). In a tients suf fer ing from peri to ni tis. In gen eral, sub se quent study [1695], the au thors de - rived trough peritoneal fluid con cen tra tions and ciprofloxacin dur ing 10 days or weeks.
12-hourly for sev eral days They sug gested whether the sys temic route of ad min is tra - tion of the an ti bi ot ics was an al ter na tive to other in fec tions in CAPD pa tients, ad min is - the usual and in con ve nient IP drug ap pli ca - tra tion of oral ciprofloxacin should be lim - vacomycin and oral ciprofloxacin ad min is - tra tion is a sim ple and ef fi cient first-line pro - duce an op ti mal ther a peu tic ef fect.
to col an ti bi otic ther apy for peri to ni tis, and uIn a multicenter study in the Neth er lands oral ciprofloxacin pro vides sat is fac tory re - [1701], 98 out of 367 CAPD pa tients de vel - sults in gram-neg a tive in fec tions, com pared oped peri to ni tis, 44 of whom were treated with IP ciprofloxacin plus rifampicin (each uLeblanc [1667] de scribed 3 cases of peri to - ni tis in CAPD pa tients who were suc cess - fully treated with oral ciprofloxacin.
bag). Ini tial and late clin i cal suc cesses were50% and 37% in the cephradine group andin 75% and 64% in the cipro floxa cin/ Intraperitoneal ad min is tra tion rifampicin group. Bac te ri o log i cal suc cess in uOne group [1697,1698,1699], used IP ad - the group treated em pir i cally oc curred in min is tra tion (25 or 50 mg/l in each bag over 30% of the cephradine group and in 59% in sev eral days) in CAPD pa tients with peri to ni - tis; mean plasma con cen tra tion 0.3 and 1.1 uOne study [1703] com pared oral ver sus IP mg/l, mean con cen tra tion in the ef flu ent ciprofloxacin as pri mary treat ment of bac te - dialysate 6.1 and 10.0 mg/l, re spec tively.
The 25-mg/l ther apy was suc cess ful in 79% sodes in 46 pa tients); pri mary care rate was of the ep i sodes, and the 50-mg/l ther apy ~42% in the oral group and ~67% in the IP was suc cess ful in 83% of the ep i sodes.
group. The au thors fa vour IP treat ment and uIn one re port [1700], an IP load ing dose of rec om mend 50 mg/l per bag in stead of 25 ciprofloxacin was given for 24 hrs, si mul ta - neously the drug was given orally and there - uIn a pro spec tive, ran dom ized, con trolled af ter only orally; mean dialysate con cen tra - trial with 40 CAPD pa tients, IP ciprofloxacin tions were ini tially ~6 mg/l which de creased was shown to be as ef fec tive as the cur - sub stan tially dur ing the course of the treat - rently rec om mended reg i men of IP vanco - mycin and gentamicin for treat ment of peri - uPharmacokinetics of IP ciprofloxacin were to ni tis, and has ad van tages over the oral in ves ti gated in 6 non-in fected CCPD pa tients [1661]. A load ing dose of 25 mg/l in uPérez-Fontán et al. [1668] an a lyzed 682 ep - the dialysate of 4 short-dwell ex changes re - i sodes of bac te rial peri to ni tis treated with IP sulted in dialysate lev els of 21 – 13 mg/l hrs). In the sub se quent last bag, de void of (1988 – 2007). Fol low ing sat is fac tory early the drug, a peak level of ~1.4 mg/l was ob - re sults, the ef fec tive ness of ciprofloxacin as served at 30 min. In stil la tion of 100 mg/l in a monotherapy in PD-re lated peri to ni tis has the last bag yielded peak dialysate lev els of de clined mark edly in the long-term for not 99 mg/l, fall ing with a t1/2 of 3.3 hrs to wards lev els of 2 mg/l at ~20 hrs. In stil la tion of 25mg/l ciprofloxacin in the last bag yielded a Al though fre quently and of ten suc cess fully peak level in the dialysate of ~22 mg/l, fall - used, var i ous in ves ti ga tors state that oral and ing with a t1/2 of 3.9 hrs to wards dialysate IP ad min is tra tion of gyrase in hib i tors, such as lev els of <2 mg/l at 15 hrs. The rapid ab - ciprofloxacin, have not been en dorsed as a sorp tion of the drug from the dialysate into first line treat ment of peri to ni tis com pli cat ing the tis sues means that ciprofloxacin has to CAPD, partly due to fail ure or re lapse be cause be added to all CCPD bags to en sure bac te - of re sis tant gram-pos i tive bac te ria. Con cern - ri cidal dialysate lev els; on the other hand, such high an ti bi otic con cen tra tions, even ences in the rate of dif fu sion through the peri - though they are of short du ra tion, at the in - to neum in both di rec tions, from the vas cu lar sys tem and from the peritoneal cav ity, in the ties, in clud ing au to im mune hemo lytic ane mia case of peri to ni tis where the dif fu sion through [1677, 1679]. Nearly all pa tients de vel op ing the in jured peri to neum is higher when com - acute re nal fail ure were over 50 years of age.
pared to the non-in fected sit u a tion. The frac - Other risk fac tors were high doses of the drug tion of the ad min is tered dose of the drug re - (over dose) [1687], in ad e quate hydration, as moved by CAPD or CCPD is < 2% of the dose.
well as the use of other nephrotoxic drugs and Al though the low peritoneal clear ance has al - the pres ence of other pro cesses likely to con - trib ute to re nal dam age such as di a be tes.
A very few cases of crys tal nephropathy have within or around the in fected peri to neum are the key fac tors in the treat ment of peri to ni tis.
1688]. Al though ex per i men tal stud ies in di -cated that crystalluria may be as so ci ated with CRRT in ICU: Us ing mod i fied CVVHDF (QD and ciprofloxacin [1684, 1687], the likelyhood in QF 1 – 2 l/hr), based on in-vi tro cal cu la tions hu mans was be lieved to be very low be cause 300 mg IV was in jected twice daily, 60 min af - ter ini ti a tion of CRRT [628]. The mean AUC pended on a urine pH >6.8. In the mean time, reached a level higher than the tar get AUC, cases of crystalluria in hu mans have oc curred and in fec tions were suc cess fully con trolled.
with a urine pH <6.6 and <6.0. In the case of Other dos age reg i mens: Us ing CVVHD (QD 1 – de creas ing re nal func tion dur ing quinolone 2 l/hr, QUF 1 l/hr) or CVVHDF (QD 1 l/hr, QUF 1 – treat ment a uri nary sed i ment anal y sis is man - 2 l/hr) 200 mg IV was given 2 – 3 times daily treated with ei ther CVVHF or CVVHDF. All pa - In or der to eval u ate the prev a lence and in ci - tients re ceived IV in fu sions of 400 mg once dence of ciprofloxacin nephrotoxicity, Burke et daily which was suf fi cient to main tain ef fec - al. [236] asked 4,253 stu dents to take one tive drug con cen tra tions in plasma [1691].
oral dose of 500 mg ciprofloxacin and about3,200 stu Fluoroquinolones are gen er ally well tol er ated.
Ad tract, CNS, and skin. Ciprofloxacin and a fewother quinolones are po ten tially nephrotoxic A widely un rec og nized and even ig nored prob - which has to be taken into con sid er ation when lem re gard ing drug treat ment in re nal pa tients the drug is given to pa tients with im paired re - is that all phos phate bind ers also bind orally nal func tion. It should be noted that the po ten - ad min is tered drugs (Prob lem 1). In this con - tial nephrotoxicity of the drug may worsen ex - text, a sec ond se ri ous prob lem is that data on ist ing re nal func tion and im pair any re sid ual ab sorp tion ex ists only for a few drugs (Prob lem 2). A mi nor prob lem is that phar ma ceu ti cal Two re views of case re ports of re nal tox ic ity as - com pa nies are not able to or are not asked by so ci ated with ciprofloxacin in di cated that such the au thor i ties to show ab sorp tion rates for tox ic ity, al though po ten tially se ri ous, was rare drugs us ing their phos phate bind ers (Prob lem [1688, 1693]. In deed, all pub li ca tions con tain 3). A fur ther prob lem is that drugs can not dis - case re ports only whereas se ries of pa tients with re nal dam age have not been pub lished.
com pletely chem i cally bound al ready in the GI mune-me di ated in ter sti tial ne phri tis or rarely A po ten tial prob lem with the in creas ing use of acute tu bu lar ne cro sis, with out or with (re vers - quinolone-type an ti bi ot ics is the chelation and ible) acute re nal fail ure [236, 1670, 1677, in ac ti va tion of these com pounds by sev eral 1671, 1672, 1673, 1674, 1676, 1678, 1682, cat ions in con com i tantly ad min is tered med i ca - 1683, 1693], and he ma to log i cal ab nor mal i - tion. In sol u ble che late com plexes are formed be tween the cat ions and the drug, re sult ing in and 10 – 15% as ac tive or in ac tive me tab o - dra mat i cally re duced bioavailability of the lites; elim i na tion t1/2 4 – 7 hrs.
agent. One of the best in ves ti gated drugs inthis re spect is ciprofloxacin. About ~50% of an Dos age in re nal in suf fi ciency and di al y sis oral dose (range 22 – 76%) [1690] is bound when given to gether with cur rently used phos - è Lim ited data avail able, but dos age phate bind ers, such as cal cium-, mag ne sium-, and alu mi num-con tain ing salts as well as thecationic poly Elim i na tion t1/2 is pro longed in re nal im pair - (most likely also sevelamer car bon ate), and lan tha num [673, 1694, 1663, 1690, 1662, l Usual doses can be given in CKD Stage 2 to 1664, 1689]. This lo gis tic prob lem was de - scribed for ciprofloxacin shortly af ter its in tro - l re duce dos age by 25% in CKD Stage 4GFR duc tion [1689, 1696]. Fol low ing oral ad min is - l give 50% of the usual dos age in ESRD (CKD ciprofloxacin in the dialysate achieved in CAPD pa tients on phos phate bind ers were 8 – 33% of those ob served in sub jects not re ceiv - No data avail able re gard ing re moval by HD should be avoided in all di al y sis pa tients, al - The most fea si ble and safe so lu tion to over - though some sources rec om mend dose ad - come this com plex se ries of prob lems is to al - just ment in HD and no dose ad just ment in ter the dos age reg i men in the pa tients. It is be - com ing com mon prac tice to take phos phatebind ers to gether with the meals (for ac tualand con tin u ous phos phate bind ing) and to in -gest other pre scribed drugs 2 hrs be fore or af - ter meals. Phos phate bind ers should be with - (MW 345.4; for oral application used as magnesium salt MW 767.2, for IV injection used as sodium salt MW 368.4) GI fate: Be cause esomeprazole is acid-la bile, med i ca tions are pro vided in an en teric-coated first-pass me tab o lism; PPB >70%; bio avai la - gran ule for mu la tion. Ab sorp tion is rapid, plasma lev els peak within 1 – 2 hrs. Fol low ing Me tab o lism: Con verted in the liver by hepatic a sin gle dose, ab so lute bioavailability (com - P450 isoenzyme to its prin ci pal ac tive me tab - pared to IV ad min is tra tion) is ~ 65%, fol low ing o lite; both are widely dis trib uted, and tis sue main te nance treat ment (20 – 40 mg daily), ab so lute bioavailability is ~ 90%, much higher part be cause of intracellular up take.
be cause of a sat u ra ble first-pass ef fect. PPB Elim i na tion: At steady-state up to 55% of the is ap prox i mately 97%; plasma t1/2 in healthy dose is ex creted in the urine, 40% un changed sub jects 1.3 hr; aVD 0.25 l/kg (small).
Me tab o lism: Esomeprazole is al by HD and PD, but re moval is un likely due to pletely me tab o lized in the liver, pri mar ily by CYP2C19 and to a lesser ex tent by CYP3A4.
l Usual doses may be given in CKD stage 2 to Note: As with many other drugs, there are 3 prob lems with esomeprazole in re nal im pair - l it is pru dent to avoid ad min is tra tion in CKD such as CYP2C19 and CYP3A4, ex hibit a ge - l in di al y sis pa tients give min i mal doses or netic poly mor phism due to their de fi ciency in avoid ad min is tra tion be cause of lack of ex - some sub-pop u la tions (poor metabolizers). In re nal im pair ment, 1. esomeprazole me tab o - Be cause of the po ten tial nephrotoxicity of the lism may not only be de layed be cause of ac cu - drug it is ad vis able to eval u ate re nal func tion mu la tion of me tab o lites not yet ex creted, but pe ri od i cally in pa tients with out re nal im pair - 2. may also be slow in poor metabolizers. If drugs are ad min is tered con com i tantly which 3. use the same CYP450 isoenzyme for me -tab o lism (po ten tial CYP450 in hib i tors), thesein hibit con ver sion of esome prazole. Thus, avoid such in hib i tory drugs in re nal pa tients.
Var i ous cases of omeprazole-in duced acute (toxic) in ter sti tial ne phri tis have been re - ~80% of the dose as in ac tive me tab o lites, ported. Since esomeprazole is an iso mer of <1% of the dose un changed; the re main der is omeprazole, the same has to be an tic i pated found in the fe ces, also as in ac tive me tab o - for esomeprazole, but so far only one case has been pub lished [527].
Pro ton pump in hib i tor-re lated acute in ter sti -tial ne phri tis is rare, id io syn cratic, and dif fi cult Dos age in re nal in suf fi ciency and di al y sis to pre dict. Dur ing the pe riod 1970 – 2006, 64 cases were pub lished, 59 cases con firmed by è No, or lim ited data avail able, but dos age ad just ments ad vis able! Ac cord ing to the man u fac turer, pharmaco -kinetics in pa tients with im paired re nal func - tion are not ex pected to be al tered rel a tive to healthy vol un teers, as <1% of the dose is ex - creted un changed in the urine. There fore hisad vise is that usual doses can be given to all Usual dos age: Ini tially 50 mg once daily by dose range of 100 – 300 mg/day in two di - This state ment, how ever, is in need of cor rec - vided doses; not to ex ceed 300 mg per day.
tion. The rea son for this is that in se vere re nalim pair ment in ac tive me tab o lites will ac cu mu -late, and there is no in creased re moval by the in tes tine will com pen - GI fate: Readily ab sorbed; plasma lev els peak sate for the ac cu mu la tion. More over, ac cu mu - within 3 – 8 hrs; plasma t1/2 15 hrs; ab so lute la tion of the me tab o lites leads to a slow ing bioavailability 53% of the dose; PPB 80%; down of me tab o lism of the par ent drug its ac - mean aVD ~25 l/kg (ex tremely large), sug - cu mu la tion, and the risk of se ri ous ad verse or gest ing ex ten sive tis sue dis tri bu tion.
toxic ef fects. UK li censed prod uct in for ma tion Me tab o lism: Ex ten sively me tab o lized by the ad vises cau tion in pa tients with CKD stage 4 liver; 9 me tab o lites have been iden ti fied, con - to 5GFR ≤29, as ex pe ri ence in these pa tients is sti tut ing ~85% of the uri nary ex cre tion prod - lim ited. No data avail able re gard ing re moval Elim i na tion: Al most com pletely ex creted in the urine (94% of the dose), ~2% un changed, the re main der as me tab o lites. Elim i na tion t1/2 Syn onyms: Glybenzcyclamide, Glyburide Dos age in re nal in suf fi ciency and di al y sis mouth; if nec es sary in creased by 2.5 mg daily è No, or lim ited data avail able, pro posed dos age ad vice is pre lim i nary! Fol low ing treat ment with 50 mg fluvoxamine Sec ond-gen er a tion sulfonylurea with much twice daily for 4 and 6 weeks in pa tients with dif fer ent de grees of re nal im pair ment (CKD stage 3 to 5GFR ≤59), min i mum plasma con cen - GI fate: Al most com pletely ab sorbed; plasma tra tions of the par ent drug are com pa ra ble, lev els peak within 4 hrs; PPB >97%; plasma sug gest ing that in re nal pa tients ac cu mu la - t1/2 2 – 2.5 hrs; aVD 0.1 l/kg (very small).
Me tab o lism: The drug is al most com pletely In view of the fact that the drug is elim i nated con verted by hepatic me tab o lism to hydroxy glibenclamide and 2 mi nor me tab o lites, which seems ques tion able. Most of the drug is re - moved as (un mea sured) me tab o lites in these glycemic ac tion since they are al most in ac tive pa tients, and only 2% of the dose are re moved (<10% of the po tency of the par ent drug).
un changed from the plasma but any pre cise Elim i na tion: 50 – 55% of the dose ex creted mea sure ment of such low con cen tra tions is also ques tion able. In this con text and in con - changed; about 45 – 50% ex creted via bile in trast to pharmacokinetic ob ser va tions, ac cu - the fe ces, mainly as me tab o lites, 4 – 6% un - mu la tion of me tab o lites in pa tients with se - changed. Elim i na tion t1/2 8 – 10 hrs.
vere re nal fail ure un der long-term treat ment is likely and must be an Dos age in re nal in suf fi ciency and di al y sis quence is a con cen tra tion-bal anced slow- down of me tab o lism of par ent drug and pos si ble ac - è Dos age ad just ments are ad vis able! Be cause of a com pen sa tory in crease in ex cre - tion via bile in the fe ces, no clear cor re la tion was found be tween par ent drug and its me - l ad min is ter a usual dose of 50 mg once a ciency; also hemodialysis did not af fect the dose care fully ac cord ing to clin i cal re - pharmacokinetics, fol low ing sin gle or mul ti ple l no dos age re duc tion is re quired in re nal in - and in all di al y sis pa tients (not data avail - How ever, in CKD stage 4GFR 29-15, some de layin ex cre tion has to be an tic i pated; there forel avoid us ing the drug in ESRD; pre scribe gliquidone in stead or use in su lin which ismore suit able be cause dos age can be ti -trated.
Dis tri bu tion and me tab o lism: Steady-state 0.2 – 0.3 l/kg (mod er ate); ex ten sively con -verted in the liver to at least 7 in ac tive me tab - Usual dos age: 12.5 – 75 mg daily by mouth.
Elim i na tion: 60 – 70% of the dose ex cretedin the urine and 10 – 20% in the fe ces, all as Sec ond-gen er a tion sulfonylurea with much Dos age in re nal in suf fi ciency and di al y sis GI fate: Al most com pletely ab sorbed (>90% of è Dos age ad just ments are ad vis able! sively con verted to at least 6 me tab o lites with l In CKD stage 2 to 3GFR 89-30, ad min is ter cau - lit tle or no hypoglycemic ac tiv ity.
tiously with close mon i tor ing of blood sugar Elim i na tion: About 66% ex creted in the urine and 33% via bile in the fe ces as me tab o lites; drug is sig nif i cantly pro longed (up to 22 hrs),which may cause pro longed re lease of in su lin Dos age in re nal in suf fi ciency and di al y sis l the use of oral antidiabetics in clud ing No dos age ad just ments nec es sary! gliclazide should be dis con tin ued in CKD Even though the elim i na tion of in ac tive me - stage 4 to 5GFR ≤29 and in di al y sis pa tients tab o lites is pro longed up to 4 fold, no dos age re duc tion is nec es sary in re nal in suf fi ciency; No data avail able re gard ing re moval by HD ad min is ter glibornuride with cau tion in CKD stage 3 to 5GFR ≤59 and in di al y sis pa tientsbe cause the elim i na tion t1/2 of the par entdrug may be pro longed.
In CKD stage 5GFR <15 (ESRD) in su lin is moresuit able be cause dos age can be ti trated.
No data avail able re gard ing re moval by HDand PD (CAPD).
mouth, may be in creased if nec es sary up to 8mg daily for main te nance.
Sec ond-gen er a tion sulfonylurea with much Usual dos age: Ini tially, 40 – 80 mg daily by mouth, grad u ally in creased, if nec es sary, up GI fate: Com pletely ab sorbed (100%); plasma lev els peak within 2 – 3 hrs; plasma t1/2 af termul ti ple dos ing 5 – 9 hrs; PPB 99.5%; aVD Sec ond-gen er a tion sulfonylurea with much Me tab o lism: Glimepiride is ex ten sively me tab - o lized by CYP2D9 in the liver to one main me - tab o lite, a hydroxy de riv a tive with low ac tiv ity.
GI fate: Al most com pletely ab sorbed; plasma An other path way in volves for ma tion of an in - lev els peak within 4 – 6 hrs; PPB 85 – 97%.
Elim i na tion: About 60% of the dose is ex Me tab o lism: Mostly con verted to 2 ac tive and creted in the urine and 40% in the fe ces. No 2 in ac tive me tab o lites; me tab o lite 1 (norke - par ent drug is re cov ered from urine or fe ces.
tamine) has 10% and me tab o lite 2 (de hydro -norketamine) 1% of the nar cotic ef fect of the Dos age in re nal in suf fi ciency and di al y sis Elim i na tion: Pre dom i nantly ex creted in the è Dos age ad just ments are ad vis able! urine (80 – 95% of the dose), mainly as me -tab o lites, lit tle un changed (2 – 3%); 2 – 8% Glimepiride is well tol er ated in mild, mod er ate elim i nated in the fe ces; es ti mated elim i na tion and se vere re nal im pair ment. Be cause of com pen sa tory elim i na tion via the GI tract, ac - 1/2 of the par ent drug is ~2.5 hrs, that of the me tab o lites (in an i mal ex per i ments) 4 – 6 hrs.
cu mu la tion of par ent drug is un likely, and atran sient in crease in se rum con cen tra tions ofboth me tab o lites does not re sult in clin i cal Dos age in re nal in suf fi ciency and di al y sis A start ing dose of 1 mg glimepiride can be è Dos age ad just ments are ad vis able! given to di a betic pa tients with chronic kid ney In the el derly ketamine ap pears to in flu ence dis ease, and the dose ti trated based on fast - nei ther urine out put nor glo mer u lar fil tra tion rate and ef fec tive re nal plasma flow (nephro - l be cause of the pos si ble ac cu mu la tion of toxicity there fore un likely). It has been shown the ac tive me tab o lite (risk of hypoglycemia) the com bin ing ketamine with di az e pam or glimepride should be used with cau tion in dence of ad verse re ac tions. In HD pa tients the l the drug should be avoided in CKD stage agent does not in flu ence the clin i cal con di - 5GFR <15 (ESRD); pre scribe gliquidone in - stead or in su lin which is more suit able be - Ex pe ri ence from ICU con cern ing the long-term se da tion is avail able for crit i cally ill pa tients with pre-ex ist ing acute re nal fail ure who re - shown but is un likely be cause of the high PPB and ex ten sive con ver sion to me tab o lites.
25% above the lev els in vol un teers. The de -sired ther a peu tic ef fect was achieved, and no toxic symp toms were ob served; how ever, sig - nif i cant ac cu mu la tion of me tab o lite 2 isknown. For gen eral an es the sia pur poses in pa tients with chronic re nal in suf fi ciency, l it is ad vis able to ap ply usual nar cotic doses PPB var ies from 10 to 47%, and is much lower with cau tion in CKD stage 2 to 3GFR 89-30, and than with the other parenteral an es thet ics.
l to avoid ad min is tra tion in CKD stage 4 to 5GFR ≤29 if pa tient is not yet di a lyzed.
thio pental, ketamine is wa ter-sol u ble andavail able as so lu tions in NaCl plus the pre ser - Re moval of ketamine by HD is lim ited (range va tive benzethonium chlo ride. Fol low ing IV 4 – 10% of the dose dur ing one 4-hr HD) due to bolus, the drug is rap idly and widely dis trib - the wide dis tri bu tion into body tis sues and rapid me tab o lism. Re moval by PD not proven min); aVD ex tremely large (3 l/kg). The phase but ap pears also to be in sig nif i cant.
of an es thetic ac tion lasts for about 45 min With re gard to HD pa tients un der long-term se - and is determinated by re dis tri bu tion from the CNS to pe riph eral tis sues and hepatic me tab - l to in crease the dos ing in ter val ac cord ing to l al ter na tively, to in crease the du ra tion of di - Due to sig nif i cant ad verse ef fects, avoid ad - al y sis up to 24 hrs (con tin u ous di al y sis/he - min is tra tion to pa tients with re nal in suf fi - (MW 171.2, as benzoate MW 275.3, as hydrochloride MW A pro ges ter one (see there). Lim ited data avail - 60 – 80% of the dose, plasma lev els peak within ~4 hrs; PPB low (5 – 20%); fol low ing oral ad min -is tra tion, bioavailability is 90 – 100% of the Dos age in re nal in suf fi ciency and di al y sis dose; aVD mod er ate (0.6 – 0.9 l/kg).
Me tab o lism: About 40% of the dose (par ent è No, or lim ited data avail able, pro posed drug) is con ju gated with glucuronic acid or sul - dos age ad vice is pre lim i nary! fates, the re main der un der goes ox i da tive me - tab o lism. About 10% of the dose is con verted The drug may be used as con tra cep tive in to an acid de riv a tive which pos sesses ~5% of the ac tiv ity of the par ent drug and which is Be cause of lack of clin i cal ex pe ri ence it is ad - vis able to avoid the agent in CKD stage 4 to 5GFR ≤29 and in all di al y sis pa tients.
Elim i na tion: Up to 75% of the dose ex cretedin the urine, half of the amount as a hydroxyde riv a tive and a small amount as an acid de - riv a tive, the re main der un changed; up to 15% found in the fe ces. Elim i na tion t1/2 of par ent (MW 246.3, as hydrochloride MW 222.7, and as propionate drug 8 hrs (range 6 – 10 hrs), that of hydroxy me tab o lite 10 hrs (range 8 – 14 hr).
mech a nism of ac tion of the drug is not known.
Dos age in re nal in suf fi ciency and di al y sispa tients: è Dos age ad just ments are rec om mended! Well ab sorbed through dam aged skin (wounds).
Af ter en ter ing cir cu la tion, mafenide is me tab - Be cause of ex ten sive me tab o lism, plasma t1/2 o lized to an in ac tive me tab o lite which re tains of the par ent drug is not al tered in im paired re - the abil ity to in hibit car bonic an hydrase.
hydroxy me tab o lite is pro longed in ESRD up to creted in the urine, prob a bly com pletely as 40 hrs, re sult ing in sig nif i cant ac cu mu la tion in plasma.
l Usual doses can be given to pa tients with Dos age in re nal in suf fi ciency and di al y sis l It is ad vis able to re duce the dos age in CKD è No, or lim ited data avail able, no dos age stage 3GFR 59-30, and to closely mon i tor for side ef fects and ef fi cacy of the drug.
Be cause of the dan ger of ac cu mu la tion of the nally me tab o lized by CYP1A2, CYP2D6, and ma jor ac tive me tab o lite and as long as its toxic CYP3A4; ge netic poly mor phism in re la tion to CYP2D6 has been iden ti fied. Sev eral me tab o - l it is pru dent to avoid ad min is tra tion in pa - lites have min i mal antiarrhythmic ac tiv ity (up to 20% as po tent as the par ent drug).
Elim i na tion: Ex creted en tirely in the urine,10% (range 5 to 20%) un changed and the re - Re moval by HD is sub stan tial; elim i na tion t1/2 main der as me tab o lites. Be cause mexiletine of the par ent drug is <2.5 hrs and that of the is a weak base, re nal clear ance de pends on hydroxy me tab o lite <7 hrs dur ing di al y sis.
pH of the urine. Re moval in al ka line urine is ex - l Be tween di al y ses, ei ther the dose should be re duced or the dos age in ter val dou bled.
l A usual, sup ple men tal dose should be given Dos age in re nal in suf fi ciency and di al y sis Peritoneal di al y sis and CAPD [238, 253, 579]: Fol low ing oral ad min is tra tion, the pen e tra tion è Dif fer en ti ated dos age ad just ments are to the peri to neum dur ing PD is sub stan tial.
Con cen tra tion in the dialysate may reach up to Con sis tent with the lim ited re nal elim i na tion 65% of the trough plasma con cen tra tion.
of the par ent drug, lit tle change in the elim i na - l A dose of 500 mg ev ery 12 hrs has proved to be ef fec tive and does not seem to cause 1/2 has been de tected in pa tients with re - duced re nal func tion. In 8 pa tients with CKD ma jor side ef fects. Fol low ing oral ad min is - tra tion in CAPD, plasma and di al y sis fluid GFR < 15, mean plasma t1/2 was 15.7 hrs, l usual dose should be given dur ing CAPD to plasma lev els of the drug as a re sult of ac cu mu - achieve ef fec tive peritoneal con cen tra tions la tion have not been seen in such pa tients. It in the treat ment of peri to ni tis.
has been shown that >90% of the dose is ex -creted in urine as poorly ac tive or in ac tive me -tab o lites.
l Initially usual doses may be given to pa tients with CKD stage 4GFR 29-15 but dos age should Usual dos age: Ini tial dose 200 mg ev ery 8 hrs; ad just in 50 or 100 mg in cre ments ev ery 8 to l in pa tients with CKD stage 5GFR <15 and in all di al y sis pa tients, ini tial doses should be re -duced and main te nance dos age should be tai lored ac cord ing to clin i cal re sponse.
More over, it is pru dent to avoid ad min is tra - sorbed, plasma lev els peak within 2 – 3 hrs; tion to these two groups of pa tients.
Re moval by HD and PD is neg li gi ble, <3% of Me tab o lism and dis tri bu tion: Mexiletine is a the dose is re moved by HD, no re moval by close struc tural an a logue of lidocaine. Un like CAPD. The drug is mostly lo cated out side the bioavailability is there fore 80 – 90% of the fore, not be reached by di al y sis mea sures.
dose. Mexiletine is widely dis trib uted into alltis (5 – 12 l/kg). The drug eas ily passes phys i o - log i cal bar ri ers; thus, only 1% of the dose re - mains in the blood. 58 – 95% of the dose is fi - rhythmic agent should be ad justed to clin i cal and/or tis sue bind ing of the drug. Paclitaxel is ef fi cacy and re sponse. The same ap plies in me tab o lized in the liver by CYP2C8 pri mar ily to pa tients with im paired re nal func tion.
the ma jor me tab o lite, and by CYP3A4 to 2 mi -nor me tab o lites.
Elim i na tion: Mostly ex creted in the fe ces (70% changed); up to 12% of the dose is ex creted in the urine, in di cat ing ex ten sive non-re nal Usual dos age: An ti dote, used in the treat ment clear ance; elim i na tion t1/2 up to 50 hrs.
of poi son ings with organophosphates or re -lated com pounds. For its dos age con sult tox i - Dos age in re nal in suf fi ciency and di al y sis pa tients:è No data avail able, no dos age sugges- Sim i lar to pralidoxime (see there); no ap pre - Be cause of (ther a peu tic) cell tox ic ity and un - clear ex cre tion char ac ter is tics, stud ies in re -nal pa tients have not been con ducted.
Dos age in re nal in suf fi ciency and di al y sispa tients: è No, or lim ited data avail able, butdos age ad just ments ad vis able! with paclitaxel, 5 pa tients had re nal tox ic ity of Char ac ter is tics of obidoxime did not change grade III or IV (re nal in suf fi ciency with re vers - sig nif i cantly in a poi soned pa tient with a CrCl ible el e va tions in sCr). These few cases of pos - of 54 ml/min; 80% of the dose was ex creted in si ble re nal dis tur bance, are in suf fi cient to the urine over 5 hrs [133]. No data avail able clas sify paclitaxel as po ten tially nephrotoxic.
re gard ing re moval by HD or PD (CAPD).
Be cause of the char ac ter is tics of the drug,l it is ad vis able to ad min is ter usual doses in to re duce dos age in CKD stage 3GFR 59-30;and l to avoid ad min is tra tion in CKD stage 4 to An ti vi ral drug (in hib i tor of neuramidase ac tiv - ity of in flu enza A and B, in clud ing H1N1 in flu - GFR ≤29 and in di al y sis pa tients.
Usual dos age: Adults and ad o les cents ≤18 years: 600 mg IV once daily in fused for 5 – 10 days; chil dren ≥6 years and ad o les cents ≤17years: 10 mg/kg IV once daily in fused (not to ex ceed 600 mg/dose) for 5 – 10 days. Dos age in smaller chil dren, see drug in sert.
PPB <30%; not sig nif i cantly me tab o lized.
Elim i na tion: Al most com pletely ex creted in the urine (90% of the dose); elim i na tion t1/2 Dis tri bu tion and Me tab o lism: At steady-state, var ies from 7.7 to 20.8 hrs; no ac cu mu la tion mean aVD is very large (range 5 – 15 l/kg), in - ob served dur ing mul ti ple dos ing.
di cat ing ex ten sive extravascular dis tri bu tion Dos age in re nal in suf fi ciency and di al y sis cally ill pa tients dur ing SLED treat ment (QB 200 ml/min, QD 300 ml/min) [1769]. With a è Dos age ad just ment is rec om mended! daily IV dose of 600 mg, mean peak peramivirplasma lev els (~27,000 ng/ml) were in the In re nal pa tients with CKD stage 2GFR 89-60, the range of those in healthy sub jects (45,200 mean sys temic ex po sure is 24% higher than in ng/ml). Both pa tients re cov ered from the vi ral those with nor mal re nal func tion (an in crease not ex pected to be clin i cally rel e vant); withCKD stage 3GFR 59-30, 3.4-fold higher; with CKD stage 4GFR 29-15, 6-fold higher; with CKD stage Since peramivir is elim i nated pri mar ily by the kid ney, coadministration with drugs that re - In adults and ad o les cents ≤18 yearsl duce re nal func tion or com pete for ac tive tu - with CKD stage 2GFR 89-60, give the usual bu lar se cre tion (see un der In tro duc tion) will the o ret i cally in crease plasma con cen tra tions with CKD stage 3GFR 59-30, give 150 mg daily; with CKD stage 4GFR 29-15, give 100 mg daily; with CKD stage 5GFR <15 but not yet di a lyzed, give 100 mg on day 1, then give 15 mg daily.
enzyme sys tem should not al ter the elim i na - yearsl with CKD stage 2GFR 89-60, give the usual l with CKD stage 3GFR 59-30, give 10 mg/kg l with CKD stage 4GFR 29-15, give 2.5 mg/kg Dos age in re nal in suf fi ciency and di al y sis l with CKD stage 5GFR <15 but not yet di a lyzed, è No dos age ad just ments nec es sary! give 1.6 mg/kg on day 1, then 0.25 mg/kgdaily.
Dos age ad just ment for smaller chil dren, see Hemodialysis [1768]: Ap pre cia ble re moval byHD, thus ad min is tra tion af ter di al y sis.
An immunosuppressive agent for top i cal use l give 100 mg on day 1, then 1.6 mg/kg 2 hrs in atopic der ma ti tis (like tacrolimus); min i mal af ter each HD, no fur ther dos ing be tween sys temic ab sorp tion; me tab o lized in the liver, PD and CAPD: No data avail able.
CRRT in ICU: There is ev i dence that the drug is Drug dos age in re nal in suf fi ciency and elim i nated by CVVHF and CVVHD but, at pres - ent rec om men da tions can not be made. Re - è No dos age ad just ments nec es sary! cently, peramivir was ad min is tered to two crit i -

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