Effect of topiramate on hippocampus-dependent spatial memory in rats

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1 Phrmologil Reports 0, 65, 5 6 ISSN 7-0 Copyright 0 y Institute of Phrmology Polish Ademy of Sienes Effet of topirmte on hippompus-dependent sptil memory in rts Bogus³w Pietrzk, Agnieszk Konopk, Jku Wojieszk Deprtment of Phrmodynmis, Medil University of Lodz, Muszyñskiego, PL 90-5, ódÿ, Polnd Correspondene: Bogus³w Pietrzk, e-mil: oguslw.pietrzk@umed.lodz.pl Astrt: Bkground: Topirmte, new genertion ntiepilepti gent with omplex mehnism of tion, hs rod phrmologil profile whih inludes neuroprotetive effet. It hs een proven to e effiious in treting lohol dependene through previously onfirmed ssoition with memory proesses. Methods: Topirmte ws dministered in single doses of 0 nd 0 mg/kg nd multiple doses of 60 mg/kg for dys. Its influene on the sptil memory of rts ws evluted using the Morris wter mze test. The time needed to lolize the pltform, the distne trvelled nd time spent in the pltform zone were reorded. Results: Single doses of topirmte indue deteriortion of sptil memory, with high doses hving more pronouned nd longer lsting effets. Multiple dministrtion of medil dose does not signifintly ffet the lerning proess. Conlusions: The influene of topirmte on the hippompus-relted memory proesses my ply key role in its nti-lohol effet. Key words: topirmte, rts, Morris wter mze, sptil memory, lohol ddition, hippompus Introdution Topirmte is new genertion ntiepilepti gent with omplex mehnism of tion: it loks plsmlemml sodium hnnels [0], enhnes GABA-ergi trnsmission [] nd loks kinte reeptors [9], L- type lium hnnels nd meditor relese [5], s well s stimulting potssium hnnels []. Additionlly, it loks roni nhydrse isoform II nd IV, lthough to lesser degree thn etzolmide [7]. Topirmte hs proven effiy ginst fol, generlized nd seondly generlized seizures [8]. Its omplex mode of tion hs enourged reserh into new pplitions other thn those ssoited with epilepsy. Topirmte hs een found to e effetive in the tretment of neuropthi pin syndrome [], hyperkineti movement disorders [8], ipolr ffetive disorder [] nd other psyhitri onditions suh s shizophreni [], orderline personlity disorder [0] or inge eting disorder []. It hs een demonstrted tht topirmte filittes the dey of memory tres, whih justifies its pplition in post trumti stress disorder []. It is lso used in the tretment of migrine [7] nd luster hedhes []. It is worth mentioning tht topirmte hs neuroprotetive properties, whih hve een proven on vrious niml models of ishemi hypoxi [9], neuronl lesion, sttus epileptius [7], hyperthermi seizures [5] or exitotoxiity [6]. The neuroprotetive effet ws found to e dose-dependent in the mjority of studies. Topirmte lso hs demonstrted protetive properties in neuronl ell ultures. It hs een noted tht it stimultes neurite outgrowth in primry rt ortil nd hippompl ell ultures in dose-dependent fshion [9]. 5 Phrmologil Reports, 0, 65, 5 6

2 The effet of topirmte on memory in rts Bogus³w Pietrzk et l. Reently, it hs een found tht topirmte dereses lohol nd niotine rving in ddited individuls []. Administrtion of topirmte ws found to redue the mount of lohol onsumed y ptients nd the proility of returning to dependeny fter ompletion of therpy, s well s lower the numer of hevy drinking dys during -week therpy [5]. Moreover, in rndomized ontrolled tril, topirmte signifintly deresed osessionl thoughts nd ompulsions out using lohol, inresed sujets psyhosoil well-eing, nd improved some spets of qulity of life, therey diminishing the risk of relpse nd longer-term negtive outomes []. Topirmte hs lso een proven to e more effetive thn nltrexon, n opioid reeptor ntgonist ommonly used in the therpy of lohol ddition [5]. Furthermore, therpy with topirmte n e initited whilst the individul is still drinking, mking topirmte suitle for tretment of most lohol dependeny ses []. However, the preise mehnism of this tion hs not yet een eluidted. It is suggested tht it n e relted to hippompus-dependent memory proesses, whose ontriution to the pthogenesis of ddition is urrently eing emphsized. A study on the rt model of loholism reveled tht topirmte redues the mount of lohol onsumed, nd its effiy my depend on geneti predispositions ut not on the level of drinking [6]. Erlier phrmo-eeg studies hve demonstrted tht topirmte lters the EEG ptterns of the hippompi of rits treted with n ute dose of ethnol. No similr effet ws oserved in ny other exmined rin strutures, whih my indite tht the hippompus enjoys some protetion ginst the toxi effets of lohol []. The im of this work ws to evlute the effet of ute nd multiple topirmte dministrtion on the hippompus-dependent sptil memory of rts. The results my roden knowledge out the ontriution of memory proesses to the pthogenesis of lohol dependene. Mterils nd Methods Animls Mle Wistr rts weighing 0 60 g were used t months of ge. The nimls were housed in groups of in plsti ges with free ess to wter nd stndrd how. The room ws ir onditioned nd h light/drk yle ws mintined: lights on t 8:00.m. Experiments were rried out etween 9:00.m. nd :00 p.m. All proedures were pproved y the Lol Ethis Committee of the Medil University of Lodz (77/ B- 587/0). Drug To study the ute influene of topirmte on sptil memory, the nimls reeived 0. ml/kg of drug suspension in single dose of 0 mg/kg or 0 mg/kg orlly, 0 min efore the first tril eh dy. To study the effet fter prolonged dministrtion, rts reeived 0. ml/kg of drug suspension t dose of 60 mg/kg orlly. The drug ws dministered eh dy for the onseutive dys efore the strt of the experiment nd on dys,, nd of the experiment fter ompletion of the finl tril for the dy. Topirmte suspension ws otined y triturting Topmx (Jnssen-Cilg Interntionl N.V.) tlets with % queous solution of methylellulose. The nimls in the ontrol group reeived 0. ml/ kg of % queous solution of methylellulose. EXPERIMENT Apprtus The influene of topirmte on the sptil memory of rts ws exmined using the Morris wter mze (ANY-mze, USA), whih onsists of irulr pool filled with wter (dimeter 80 m, wlls 50 m high, wter level 0 m, wter temperture C). The pool ws virtully divided into four setions, nmed N, S, W nd E. During the experiment, trnsprent irulr Plexigls pltform ws used, whih ws 8 m in dimeter nd invisile to the nimls. It ws pled in the enter of one qudrnt, sumerged m eneth the surfe of wter. The pool ws pled in room furnished with severl extr-mze ues. Experiments were ptured on mer pled ove the pool. Rt position, movement nd entrne to the pltform ws deteted using ANY-mze softwre (ANY-mze, USA). Phrmologil Reports, 0, 65, 5 6 5

3 PROCEDURE Aute effet During the first three dys of the experiment, rts were pretrined in order to lern the mehnism of the experiment. The pltform ws pled in the enter of the S qudrnt nd remined there for three dys. Eh niml ws put in pool nd llowed to swim for 90 s. If it mnged to find the pltform, it ws llowed to sty on it for 5 s nd oserve the room. Susequently, the rt ws trnsferred to ge nd dried out with pper towel. After 60 s rest, the experiment ws repeted totl of three more times. At the eginning of eh tril, the niml ws pled in pool in different qudrnt, fing the wll. If the niml didn t mnge to find the pltform, it ws pled there mnully y the experimenter for 5 s nd then the sme proedure ws followed s if the rt hd found the pltform itself. After dys of pretrining, the retention test ws performed. In the retention test, the nimls were pled in the pool without the pltform nd llowed to swim for 90 s. During this stge of the experiment, the time spent y rts in the zone where the pltform hd een loted previously ws mesured. An inility to lote the pltform in the memorized spot used the nimls to serh for it long the length of the entire pool in the following stges. On the fifth dy of the experiment, the rts were divided into groups of 6 nimls eh. Rts from the first group reeived topirmte suspension 0 min efore the strt of the first tril. The remining 6 rts were used s ontrol group, reeiving only the vehile solution 0 min efore the strt of first tril. The pltform ws moved to the W qudrnt nd remined there until the end of the experiment. The following steps were identil to dys. Prolonged effet To evlute the prolonged effets of topirmte tretment, rts whih previously hd een used in the investigtion of the ute effet of one dose were used fter -month rek. Sine they hd een lredy pretrined, nd euse of the prolonged dministrtion of topirmte, no dditionl pretrining ws onduted. The pltform ws pled in the N qudrnt nd remined there until the end of experiment, whih lsted for 5 onseutive dys. On dys,, nd, topirmte ws dministered fter ompletion of ll trils, while on the fifth dy no drug ws dministered. The reminder of the experimentl proedure ws identil to tht desried in the study of ute effet. Dt nlysis Sttistil evlution ws performed using Student s t-test. Dt re presented s the men ± stndrd devition; p vlues < 0.05 were onsidered signifint. Results Effet of ute 0 mg/kg topirmte dministrtion on the sptil memory of rts in the Morris wter mze test A single dose of 0 mg/kg topirmte inresed the time needed to find the pltform (Fig., T. ). Sttistilly signifint differenes etween the ontrol nd T.. Effets of ute 0 mg/kg topirmte dministrtion on the performne of rts in the Morris wter mze test. Vlues re the men ± SD Drug group Test Test Test Test Time (s) 8.67 ±.7.70 ±.8 5. ± ±.95.0 ±.7.97 ±.6 9. ± 6.7 Distne (m) 0.98 ± ± ± ± ± ± ± 7.5 Time in zone (%) 8 ± 5 6 ± 6 0 ± 5 ± ± 0 8 ± 6 ± 6 group Test Test Test Test Time (s) 8.60 ± ± ±.5.7 ± ± ± ± 0.5 Distne (m).5 ± ± ± ± ±.8.7 ± ±. Time in zone (%) ± 7 5 ± 7 ± 0 9 ± 0 5 ± 7 8 ± 7 9 ± 9 5 Phrmologil Reports, 0, 65, 5 6

4 The effet of topirmte on memory in rts Bogus³w Pietrzk et l. Fig.. Effet of ute dministrtion of 0 mg/kg topirmte on the time needed to lolize the pltform. Sttistilly signifint differene etween topirmte nd ontrol group on tht dy. p < 0.05, Student s t-test. Sttistilly signifint differene etween prtiulr test dy nd test dy (referene). p < 0.05, Student s t-test. Sttistilly signifint differene etween prtiulr trining dy nd trining dy (referene). p < 0.05, Student s t-test Men espe ltenies [s] Topirmte 0 dy dy dy Fig.. Effet of ute dministrtion of 0 mg/kg topirmte on the distne trvelled y rts in order to lolize the pltform. Sttistilly signifint differene etween topirmte nd ontrol group on tht dy. p < 0.05, Student s t-test. Sttistilly signifint differene etween prtiulr test dy nd test dy (referene). p < 0.05, Student s t-test. Sttistilly signifint differene etween prtiulr trining dy nd trining dy (referene). p < 0.05, Student s t-test Men distne trvelled [m] Topirmte 0 dy dy dy Fig.. Effet of ute dministrtion of 0 mg/kg topirmte on the time spent in the zone with pltform. Sttistilly signifint differene etween topirmte nd ontrol group on tht dy. p < 0.05, Student s t-test. Sttistilly signifint differene etween prtiulr test dy nd test dy (referene). p < 0.05, Student s t-test. Sttistilly signifint differene etween prtiulr trining dy nd trining dy (referene). p < 0.05, Student s t-test Time spent in qudrnt with pltform [% totl] 70% 60% 50% 0% 0% 0% 0% 0% Topirmte dy dy dy Phrmologil Reports, 0, 65,

5 the drug groups were oserved on ll test dys. In ddition, sttistilly signifint differenes were oserved etween test dy nd the remining test dys (, nd ) in the ontrol group, nd etween test dy nd dys nd in the drug group. A single dose of 0 mg/kg topirmte lso inresed the distne trveled in order to lolize the pltform (Fig., T. ). Sttistilly signifint differenes in distne trvelled etween the ontrol nd the drug groups were oserved on ll test dys. A signifint derese in reltion to test dy ws oserved on test dys, nd in the ontrol group nd on test dy nd in the drug group. Rts from the topirmte group spent signifintly less time in the zone with the pltform on test dys nd (Fig., T. ), ompring to ontrol group, while n upwrd trend in the perentge of time spent in the proximity of the pltform ws oserved in oth groups. Only test dy ws found to e signifintly different from test dy for oth groups. During the trining phse, rts rehed the pltform fster nd trveled shorter distne eh onseutive dy. The length of time spent in the proper zone ws seen to inrese s the trining period went on. The effet of ute 0 mg/kg topirmte on the sptil memory of rts in the Morris wter mze test The rts dministered with single 0 mg/kg dose of topirmte were seen to require more time to lolize the pltform on ll test dys thn the ontrol nimls (Fig., T. ). In the drug group, espe lteny deresed signifintly on dy nd remined t similr level on dys nd. In the ontrol group, signifint derese ws oserved on dys nd in reltion to dy. Similrly, single dose of 0 mg/kg topirmte signifintly inresed the distne trveled y rts in reltion to the ontrol group on ll test dys (Fig. 5, T. ). In the ontrol group, the distnes oserved on the test dys nd were muh shorter thn those seen on test dy, however, suh derese ws not oserved in the topirmte group. Rts given single dministrtion of 0 mg/kg topirmte spent less time in the zone with the pltform in reltion to ontrol nimls, ut these differenes were not sttistilly signifint (Fig. 6, T. ). Signifintly longer journeys were oserved on dy in the drug group, nd on dys, nd in the ontrol group, ompred to dy. During the trining stge, the time needed to find the pltform ws signifintly shorter on dys nd thn on dy. A signifint redution of the distne trveled ws oserved on dy in reltion to dy. The time spent in the proper zone grdully inresed on eh onseutive dy during the trining stge. The effet of prolonged 60 mg/kg topirmte dministrtion on the sptil memory of rts in the Morris wter mze test Prolonged dministrtion of 60 mg/kg topirmte did not signifintly lter the time needed to lolize the pltform in reltion to the ontrol group (Fig. 7, T. ); signifint differene ws only oserved on test dy. Both groups demonstrted signifint redution of time during the test in reltion to dy, strting on dy nd remining until the end of the test. Topirmte dministered in multiple 60 mg/kg doses did not use ny signifint hnge in the distne trveled in order to find the pltform in reltion to ontrol group (Fig. 8, T. ), signifint differene T.. Effets of ute 0 mg/kg topirmte dministrtion on the performne of rts in the Morris wter mze test. Vlues re the men ± SD Drug group Test Test Test Test Time (s) 8. ± ± ± ± ±.99.7 ± ±.0 Distne (m) 6.76 ± ± ± 7.. ± ± 0..6 ± 8.6. ± 9.0 Time in zone (%) 0 ± 0 8 ± 0 ± ± 8 5 ± 7 ± 0 ± group Test Test Test Test Time (s) 8. ± ±. 8. ± ± ± ±.6.55 ±. Distne (m) 7.50 ± ± ± ± ± 5.0. ±.76. ±.56 Time in zone (%) ± 8 5 ± 8 ± 9 5 ± 5 ± 7 ± 5 9 ± 7 56 Phrmologil Reports, 0, 65, 5 6

6 The effet of topirmte on memory in rts Bogus³w Pietrzk et l. 0 Topirmte Fig.. Effet of ute dministrtion of 0 mg/kg topirmte on the time needed to lolize the pltform. Sttistilly signifint differene etween topirmte nd ontrol group on tht dy. p < 0.05, Student s t-test. Sttistilly signifint differene etween prtiulr test dy nd test dy (referene). p < 0.05, Student s t-test. Sttistilly signifint differene etween prtiulr trining dy nd trining dy (referene). p < 0.05, Student s t-test Men espe ltenies [s] dy dy dy Fig. 5. Effet of ute dministrtion of 0 mg/kg topirmte on the distne trvelled y rts in order to lolize the pltform. Sttistilly signifint differene etween topirmte nd ontrol group on tht dy. p < 0.05, Student s t-test. Sttistilly signifint differene etween prtiulr test dy nd test dy (referene). p < 0.05, Student s t-test. Sttistilly signifint differene etween prtiulr trining dy nd trining dy (referene). p < 0.05, Student s t-test Men distne trvelled [m] Topirmte 0 dy dy dy Fig. 6. Effet of ute dministrtion of 0 mg/kg topirmte on the time spent in the zone with pltform. Sttistilly signifint differene etween prtiulr test dy nd test dy (referene). p < 0.05, Student s t-test. Sttistilly signifint differene etween prtiulr trining dy nd trining dy (referene). p < 0.05, Student s t-test Time spent in qudrnt with pltform [% totl] 70% 60% 50% 0% 0% 0% 0% 0% Topirmte dy dy dy Phrmologil Reports, 0, 65,

7 only eing oserved on test dy. Signifint differenes in reltion to test dy were oserved, strting on dy nd remining until the end of the test, with the exeption of the topirmte group on dy. Topirmte dministered in multiple 60 mg/kg doses did not use signifint differenes in time spent in the zone with the pltform in reltion to the ontrol group (Fig. 9, T. ). In reltion to test dy, no signifint inrese of time spent in the pltform zone ws oserved in either group. Disussion The phrmologil properties of topirmte hve drwn widespred interest from the demi ommunity nd hve een the sujets of numerous experimentl nd linil studies. Not only is topirmte regrded s one of the most effiient ntiepilepti drugs, ody of evidene lso exists of its enefiil effets in mny disorders used y disturnes of neuronl trnsmission, prtiulrly those ssoited with glutminergi nd GABA-ergi pthwys. The proven effiy of topirmte in the tretment of lohol dependene is of signifint linil importne. So fr, lthough the preise mehnism of this tion hs not een eluidted, it seems tht its influene on memory proesses my e mjor ftor. Neuropsyhologil exmintions of ptients tking topirmte showed one of its side effets to e impirment of work memory, espeilly t the eginning of tretment []. However, s these symptoms re generlly of modest intensity, ptients usully willing to tolerte them during the ourse of topirmte therpy euse of its effetiveness in preventing seizures [8]. T.. Effets of prolonged 60 mg/kg topirmte dministrtion on the performne of rts in the Morris wter mze test. Vlues re the men ± SD Drug group Test Test Test Test Test 5 Time (s).9 ± ± ± ± ± 7.6 Distne (m) 7.55 ± ± 5.8. ±.9.0 ±.7. ±.08 Time in zone (%) 0 ± 0 9 ± 6 0 ± 9 ± ± group Test Test Test Test Test 5 Time (s).5 ± ± ± ± 5.. ± 0.5 Distne (m) 7.6 ± 7.. ±.7.75 ± ±.80.8 ±.7 Time in zone (%) ± 5 ± 5 ± 7 5 ± 6 ± 8 Men espe ltenies [s] Topirmte Fig. 7. Effet of prolonged dministrtion of 60 mg/kg topirmte on the time needed to lolize the pltform. Sttistilly signifint differene etween topirmte nd ontrol group on tht dy. p < 0.05, Student s t-test. Sttistilly signifint differene etween prtiulr test dy nd test dy (referene). p < 0.05, Student s t-test Phrmologil Reports, 0, 65, 5 6

8 The effet of topirmte on memory in rts Bogus³w Pietrzk et l. Fig. 8. Effet of prolonged dministrtion of 60 mg/kg topirmte on the distne trvelled y rts in order to lolize the pltform. Sttistilly signifint differene etween topirmte nd ontrol group on tht dy. p < 0.05, Student s t-test. Sttistilly signifint differene etween prtiulr test dy nd test dy (referene). p < 0.05, Student s t-test Fig. 9. Effet of prolonged dministrtion of 60 mg/kg topirmte on the time spent in the zone with pltform In study sed on verl memory test, topirmte ws found to use more pronouned deteriortion of ognitive funtions thn vlproi id. However, the uthors suggest tht this ws n ute effet of too rpid n dministrtion of high dose of the sustne, whih n e voided y grdully inresing the dose []. Cognitive funtions were lso exmined in group of ptients with drug-resistnt epilepsy y ompring evlutions performed efore the strt of therpy nd fter 6 months of tretment with high doses of topirmte. A deteriortion of semnti verl flueny, verl lerning, work memory nd visuomotor skills ws seen during the ourse of therpy []. Although impirment of GABA-ergi trnsmission is onsidered n importnt element in the mehnism of ognitive disorders, some miguous dt still exist: for exmple, ognitive funtions were oserved to improve in ptients tking low mintenne doses of topirmte [0]. These results support the need for further study onerning the influene of topirmte on ognitive proesses, whih will llow therpy to e optimized nd for the neuroprotetive properties of low doses to e utilized. The im of this work ws to evlute the influene of topirmte on the memory of rts fter ute nd prolonged dministrtion. The Morris wter mze ws employed in experiments s si ssy of sptil memory nd ssoited lerning ility, euse of its suitility to ssess memory funtions dependent on the hippompus, whih is struture involved in the development of dependene. The hippompus plys Phrmologil Reports, 0, 65,

9 ruil role in the mehnism of positive reinforement, whih strengthens the retion nd inreses the likelihood tht ertin ehvior will our gin in order to reeive stimulus. Animls with dmged hippompus re more sensitive to stimuli, nd mke greter efforts to ontt positive stimuli []. Bsed on the literture, two single doses onsidered low nd high were seleted, s well s multiply-dministered medil dose. Mesurements of the time needed to lolize the pltform, distne trveled in order to espe nd time spent in qudrnt ontining the pltform were reorded. Before the tretment, the nimls were pretrined in order to evlute their ility to lern nd to llow the further seletion of two groups (ontrol nd topirmte) with similr seline lerning ilities. All nimls were le to lern the lotion of the pltform nd the lyout of the room, whih resulted in redution of oth the time needed to find the pltform nd the distne trveled on eh onseutive dy, s well s n dditionl inrese of time spent in the zone with the pltform. The rte of lerning ws different for eh rt, produing ler spred of results. However, sttistil nlysis identified signifint differenes etween onseutive dys, nd no differene ws oserved etween the two groups of nimls during the trining shedule. Susequently, fter rek of few dys nd ersure of memory tres, the rts were used in similr experiment, preeded y drug dministrtion. A high, ute dose of topirmte signifintly inresed oth the time needed to lolize the pltform nd the distne trveled to get there, while it redued the time spent in the proper zone. The otined results indite tht single high dose of topirmte hs n inhiitory effet on the sptil memory of the rts. This effet grdully wers off on following dys, however, signifint level of hippompus-dependent sptil memory deteriortion is retined, whih orreltes with linil oservtions inditing temporry side effets in humns [8]. Furthermore, other uthors suggest tht redued ognitive funtion is used y exessively rpid dministrtion of high dose of topirmte, whih n e voided y inresing the dose grdully []. A lower dose produed similr effet, ut one tht lsted for shorter time. Topirmte is usully given t low or medium doses in long-term therpy, whih fits the experimentl model of multiple dministrtion. In the present study, topirmte (60 mg/kg) dministered for dys did not enhne the time spent in serh of the pltform nor the distne trvelled. A signifint improvement of prmeters ws oserved during the experiment, nd this improvement ws mintined until the end, whih suggests tht multiply dministered topirmte hs no dverse effets on hippompus-dependent memory proesses. However, the shre of time spent in the zone with the pltform ws oserved to e signifintly longer on the fourth dy. Amnt nd Akuhekin [] emphsize the enefiil spet of the effet of topirmte on ttenuting memory tres in linil studies, whih is of gret importne in vrious psyhologil disorders. Bsed on the results of the present study, whih re onsistent with linil reports, it n e ssumed tht the effetiveness of topirmte in the mngement of lohol dependene n e relted to its impt on hippompus-dependent memory proesses. Topirmte ffets lso the funtions of the hypothlmus struture whih plys key role in the regultion of ppetite nd energy expenditure. Both redution of ody mss oserved in ptients tking topirmte nd hnges in the dipose tissue distriution seen in oese individuls prompted the use of topirmte in the tretment of eting disorders [6]. However, the preise mehnism of this spet of topirmte tivity hs not een fully eluidted. It is thought tht the loss of ody weight does not result from the inrese of resting metoli rte, ut is possily the effet of redued ppetite. This phrmologil property of topirmte my e lso of signifine in reduing the lohol rving nd intke y ddited individuls. The neuroprotetive effet of topirmte, whih hs een onfirmed in mny linil nd experimentl studies, nnot e ruled out. Although it is hrd to unmiguously indite the key element of the nti-lohol tivity of topirmte, the results otined in the present study offer further support to the thesis tht its influene on the hippompus-dependent memory is min ftor. The uthors of this pper intend to further investigte the influene of topirmte on the development of lohol dependene in rts, nd on the severity of withdrwl symptoms. Aknowledgment: This work ws supported y the Medil University of Lodz (50/-0-0/50-0). 60 Phrmologil Reports, 0, 65, 5 6

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