September 1967
NOTES
97 1
making it well ::uit'ed for use in oral pediatric suspeiisions. -1 comparison of the antiamebic properties 01' clamoxyquin hydrochloride and pamoate indicatecl pound could not be oxidized to 3',5'-diacetyl-5-r~rbnxy-2'that the potent aiitianiebic activity of the hydrochloridc deoxyuridine with "active" l I n 0 2 ,KMnOa, or 0 3 . 3alt is ret,ained by the pamoate.*,* Thus, both salts were active agaiiwt Entamoeba histolytica (200 strain) i i i rats when administered in the diet i i i dose levels of 160-679 mg"kg day for 7 days or b\. gavage in dows of 7.5-600 m g .kg day for 4 days. When dogs infected wit'li E . h.istoZytica were treated orally for 10 days, botlt Preparation and Properties of Clamosyquiri t'he hydrochloride and panioate salts were active, thc, Pamoate,' an Antiamebic and cure rate being dependent upon the dosage in the range of 3.13-50 nig, kg/day and 12.5-25 mg/kg/daj., Antidiarrheal Agent respectivell-. These doses were well tolerated :I::, judged by gross EDMAHD F. ELZL IGEK L N D DON ILD F. W O K ~ H Toxicologic studies with vlamoxyyuiil hydrochloridc Research I,ahoratories, Parke, Daws and C o n i p u n y . and pamoate were carried out in mice. rats, dogs, aiid Ann --trbor, Vichigan niotikeys.8,g Acute oral LDjo values in albino miw K ~ c e i ~ rJ lda r c h 2Li3 1967 were much higher for the panioate (>2500 mg/kg) thgn for the hydrochloride (891.3 f 33.7 1~1g/kg).~1 1 1 -4 wide variety of bubstituted 8-quitioIiiiola httb heell chroiiic oral-tolerance studies in albino rats, both salt:: examined in these laboratories for antiamebic arid were tolerated well for 28 days at average daily drugmtibacterial properties. 2 - 4 Among them. 5-chloro-idiet doses of 25 nig. kg: at greatly exaggerated daily ( { [3-(diethylamino) propj.1 ]amino }methyl)- 8-y uiiiolinol doses of 200 nig,'kg over the same period, t8hepamoate dihydrochloride (clamoxyyuiii hydrochloride. Ia) has was vlearly better tolerated than was the hydrochloridc. shown a particularly interesting degree of aiitianiebic *alt', although in neither case was evidence of org:iii wtivity in experimental animals.3-5 Clanioxjyuin damage observed.9 hydrorhloride formulated i i i gelatin ~ ' a p 1 1 1 eTVR~ The two salts were also compared ill subacute risiiigdose-tolerance trials in dogs and monkeys.9 Dogs tolerated up t o 525 mg/lig of claiiiosyquin pamoat(\ b\. the elid of :I %?-day dosing period with manifest:iimilar to, but much less severe than, the gastrointestinal irritation that was seen during the administration of 250-275 mgikg of the h>.drochloride salt I e1 during 24-23 days. I n monkeys: a maximum dose of' 1100 nig/kg of clamoxj~quiri panioate was dictated Ia, 2HCI COOH ~ i i l >by . the bulk of drug required to deliver the dose.. b, .pamoic acid .It this level, signs of intoleraiice were modest, compared panioic acid with those produced by similar doses ( i f the hydrochloride aalt. Therefore, in all species of animals studied tolerated well iti iiiaii following dail\- 15-nigj kg &)>e;. t,o date, calamoxyquiii pamoate was uniformly better for 5-10 days arid was high]?. eff e d v e against v:iriow tolerated than the hydrochloride salt.9 forms of intestinal amehiasis.6,' In definitive clinical trials, clamoxyquin pamoat(' Tablet and suspensioii forniulatioii* o f c l a i n o q ~ y u i t ~ formulated as compressed tablets or as a ~;u~peiision was were of special interest for expanded clinical s t udies. cwmpared with ii)d~)c.hlorhydroxyquitl1" in the treatIu order to find a salt form of clamoxyquiri whose taste iiient of diarrheal disease." Clamosj-quin pamoatc. would be more acceptable for use in aqueous wspenwas administered i i i a dose of 16 mg of cblamoxyquiti sions for oral pediatric use. a series of salts was prepared base:kg of bod!. weight daily, in divided doses, for 5 (Table I). Among them, clanioxyquiii pamoate (Ib); days. Iodochlorh\-droxyquiti was given ar8the reconia salt of clamoxyquin with 1 formula weight of &4'mended dosage regimen, namely 1500 mg (500 mg tid) met hylenebis (3-hydroxy-2-napht hoic acid) , :t ppeared daily for 10 days. Clamoxyquin pamoate was tolerat,ed to be of particular interest and was selected for exteiiwell and was equal to iodochlorhydrox\-quili in reducbiiig sive chemical and biological evaluation. the dail!. number of stools, in improving stool consistClamoxyquin pamoate as the anhydruus Jalt WIIencj., and eliniinatiiig fetid odor. Both drugs were. t ains 45.3% clamoxyyuin base. The conipouiid is effective i t i eliminating blood and I ~ ~ U ( ~ in U F st,ools;. relatively insoluble in water (0.00441,) and is tastelesh. Clamoxyquin pamoate was usually better than iodo1) Clamoxyquin pamoate is rlie generic name fur 5-cliluro-i-({ [schlorhydroxyquin in ameliorat,ing subjective gastroi diet~iylamino)propyl]amino)met.hyl)-8-quinolinoI salt n-ith 1 formula aeieht intestinal s y m p t o m and was superior or equal t o iodouf 4,4,-methylenebis(3-hydroxy-Z-naphthoic acid) (ClamoxylE), ( 2 ) P. E. Thompson, J. \i. Reinertson, A. Rayles, 11. .\, IIrC'arthy, and chlorhydroxyyuin in eliminating E . histolytica. O i a d i a 1.:. F. Elslager. A m . J . T r o p . .)fed. H u g . , 4, 224 (1955). lamblia, and Shiyella.7*11 0 ) J. H. Burckhalter. \i S., Rrinigar, and P. E. Thomi~sun..I. 0 r . y . C'ftem..
of 5-carboxyuracil. The yield was increased to 61% wheu the "active" MnOt was washed with 157, HNOa, followed by washiiig with distilled water to pH 5 (cf. ref 14). Attempted Oxidation of 3',5'-Diacetylthymidine.-Thib coni-
\
26, 4 O i O (1961). (4) P. E. Thompson, .\. Bayler. P. McCIay, and .J. E. 1 I e i ~ e n t i ~ l d e .rl.. I'nraeitol., 61, 817 (1965). ( 5 ) R . Carier and F. Glaudon, I'herupiP, 18, 1153 (1963). 16) R . H. Hugonot, E. Granotier, and J. P. Farges, i h k l . , 20, 399 191% i 7 ) li. 0. Corirtney. personal rommiinication. 1 9 6 i .
r8) Drug concentrationr and doses are expressed i n t r r n l r c j f t h e free h s e content. (9) 11. ti. Kaump, R . .i, Fisken, J . E. Fitzgerald. .J. A . Lucas, T. P.. Reutner, L). E. Roll, and J . I.. Schardein. perronal commiinicntion. 1 4 f i i . I 10) Entero-Vioforms. ' 11) F. Fernandee. ISemt>itr, . l l e , l . .lfexi
