Excretion and diuretic action of mercurial diuretics

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  • [15. VIII. 1957] Kurze Mitteilungen - Brief Reports 327

    (3ber ein neues Ana lget i cum-Ant ipyret i cum (4 -Oxycumar in )

    Die analgetische \Virkung des K-Vitamins I veran- lasste uns in einer frtiheren Arbeit zu untersuchen, ob auch Antagonisten des K-Vitamins, also das ihm chemisch verwandte Dicumarol und seine Derivate, eine solche \Virkung haben. Diese Vermutung konnten wit best/itigen 2. Zugleich haben wir auch sowohl auf die Verwandtschaft der Dicumarolderivate mit der Salizyl- s~ure hinsichtlich ihrer chemischen Konstitution, als aueh hinsichtlich ihres Einflusses auf den Blutgerin- nungsprozess und den analgetischen Effekt hingewiesen. In einer weiteren Arbeit untersuchten wir eine Reihe neuer, dem t(-Vitamin bzw. Dicumarol verwandter Verbindungen (insgesamt 19) auf ihren analgetischen, antipyretischen und sedativen Effekt. Es zeigte sich, dass 4-0xycumarin bereits in sehr kleinen Dosen (0,025 y/kg an der Maus und 0,1 y/kg am Meerschweinchen) analge- tisch, an der Maus auch sedativ wirkt. Am Kaninchen konnten \vir auch einen antipyretischen Effekt fest- stellen (1 7/kg). Die therapeutische Breite dieser Sub- stanz ist aussergew6hnlich welt. Intramuskul~r und per os vertr/igt die Maus ohne irgendwelche St6rungen auch 40 mg/kg, wAhrend schon 0,025 y/kg deutlich anat- getisch wirken. Gr6ssere Dosen verabreichten wir in 01suspension, well diese Verbindung schwach wasser- 16slich ist. Die bisherige allgemeine pharmakologische Analyse ergab, dass es sich um eine Iiir das Kardio- vaskularsystem sehr schwach toxische Verbindung handelt. 4-Oxycumarin erzeugt eine viel schwAchere Hemmung der Blutgerinnung als Dicumarol.

    4-Oxycumarin ist also das stiirkste bis heute in der Literatur fiir Tiere beschriebene Analgeticum-Antipyre- tieum.

    1 "). STERN

    Pharmakologisches Institut der fvledizinischen Fahultdit, Sara~evo (Jugoslavien), den 9. Apri l 7957.

    Rdsumd Le 4-oxycumarine, chimiquement voisin de l'acide

    salicylique, a sur les animaux de taboratoire un effet f0rtement analgOsique, antipyrOtique et sOdatif.

    1 M. KcBovtc, M. PRAZI6 und D. ATANACKO16, Proc. Soc. exp. Biol. Med. 90, 660 (1955}.

    2 p. STERN, R. I{OSAK und E. BASAGIC, Acta pharm, jugoslav. {im Druck).

    Excretion and Diuretic Act ion of Mercurial Diuretics

    WEINER, BURNETT, and RENNICK 1 recently have pre- sented evidence of tubular secretion of the mercurial diuretic, mersalyl by the kidney of the chicken, utilizing the renal portal circulation technique of SPERBER.

    Since in our laboratory we have been engaged in similar studies also using the SPERBER technique 2, the present short report of our observations supporting and extending those of x,'VEINER et al. might be of some interest. The following mercurial diuretics have been

    1 I. M. WEINER, A. BURNETT, and B, RENNICK, J. Pharmacol. exper. Therap. 118, 470 (t956).

    2 K. LINDAHL and I. SPERBER, Acta physiol, scand. 36, 13 (1956).

    investigated : Chlormerodrin NNR, [3-(chloromercuri)-2- methoxypropyl]-urea; Diurgin (Astra, Sweden), N-suc- cinyl - N'- [(3 - carboximethylmercaptomercuri - 2 - metho- xy)propyl]-urea disodium salt; Esidron (CIBA, Basel), N - (3 - hydroxymercuri- 2-methoxy)propylamidoquinolin theophylline sodium salt; Meralluride USP, 1-(3'-hydro- xymercuri-2'-methoxypropyl)-3-succinylurea theophyl- line sodium salt; Mercaptomerin NNR, N-[(3-carboxy- methyImercaptomercuri)-2- methoxypropyl] -camphora- mic acid disodium salt; Mercumatilin NNR, 8-(2'-meth- oxy-3'-hydroxymercuripropyt)-3-carboxycoumarintheo- phylline sodium salt; Mersalyl BPh, o-[(3-hydroxy- mercuri - 2 - methoxypropyl)carbamyl] - phenoxyacetic acid theophyttine sodium salt; Oration (Ferrosan, Co- penhagen), 3-oxymercu ri-2-methoxy-l-succinimidopro- pyl theophylline.

    (1.) Tubular excretion.-The mercurials were infused into a leg vein and the mercury excretion from each kidney was followed. There was a marked excess of mercury excretion on the side of the infusion with most diuretics. Mercaptomerin and Diurgin showed a highly unsymmetric excretion, mersalyl, meralluride and Esi- dron showed clearly less unsymmetry. There is proba- bly some excess excretion of chlormerodrin and no significant excess of Oradon and mercumatilin.

    (2) Water diuresis.--With suitable doses, a water diuresis can be obtained with all the diuretics tested. In the case of mercaptomerin, Diurgin and meralluride, a strictly unilateral diuresis is easily obtained following injection of the mercurial into a leg vein. With carefu|iy graded doses, it seems to be possible to obtain unilateral diuresis with all the mercurials mentioned above except Oradon and mercumatii in. With mercaptomerin this unilateral diuresis can be achieved even if the total dose (about 1.5 mg Hg/kg) is given within 1 rain. The diuresis in this case has a latency of about 15 min and a duration of about 30 min.

    (3) Salt diuresis.- After both mercumatil in and mer- captomerin, water diuresis is accompanied by sodium and chloride diuresis with no intervening time lag. Not only the amount but also the concentration of sodium and chloride seem to increase over the basal values. The maximal increase in concentration observed with inter- mediate mercurial doses is 3-4 times at the height of the diuresis. Potassium excretion is not increased but rather somewhat reduced.

    (4) Prevention o/unilateral water diuresis by probenecid or bromocresolgreen.-If 20 mg/kg probenecid NNR or 10 mg/kg bromocresolgreen is injected into a pectoral muscle 30 rain before the infusion of an otherwise effective dose of mercaptomerin into the leg vein, neither a bilateral nor an unilateral diuresis results. The excretion of mercury is suppressed.

    (5) Activity and biological hal/-li/e o/ different mer- curial diuret ics.-The mercury of different diuretics leaves the body at greatly varying rates. Expressed as biological half-life of the mercury, the order of increasing biological half-life among the tested compounds is roughly : mercaptomerin, mersalyl, Esidron, merallurid, Diurgin, Oradon, chlormerodrin, mercumatil in. The half-life of mercaptomerin is about 12 min, that of mer- cumatil in about 200 rain. With mercaptomerin the amount of mercury recovered in the urine during the first 3 h is 80-100% of that administered.

    The fact that the excretion properties are so very different is reflected in the varying diuretic activity. The order of increasing half-life is roughly the same as that for increasing diuretic act iv ity per mg Hg and the same as the order of increasing length of diuretic period.

  • 328 Br6ves communications - Brevi coinunicazioni [EXPERIENTIA VOL. XIII/S]

    These exper iments will be cont inued and a full ac- count pub l i shed in the Acta pharmacotog ica et rexco- logca Scand inav ica .

    I). CA1M[PBELL

    Institute o/ -Pharmacology, University o[ Uppsala, (Sweden), May 6, 1957.

    Rdsumd

    Hui t d iur6t iques mercur ie ls ont ~t6 6tudi~s selon la techn ique de SPERnER ut i l i sant la c i rcu lat ion por te rd- nale de la poule. Six d 'ent re eux ont mont r6s c la i rement leur ~ l iminat ion par secret ion tub:f la ire. Une diur~se acqueuse peut ~tre obtenue avec tous les d iuret iques 6tudi~s, darts la p lupar t des cas elle est uni lat~rale du c6t~ injectS. Une diur~se Na et C1 la suit. On peut sup- p r imer la diur~se uni lat~ra le par la proben~cide et le ver t de bromocr6sol . Les compos~s ~tudi6s sont ~limin6s

    des vitesses tr~s diffdrentes. Ceux qui p r~sentent l 'd l iminat ion la plus lente, mont rent 6ga lement l 'act iv i t6 d iur6t ique la plus grande et de plus longue dur6e.

    The Problem of' Conditioning' the Action of Antiphlogistic Corticoids by the Thyroid Gland

    The communicat ions pub l i shed by DOMENJOZ et al.: and STENGER et aL e repor t the loss of ant iph log is t ic act i - v i ty of cort isone, ACTH and o ther ant i - in f lammatory agents a f ter thyro -parathyro idectomy. These authors used the formal in a r thr i t i s tes t as ind icator . SELYE could not conf i rm the i r observat ions . In add i t ion to the formal in a r thr i t i s test, he also used dext ran edema of the ra t paw and the so-cal led 'g ranu loma pouch ' as an exper imenta l model ~. The par t i c ipat ion of o ther factors in the ant iph log is t ic act ion of cort icoids seemed very in teres t ing to us, and we t r ied to ver i fy these observa- t ions us ing another ind icator ' the cot ton pel let granu- loma test ' modi f ied accord ing to 2~/[EIER et al. ~, This test is f requent ly used in tes t ing ant iph log is t ic eort icoids,

    I R. DOMENJOZ, H. NAUMAN, and E. G. STENGER, Exper. tt, 403 (] 955).

    2 E. G. STENGER, H. NAU.~tAN, and R. DO~tENJOZ, Arch. int. Pharmacodyn. 57, o96 (1956).

    P. Bols and H. SE:LYE, Expcr. 1Z, 111 (1956). 4 R. ~IEIER, \V. GCHULER, and P. DESAULLES, Exper. 6, 469

    0950).

    which decrease the quant i ty of newly fo rmed granulo- matous t issue around implanted cot ton pellets.

    Methods.- -Sixty-three male Wis tar rats, kept under s tandard condi t ions on Larsen d iet and tap water ad libturn, were subd iv ided into 7 groups of 9 animuls. The average body weight of these an imals was 110-140 g. In the Group V, VI , V I I thyro-parathyro idectomies were per formed under e ther anaesthes ia . The operated an imals received 100 mg/kg of ca lc ium g luconate sub- cutaneous ly dai ly and 1% ca lc ium lac ta te in the drinking water. After a week all an imals were taken into the exper iment . Cot ton pel lets of average weight 20 -4- 1 mg were imp lanted subcutaneous ly in the interscapulary area of the back. After imp lantat ion , t reatment with predn isone (1 -dehydrocor t i sone-U l t racor ten C[BA) was in i t ia ted in Groups I I I and VI . Each an imal of these groups obta ined 5 mg of predn isone per os dai ly for 7 days. In Groups IV and VI I , the imp lanted cotton pel lets were in jected w i th a single dose of 5 mg hydro- cort isone acetate on 0.2 mI of aqueous crysta l l ine suspen- sion (Hydrocor t i sa te Leo). Groups I, I I and V served as controls. Group I inc luded the in tact contro l animals, each an imal of Group I I received 100 mg/kg of calcium g luconate subcutaneous ly dai ly for 7 days and drank 0-1% ca lc ium lac ta te to e l iminate the inf luence of in- jected and ingested calc ium. F inal ly , Group V consisted of control , thyro -parathyro idectomized alf imals. After 7 days, the granu lomas wh ich developed were excised in all groups and careful ly dissected f rom the surround- ing free tissue. The granu lomas were dr ied at 54 C over- n ight and then weighed to es t imate the dry weight. The weight of the imp lanted cot ton petter was then subtracted f rom the dry we ight of the granu loma.

    Results.-- The pr inc ipa l f indings are summar ized in the Table. The stat is t ica l eva luat ion was made after FISHER ~. The ant iph log is t ic cort icoids g iven e i ther per os (prednisone) or local (hydrocort isone acetate) inhibited the deve lopment of co t ton pel let g ranu loma. Calcium g luconate a lone d id not inf luence s igni f icant ly in any way the deve lopment of granu loma. Thyro-parathyro- idectomized an imals exh ib i ted s l ight ly reduced formation of g ranu lomatous tissue. P redn isone and hydrocortisone acetate exer ted a marked inh ib i to ry effect also in thyr0- parathyro idectomized animals. F rom these results we could not conf i rm the observat ion of Do. ,~NJoz and SrENGER. The mechan ism of ant iph log is t ic corticoids act ion is ma in ly direct, independent of thyro id and

    5 R. FISHER, Statistical methods for research workers (London 1931).

    The effect of prednisone and hydrocortisone acetate on the formation of cotton pellet granuloma in intact and thyro-parathyroidectomized rats.

    Group

    I II

    I I I IV

    V VI

    VII

    Treatment

    Intact control Intact control - 100 mg/kg calcium glu- conate daily Prednisone 5 mg per os daily Hydrocortisone acetate 5 mg Iocal . . . .

    Thyro-parathyroidectomy control . . . Thyro-parathyroidectomy - prednisone 5 mg per os daily Thyro-parathyroidectomy - hydrocorti- sone acetate 5 mg local

    Dry weight of granuh~ma (rag)

    q5

    48.3 ~ 4.7

    47.2 ~ 3-8 32-8 ~ 0.7 13.9 4- 0.5

    45.0 ~ 5.8

    31.7 -4- 0.9

    17.0 ~ 1-3

    14.3

    11.4 4- 2-3 -4- 1.5

    ::~ 17.6

    -4- 2-6

    3.0

    ms:gnifieant < 0.01 < 0'01

    < 0.01

    < 0.01

    {ib statistical average; a statistical deviation; p value of probability