New and Nonofficial Drugs

Prescription Practice

New and Nonofficial Drugs Items Recently Evaluated by the American Medical Association Council on Drugs.

Dihydrotachysterol Hytakerol (Winthrop); 9,ID-Seeoergosta-5, 7, 22-triene-3 ,,-01.- Dih ydrotachysterol is prepared in noncrystalline form as an oil solution, which is standardized biologically and adjusted to a potency equivalent to 1.25 mg. of the crystalline material per cubic centimeter. The structural formula of dihydrotachysterol may be represented as follows: CH.

effect is partially responsible for th e elevation of serum calcium when using each of the preparations. It seems unlikely that minor differences in the physiological effects of these pre para tions, such as in their effects upon serum and urine phosphate, would prove decisive in the choice of an activated sterol for the control of hypocalcemia. The same may be said concerniug even the major differences in their influence upon the absorption of calcium from the intestines. Except for the fact that dihydrotachysterol appears to act more rapidly and to be more rapidly disposed of when its admin istration is discontinued, there seems to be little ground

CH.CH.

is initiated with relatively high doses. Thcse range from 3 to 10 cc. (or 6 to ;20 capsules) per day for several days. Maintenance doses average 1 to 7 cc. (or :2 to 14 capsules) per week, depending upon the blood and urine calciulll leVels.

Hydroxystilbamidine Isethionate Hydroxystilbamidine Isethionate (Merrell) ; 2-Hydroxy-4, 4'-stilbenedicarboxamidine di(/3-hydroxyethanesulfonate) .- The structural formula of hydroxystilbamidine isethionate may be represented as follows:

HO

,NH. ,r;,. O~ CH=CH O~ C ,,'

H.N, HN

HO

Actions and Uses. Dihydrotachysterol is obtained by the reduction of tachysterol, a derivative of irradiated ergosterol. Chemically, however, it is more closely related to calciferol (vitamin D 2 ), differing from it structurally in that the = CH 2 group at C-19 is reduced to - ·CHa, with the elimination of the double bond. This difference is responsible for the fact that dihydrotachysterol has only a small fraction of the antirachitic potency of calciferol (1/400 to 1/.500), although it r etains the abil ity to raise the calcium concentration of the blood. Because of its chemical similarity to calciferol and its strong "calcemic" activity, for which it is chiefly used in therapy, the current trend is to regard it as a form of vitamin D. Dihydrotachysterol, when administered in appropriate doses, raises the level of total calcium and, consequently, the concentration of ionic calcium in the serum. Because of this calcemic effect, it is of value in correcting the hypocalcemia of hypoparathyroidism (idiopathic or postoperative) and pseudohypoparathyroidism thereby controlling tetany and preventing cataract formation and other manifestations of hypocalcemia. Another important use of dihydrotachysterol, presumably also dependent upon its calcemic effect, is in the treatment of vitamin Dresistant rickets. Its effectiveness in this disease appears to equal the effectiveness of la rge doses of calciferol. Dihydrotachysterol may be given orally over considerable periods of time, provided that the serum calcium is not permitted to rise above normal levels. The weight of evidence at the present time is that four substances, namely, calciferol (vitamin D z ), vitamin D" dihydrotachysterol, and parathyroid hormone, all have a direct effect on the mobilization of mineral from bone, and that this

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for a choice between calciferol and dihydrotachysterol, either on the basis of the effectiveness of the calccmic action, common to both. or of relative toxicity or other undesirable side-effects. Both of these preparations are u seful, and the selection of one for use is largely a matter of individual preference. Possibly the recent suggestion that the medication be changed occasionally from one preparation to the other in the coursc of longcontinued replacement therapy will prov e of value. Dihydrotachysterol has been reported to have beneficial effects in treating scleroderma. but this evidence is scanty and inconclusive. Successful use in the tetany of pregnancy has also been reported, but the desirability of such use has been questioned. Administration of dihydrotachysterol or any other preparation to raise the serum calcium level is contraindicated in hypocalcemia associated with renal insufficiency and hyperphosphatemia. Dihydrotachysterol, like calciferol, is a highly potent preparation. The doses required to maintain the serum calcium at or near the normal level border on those doses that are definitely toxic. For this reason eith er preparation must be used with extreme care, especiall y during the initiation of therapy when the dosage for the individual is being established . After this has been accomplished, the Sulkowitch test for excessive excretion of calcium in the urine is a useful adjunct to therapy. Dosage.- Dihydrotach ysterol is adm inistered orally either as an oil solution of which 1 cc. is equivalent to 1.25 mg. of the crystalline material, or in capsules each containing 0.5 cc. of the solution or the equivalent of 0.625 mg. of crystalline dihydrotachysterol. For the treatment of the hypocalcemia of h ypoparathyroidism or of vitamin D-resistant rickets, therapy

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2 HOCH.CHzSO.H

NH

Actions and Uses. Hydroxystilballlidine isethionate, an aromatic diamidine base. is a derivative of stilbamid ine isethionate and exerts the same type of antifungal-antiprotozoan activity as the latter agent. The chemotherapeutic spectrum of hydroxystilbamidine appears to be identical with that of its predecessor, stilbamidine. The chief difference b etween these agents lies in the fact that whereas stilbamidine frequently produces a late trigeminal neuropathy, this has not been observed with use of hydroxystilbamidine. This difference is considered sufficiently important to warrant replacement of stilbamidine by the equally effective. but less toxic, hydroxy derivative. Hydroxystilbamidine isethionate ap· pears to be the best chemotherapeutic agent available for the treatm ent of Korth American blastomycosis. Adequate ther· apy will frequently lead to complete eradication of severe pulmonary and systemic infections which, prior to the introduction of the diamidine compounds, were COI l· sidered incurable. Hydroxystilbamidine may also be used in conjunction with iodine and roentgen therapy for the treatment of the localized or cutaneous forms of the disease. Although no data are as yet available. it is possible that the drug may a lso be of some usefulness in South American blastomycosis and coccidioidomycosis It is of no value in the treatment of Torula infections or histoplasmosis. Hydroxysti!bamidine is effective for the lIIanagemcn t of certain types of leishmaniasis. Although antimony compounds are generally considered to be drugs of choice for this protozoan infection, hy· droxystilbamidine may frequently pro· duce beneficial effects in patients who fail to respond or are intolerant to antimonycontaining agents. The drug apparently Continued

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New and Nonofficial Drugs

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CI

O

'I ~ -

is equa ll y useful for Am erican mucocuta neous leish ma niasis a nd for kala-aza r (visceral leishma niasis). There is some evidence that actinomycosis is influenced favorably by use of hydroxystilbamidine. However, since thi s mycotic disease is treated effectively with antibiotics in approximately 80% or more of the cases, hydroxystilbamidine should never be considered a primary th erapeutic agent. A trial of th erapy with hydrox ys tilbamidine is warranted in actinom ycosis only in those patients who ha ve fa iled t o r espond to adequa t e trea tm ent with the preferred a ntibiotics. To date, there a re no reports on the use of hydroxystilba midin e in Africa n trypanosomiasis. H owever, on the basis of its close similarity to stilba midine, it may be predicted th a t th e h ydrox y deriv a tive, like the pa rent drug, will be effective in early cases of Gambian a nd Rho desia n trypanosomiasis ( Africa n sleeping sickness). Since neither form of the drug ga ins access to th e cerebrospina l fluid nor can be given intrathecally , it cannot be expected t o be u seful a nd should not be administered in th e la te neurolog ica l stage of the disease. Th e diamidines a re of no v a lue in South Amer ican try panosom iasis (Chagas' disease). Because of th e co mmon fac tor of h yperglobulinemia in ka la-azar a nd multipl e myeloma , the dia midines have been tried for the treatment of the latter disease. In some pa tients, such therapy a ffords marked, but temporary, relief from pain . There is a lso som e evidence tha t it can cause fa vorable m orphologic cha nges in the myelom a cells of some patients. H owever, the response is u sually inconsistent, a nd, even in the m ost fav ora ble cases, rela pse inevita bly occurs. There is no evid ence that h ydroxystilbamidine a ffect s the course of the disease, prolongs the life of pa tients with multiple myeloma , or causes arrest of the neoplastic process. In general, the use of urethan or roentgen irradia tion to localized lesions is considered preferable for the initial treatment of the disease. However, in view of the inadequac ies of th ese a nd a ll other modes of therapy, a trial of h ydroxystilba midine may also be justified for the pallia tion of pain in multiple myeloma. Aside from the a b sence of late trigem ina l neuropath y, oth er t ox ic ma nifestations refera ble to h ydrox ystilbamidine appea r to be somewh a t less frequent than with use of stilbamidine. However, any of the immedia t e sid e reactions which have been observed during or immedia tely after intravenous inj ec tion ot stilbamidine may be expect ed t o occur with the use of hydrox ystilbamidine. These effects, believed to be due t o th e release of bound hist a mine, include th e following: fa ll in blood pressure, rapid pulse, facia l flu shing, dizziness, salivation, swea ting, headache, nausea, vomiting, dyspnea, formica tion, syncope, fecal a nd urina ry incontinence, and edema of the eyelids and face. Such side effects, if present, a re usually transitory a nd disa ppear within 10 to 30 minutes They may be minimized by slow intravenous infusion of d iluted solutions.

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H ydroxystilbamidine isethiona t e in solution is unstable when exposed directl y t o heat, sunlight, and ultraviolet light. Such exposure causes partial d et eriora tion of th e drug a t the unsatura ted stilbene linkage with release of toxic breakdow n produc t s. Deterioration ma y be prevented b y storing the drug in a dry form away fr om hea t and light. Freshly prepa red solutions should be protected similarl y. After inj ec tion, patients should avoid excessive ex posure to sunlight on th e premise tha t toxic products may be form ed from the drug remaining in the skin . Th ere is n o ev id ence th a t fresh ly prepared solu tions of h yd roxystilba midine isethionate are toxic t o th e kidney or liver. Neverth eless, rena l a nd hepa tic functi on sh ould be evaluated prior to initiating th erapy , a nd the drug should be administered cautiously a nd in reduc ed dosage in th e presence of renal or hepa tic disease. D osage. Hydroxystilba midine isethi ona t e is administered by continuous, slow, in travenous drip and, ra rely, by intramuscular inj ec tion. For intravenous use, a freshly prepared solution of the dose t o be used is dilu ted in about 200 cc . o f either 5 % dex trose in water or iso tonic sod ium chloride solution. This is infused over a period of 45 minutes t o 2 hours. Slow infusion is essential t o avo id a fall in blood pressure or other side effec t s. During infusion, the solution should be prot ect ed from light by covering th e cont a iner with black paper or a heavy towe l. At wa rm tempera tures, it may be a dvisable to complete the inj ec tion in so mewha t less tha n 2 hours to avo id dangerous det erioration of the solution . In occasional cases in which int ravenou s use is not feasible, it m ay be necessa ry t o adm inister hydroxystilba midin e isethiona te by th e intramuscula r route. F or such use, the proper amount of th e dry , steril e powder is dissolved in 10 cc. o f 5 % dextrose in wa ter or isotonic sodium chl oride solution a nd is administer ed b y deep intragluteal injection. Since pain a t th e site of inj ection follow s its intramuscula r use, th e drug should be given intravenously whenever possible. F or treatment of susceptible funga l or prot ozoan infections, the suggested dosage for a dults is 225 mg. a t interva ls of 24 hours. The duration of such thera py is d et ermined by clinical improvement a nd disap pear a nce of causative agents from th e lesions. For example, a course of therapy consisting of daily inj ections of 225 mg. may be as short as 1 week to 10 days in cases of high ly susceptible ka laazar t o as long as 2 to 3 m onth s in severe blast om ycotic infections. Clinica l improvement is the sole criterion for total d osage when the drug is tried as a palliative agent in mUltiple m yeloma . For a ll indications, dosage for children is reduced proportionally according t o body weight or body surface.

Phenaglycodol

Ultran (Lilly); 2-p-Chlorophenyl3- meth yl-2,3-bu tane- dio l.

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OHOH C-C -CHl I

I

CH 3 CH 3

Actions and Uses. Ph e naglycodol is one of a series of synth etic diol compounds that exert a mild depressant effect on the central nervous syst em. At lea st at the level of the spinal cord, the drug has properties in common with the interneuronal blocking agents such as mephenesin and meproba ma te. Phenaglycodol and meprobamate have a common chemical derivat ion from mephenesin . In the case of phenaglycodol, a degree of m etabolic stabilization is achieved by full substitution on the OH-bea ring carbon a t oms. In experimenta l anima ls, ph enaglycodol produc es some degree of skelet a l muscle relaxation a nd exerts a n inhibitory influence on transmiSSiOn through polysynapt ic pathways . It a lso diminishes the severity of electrica ll y induced convulsions in animals, a nd initia l clinical experience has suggested a possible usefulne ss in epilepsy. As a muscle relaxant , ph ena gl ycodol is much less potent than mephenesin. From the st a ndpoint of overall clinica l usefulness, ph ena glycodol is probably most closely comparable to meprobamate. Hence, it m ay be cha racterized as a mild sedati ve with weak muscle- relaxing properties. Phenaglycodol has been used t o produce a calming or mood-ameliorating effect in patien'ts with emotional inst a bilit y, anxiety-tension st a tes, a nd functional disorders. Although early reports have been favo rabl e, there is need for m ore evidence to establish conclusively its usefulness as a psychoth era peut ic agent . Studies designed t o compare its tension-relieving effec t s with meproba ma t e are inconclusive. In some patients with anxiet y states, the drug has elicited a degree of behavioral improvement ; in ot her studies the effect has been primaril y th a t of a placebo . In general , phenaglycodol appears to be simila r in effectiveness t o meprob a mate, but the ultimate usefulness of this t ype of drug must await th e result s of further clinical experience. From the evidence available t o date, it would a ppea r th at ph enaglycod ol may have usefuln ess in the ad junctive management of simple neuroses. The drug probably has no place in th e treatment of the more severe psychotic type of menta l disturbance a nd cannot be classified as a tranquilizing a gent in the sam e sense as chlorpromazine or reserpine. The toxicity of ph enaglycodol is low. No adverse effect s on hepatic or hematopoietic function have been observed after long-term a dministrat ion to a nimals and patients. In clinical experience, large doses are a pparently withou t effect on blood pressure, pulse, or respiration. To da te, drowsiness a ppears to be the only side-effect r eferable t o therapy with phena glycodol. This has occurred only occasiona ll y and genera ll y follows th e administration of high doses. Dosage. Phenaglycodol is administered orally. Th e usua l dosage for adults is 300 mg. three or four tim es da ily.