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United States Patent (19) 11 Patent Number: 4,673,681 Poli 45 Date of Patent: Jun

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United States Patent (19) 11 Patent Number: 4,673,681 Poli 45 Date of Patent: Jun United States Patent (19) 11 Patent Number: 4,673,681 Poli 45 Date of Patent: Jun. 16, 1987 54 PHARMACEUTICAL METHODS HAVING tine and Amitriptyline in the Treatment of Endigenous DOPAMNERGIC ACTIVETY Depression. 75 Inventor: Stefano Poli, Milan, Italy The Lancet, vol. 1, p. 735, Apr. 8, 1978. Physician's Desk Reference 1982, p. 1684-San 73) Assignee: Poli Industria Chimica S.p.A., Milan, doz-Cont, Italy Critical Analysis of the Disability in Parkinson's Dis 21) Appl. No.: 847,395 ease by: David D. Webster, MD. 22 Filed: Apr. 2, 1986 Chem. Abst. (1969)-71 4228ip. 30) Foreign Application Priority Data Primary Examiner-Stanley J. Friedman Apr. 4, 1985 IT Italy ............................... 20234 A/85 Attorney, Agent, or Firm-Michael J. Striker 51) Int. Cl“.............................................. A61K 31/44 57 ABSTRACT 52 U.S.C. .................................................... 54/288 A pharmaceutical composition containing a-dihydroer 58) Field of Search......................................... 514/288 gocryptine, or a salt thereof, is used in combination with 56) References Cited pharmaceutically acceptable carrier means or excipient PUBLICATIONS for the treatment of Parkinson's disease, depression or A Rating Scale for Depression by: Max Hamilton. cephalalgias is disclosed. A method for administering The Evaluation of Extrapyramidal Disease by: Roger the composition to a patient is also provided. C. Duvoisin. A Comparative, Multicenter Trial between Bromocrip 4 Claims, No Drawings 4,673,681 1. 2 PHARMACEUTICAL METHODS HAVING TABLE -continued DOPAMNERGIC ACTIVITY De novo BASAL WEEKS OF TREATMENT patients VALUES 2 5 1 6 The present invention concerns a new therapeutical 5.87 5.61 5.27 5.57 555 use of a-dihydroergocryptine and pharmaceutical com Legend to Table 1 positions containing the same as an active agent for the WRS; Webster Rating Scale (Webster, D. B., 1968 Modern Treatment, 5, 217); 'CURS: Columbia University Rating Scale (DUVOISN R. C., 1970 - The evalua treatment of parkinsonism, depression and cephalalgias. tion of Extrapyramida Disease. In "Monoamine, noyaux gris centraux et syndrome a-dihydroergocryptine O 12'-hydroxy-2'-(1- de Parkinson"; de Ajuriaggera J. (Ed.) Masson, Paris, pp. 313-325). methylethyl)-5'a-(2-methylpropyl)-9,10-dihydro 10 P < 0.0i vs. basal values, ergotaman-3,6,18-trione, is a known compound, de rived from the hydrogenation of the double bond, in Moreover, dihydroergocryptine, administered in par position 9, 10 of the natural alkaloid o-ergocryptine. kinsonian patients previously treated with 1-DOPA and This compound is generally used in association with bromocriptine, allowed the complete withdrawal of dihydroergocristine and dihydroergocornine, for the 15 bromocriptine and the reduction of 1-DOPA dosage therapy of cerebrovascular disturbances especially for with an evident reduction of side effects, maintaining elderly persons. the same therapeutical activity level in the same pa The capacity of dihydroergocryptine and, generally, tients. of other similarly hydrogenated alkaloids, to binda and In Table 2 there are reported, for example, the D receptors at different levels in the CNS and peripher 20 changes of symptomatology in seven parkinsonian pa ally is known. On the basis of such pharmacological tients, already treated with BCR--1-DOPA, after re activities, the primary use for which dihydroergocryp placement of BCR with a placebo and subsequent intro tine, alone or in association, has been used up to now, is duction of dihydroergocryptine 40 mg/die: the senile cerebrovascular insufficiency in its many TABLE 2 manifestations. 25 It has now been surprisingly discovered that dihydro Patients already under treatment with BRC + 1-DOPA ergocryptine, event when active in the cited patholo Didroergo gies, can be advantageously used for the treatment of BRC Placebo cryptine pathological conditions of the Central Nervous System WRS 19.86 84 22.71 -2.01 1953* 2.23 such as parkinsonism, essential cephalalgias and depres 30 CURS 30.57k - 6.8 37.86 6.97 30.0 - 7.24 sions, the etiological causes of which can be linked to a *P a 0.01 vs. placebo dopaminergic lack. The treatments known, in fact, fore see the administration of 1-DOPA or ergolinic deriva Moreover, treatment with dihydroergocryptine was tives o-bromocriptine and ergotamine (Calne D. B., also discovered to be effective in the treatment of de Lancet (1978) 1,735 and Theohar C., Arzneim. Forsch. 35 pression; a condition in which a dopaminergic lack is (1982) 32,783). The latter treatments, however, besides present. In the treatment of depressed patients, dihydro the dopaminergic agonistic action, induce an undesired ergocryptine showed a particularly good speed of effec peripheral activity suggesting that it is preferable to tiveness and a tolerability level higher than that of tricy avoid use of such treatments in a high percentage of clic antidepressants, thus leading to the conclusion that patients due to the significant and severe side effects 0 its elective use in elderly patients with depressive symp (for bromocriptine hypertension in 28% and syncope in tomatology would yield positive results. 0.7% of cases; vomiting in 3% of cases; Physicians' Desk Table 3 reports, for example, the evolution of depres Reference, p. 1684 (36th ed. 1982). sive symptomatology in 18 patients treated with dihy Surprisingly, dihydroergocryptine, while being ac droergocryptine drops 1.5-2 mg, three times daily. 45 tive in the treatment of the CNS pathology, as indicated TABLE 3 above, did not show any of the side effects common to other ergolinic compounds already known. HAMILTON RATING SCALE FOR DEPRESSION 1 This phenomenon leads to the finding that dihydroer Values After 7 Days After 14 Days After 21 Days gocryptine has a selective dopaminergic activity for 50 34.6 24.39 1.93 7.44 - 180 14.50 - 1.72 CNS which, prior to the present invention, was neither 1.52 taught nor suggested by the prior art, Hamilton M., 1960 - J. Neurol. Neurosurg, Psychiat., 23, 56 In the treatment of Parkinson's disease, dihydroergo P a 0.01 vs. basa values cryptine, administered as methanesulfonate, resulted in reducing tremors, akinesia and rigidity, at doseage lev Chronically administered in patients with essential or els of between 10 and 100 mg daily, when administered 55 vasomotor cephalalgias, dihydroergocryptine induced a alone in de novo patients. 57.8% reduction in frequency and severity of head Typicals examples and results obtained in the treat aches, allowing a recovery to an active, normal life and ment of Parkinson's disease are presented in Table 1. In a lower consumption of antalgic agents. Table 1, there are reported changes in symptomatology 60 a-dihydroergocryptine can be administered by oral, in seven de novo parkinsonian patients treated with sublingual, parenteral or percutanous means as a phar dihydroergocryptine 40 mg/die: maceutical composition prepared for the foreseen use. TABLE For the treatment of parkinsonism, daily dosage, De novo BASAL WEEKS OF TREATMENT expressed as methanesulfonate, can vary from 10 to 200 patients VALUES 2 5 11 16 65 mg, according to weight and conditions of patients. WRSl 14.86 - 13.28 12.14 1143* - 10.43 Lower dosages are preferred, on the contrary, for the 1.67 1.91 1.67 1.68 1.69 treatment of depression and cephalalgias, for example, CURS2 30.14 28.86 26.71 - 23.57 21.7 - from 2 to 20 mg in 1-3 administrations. 4,673,681 3 4 Pharmaceutical compositions, the object of the pres Capsules ent invention, will be prepared according to conven One capsule contains: tional techniques, using compatible excipients and phar Dihydroergocryptine methanesulfonate: 3 mg maceutically acceptable carriers, and may contain, in starch, lactose, magnesium sterate, microcrystalline combination, other active principles with complemen cellulose q.s.: to 100 mg tary or, in any case, useful activity. Examples of these While only several embodiments and examples of the compositions prepared according to the present inven present invention have been shown and described, it is obvious that many changes and modifications may be tion include capsules, pills, tablets, drops, ampoules for 10 made thereunto, without departing from the spirit and i.m. and i.v. administration, possible forms for pro scope of the invention. longed administration of active principle (retard forms), What is claimed is: etc. 1. A method for the treatment of a person with Par The pharmaceutical compositions of the present in kinson's disease, cephalalgias or depression, comprising 5 the step of: vention will now be more fully described by the follow administering an effective dosage of dihydroergo ing examples of these types of preparations. It should, cryptine, or a salt thereof, in combination with a however, be noted that such examples are given by way pharmaceutically acceptable carrier means to said of illustration and not of limitation. person. 20 2. The method according to claim 1, wherein said Drops administering step includes the administration of from 10-100 mg/die of dihydroergocryptine mesylate as said 100 ml contain: effective dosage for the treatment of Parkinson's dis Dihydroergocryptine methanesulfonate 200 mg CaSc. propylene glycol q.S. 25 3. The method according to claim 1, wherein said administering step includes the administration of from Ampoules 2-10 mg/die of dihydroergocryptine mesylate as said Each ampoule contains: effective dosage for the treatment of depression. Dihydroergocryptine methanesulfonate: 0.5 mg 4. The method according to claim 1, wherein said 30 administering step includes the administration of from propylene glycol: 100 mg 2-10 mg/die of dihydroergocryptine mesylate as said methanesolfinic acid qis.: to pH=3 effective dosage for the treatment of cephalalgias. bidistilled water q.s.: to 1 ml k k k st k 35 40 45 50 55 60 65 .
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