USE OF RUBIDIUM AND IN PARTICULAR RUBIDIUM CHLORIDE AS AN ANTIMANIC AGENT AND STABILIZER FOR MOOD SWINGS

Abstract: Rubidium chloride (RbC1) is used as a stabilizer for mood swings and antimanic agent, in much lower doses than those causing an antidepressant effect.

Description: USE OF RUBIDIUM AND IN PARTICULAR RUBIDIUM CHLORIDE AS AN ANTIMANIC AGENT AND STABILIZER FOR MOOD SWINGS DESCRIPTION This invention relates to the range of drugs which act on the Central Nervous System, and in particular concerns the use of a substance known for some time (rubidium: chemical symbol Rb) , as a depressant and antimanic agent, in the dosages established below, resulting from experiments carried out. Rubidium (Rb) , discovered in 1861 by Bunsen and Kirchoff, is a monovalent alkali metal of group 1A belonging to the same periodic series as lithium, sodium, potassium and cesium. Its atomic weight is 85 and its isotope Rb 8S is widely used in biomedical experimentation. It is virtually present in all biological systems . Functionally, Rb is similar to potassium: it is also a predominantly endocellular ion, is transported through the cellular membranes by the stimulated ATPase Na + / + , Mg 2+ dependent, and uses the channels to the K + as an exit . Experimentally Rb has been and is especially used for its similarities to K + whose physiology it closely resembles . Rb was introduced in clinics in 1888 in bromide form as an anti-epileptic and as an iodide in syphilis therapy. After more than 70 years of silence, Rb was rediscovered in 1969 by Meltzer, who described its effects on animal behaviour. Rb increases the intraspecific aggressiveness of the rat subjected to harmful stimuli and increases hypermotility due to morphine in the mouse. Because of these effects it is being put forward as a possible antidepressant drug, as against lithium which presents the opposite kind of activity. The truth of the matter is that pre-clinical experiments performed so far on rubidium have not provided positive or clear results by which one can anticipate its clinical use. Rb has similar pharmacokinetics to that of K + ; it is absorbed by the same mechanisms, from the plasma it is distributed quickly, first to the remaining extracellular liquid, then slowly penetrating into the tissues: the equilibrium between extra and intra- cellular concentration is achieved 3 days after administration. Its half-life in the organism (50-60 days) is lengthier than that of K + (34 days) , probably because it is transported more slowly to the outside of the cells . Rb has a very low toxicity and only if one succeeds in substituting over 40% of the K + present in the organism does it cause serious symptoms such as convulsions and death. Practically speaking, these concentrations can only be achieved in experimental conditions, therefore the tolerability of Rb is considered extremely high. Rb has been introduced and used in clinics as an antidepressant for several decades. Despite its long half -life and the dosages used, it has never caused accumulation or obviously toxic symptoms directly related to its use. Despite the high tolerability of rubidium by the human organism, up to now there are still a number of misgivings in the scientific world about its true therapeutic faculties, and particularly its behavioural effects on the animal subjected to the experiment. In particular, rubidium has still not been used as an antimanic agent or depressant, and drugs now on the market for the treatment of these pathologies cause (or can cause) side effects. Description of the invention The purpose of this invention is to make available to doctors and patients affected by the above pathology: - • A highly tolerable drug, that is one with practically no chance of causing undesired side effects; • A drug which is effective at the suggested posological dosages; • A treatment for manic disorders at a lower therapeutic cost . All this is because, surprisingly, from studies and experiments carried out since the invention, it has emerged that Rb, at a dosage of around 1 mg/kg every three days, has a depressant and antimanic effect. This effect has been tested, as shown from the examples and tables below, based on the learned helplessness (LH) model, in other words the reduced reactivity induced in the animal, caused by repeated exposure to harmful or disagreeable stimuli in a condition of inevitability. The main observation was that 4 days from administration of rubidium in a group of rats, at doses of 0.5 mg/kg, 1 mg/kg and 10 mg/kg, an antidepressant action was achieved that, particularly in the case of the last two doses (and 1 and 10 mg/kg) , can be added to the intensely protective activities caused by the antidepressants ; imipramine (IMI) and fluoxetine (FLX) . To test the performance of rubidium over the course of time, a second experiment was carried out, from which it emerged that at doses of 1 mg/kg every 72 hours, rats subjected to the flight test (every three days) , were progressively more "depressed". In other words, this second test has shown - surprisingly - that Rb, despite its initial antidepressant action, in time produces an opposite effect. To confirm this result, RbCl was administered in a third test with a saline solution in an initial group of rats, and together with IMI and FLX, respectively, in another two groups of rats. It was seen that the addition of the antidepressants IMI and FLX found the number of flights at normal levels, whereas the administration of RbCl alone caused a depressive condition in the long run. Since the depressant effects of Rb, as shown by the test, were caused with much lower doses (from 0.2 to 5 mg/kg/day) than those for example previously proposed and used in Rubinorm ® (from 360 to 720 mg/day) , it can be deduced that an Rb or RbCl based drug as an antimanic drug at a dosage of 0.2 to 1.5 mg/kg/day, will be absolutely tolerable and also reasonably priced, given the low percentage of active principle. For clinical use two oral pharmaceutical forms were proposed; capsules (cps) and tablets (cpr) for the following dosages: 1.5, 20 mg/cpr or cps. By way of an example, but not in any sense restrictively, below are the compositions of two typical formulations : - 5 mg RbCl capsules P. A. : Rubidium Chloride 5 mg Excipients : Lactose 180 mg Magnesium Stearate 5 mg Gelatine 75.4 mg Titanium dioxide 1.54 mg 5 mg RbCl tablets P . A . : Rubidium Chloride 5 mg Excipients : Precipitated Silica 145 mg Maize starch 8 mg Tribasic citrate 43 mg Magnesium Stearate 2 mg This invention is now illustrated as an example, but not restrictively, with reference to some examples and drawings attached, in which: FIGURE 1 shows how the appetitive behaviour of rats accustomed to consuming the bait, remains constant even when these are subsequently treated with RbCl at 1 mg/kg every 72 hours; FIGURE 2 shows the serious learning deficit in rats previously treated with RbCl and subsequently taught to consume the bait. The learned helplessness (LH) model is based on reduced reactivity induced in the animal by repeated exposure to harmful or disagreeable stimuli in a condition of inevitability. This effect of reduced reactivity is thought to be an animal kind of depression: in fact this behaviour is countered selectively by drugs with antidepressant activity in clinics. The effects of Rb on LH have been studied in the rat alongside those of imipramine (IMI) and fluoxetine (FLX) . The method used has been described extensively in numerous publications of the research group to which the inventor belongs. The effects of Rb have been studied both after acute administration and after chronic administration. The research began with a preliminary experiment: since Rb is an endocellular ion which reaches equilibrium in the neurons 3 days after administration, the experiment was carried out by treating 3 groups of rats with three different doses of RbCl and testing any protective effect of the Rb after 96 hours. The information in Table 1 shows that the doses of both 1 and 10 mg/kg have confirmed considerable protective activity in acute circumstances, which can be added onto that obtained with a chronic treatment using the antidepressants IMI and FLX. TABLE 1 Effect on the development of learned helplessness of different doses of RbCl administered 3 days before the pre-test. IMI and FLX were administered daily up to the day of the pre-test for a total of 2 weeks. The values are the average ± S.E.M. calculated on the number of animals shown in brackets. Drugs with an antidepressant action generally show their • effectiveness on experimental models after prolonged treatment, such as in a clinic; moreover, this effect lasts for some time. Naturally this fact is not detrimental when it comes to evaluating the effectiveness of a substance. But in the case of Rb, which has a half-life of around two months and, therefore, an activity period which is just as long, it was essential to check whether the anti-LH effect observed after acute administration remained unchanged over the course of time. A group of rats began treatment with RbCl at doses of 1 mg/kg every 3 days. Sub-groups of these animals were subjected to the pre-test and the next day to the flight test every 3 days. The information in Table 2 shows that 3 days after a single administration, Rb fully impedes development of LH . This effect tends to diminish on the 6 th day and is practically absent on the 9 th . Based on these results, the rats in the fourth sub-group were satiated on the 12 day for the flight test without undergoing the pre-test. In conclusion, Rb brings about a clear reduction of the reactive capacity to harmful stimulants. TABLE 2 Learned Helplessness in rats treated with Rb 1 mg/kg every 72 hours The values are the average ± S.E.M. calculated on the number of animals shown in brackets. Rb therefore has an initial antidepressant action which has the appearance of tolerance and which gradually changes into an opposite effect: that is to say of depressant and, potentially antimanic type. Treatment with a drug of this kind could constitute per se a form of animal depression. To assess this possibility, two experiments were carried out : - a) 30 rats were sub-divided into 3 groups, and treated as follows :- 1) 10 animals received RbCl 1 mg/kg every 72 hours + saline solution 1 ml/kg/day for a total of 21 days; 2) 10 animals received RbCl 1 mg/kg every 72 hours + IMI 10 mg/kg/day, for a total of 21 days; 3) 10 animals received RbCl 1 mg/kg every 72 hours + FLX 5 mg/kg/day, for a total of 21 days. The test, with no pre-test, was carried out on the 22 n day. Table 3 shows the information obtained. The rats treated with Rb alone showed a serious flight deficit which both antidepressants were capable of preventing. TABLE 3 Effect of co-administration of RbCl + IMI or FLX on the development of hypo-reactivity from Rb RbCl (1 mg/kg every 72 hours) has been linked to the daily administration of IMI (10 mg/kg) or FLX (5 mg/kg) for a total of 21 days. The values are the average ± S.E.M. calculated on 10 animals. The Rb administered chronically induces symptoms of slowing down in the rat . Slowing down is a symptom of depression in man, but depression is also characterised by a reduced capacity to experience pleasure at physiologically gratifying stimuli such as food and sex. We therefore studied the effect of Rb on a type of appetence . a) Rats fed with no restrictions show a propensity for certain foods (baits) in themselves particularly palatable and are prepared, even if satiated with their standard food, to work to obtain them. Rats fed ad limitum have been trained to recognise the corridor of a Y labyrinth at the end of which the bait is located: and they learn, over the course of 10 days, making 10 consecutive attempts a day, to reduce the number of errors and to obtain 6-7 prizes per session in a period of 30 seconds. Once structured, the appetitive behaviour is very stable and resistant to treatments . We studied the effect of chronic Rb both on animals previously taught to consume the bait and on animals in the learning phase. On rats which have reached a stable base of 6-7 successes a day, Rb (RbCl 1 mg/kg every 72 hours for 21 days) has not significantly altered the expression of the appetitive behaviour monitored every 3 days, prior to the subsequent treatment (Fig. 1) . Instead, rats treated with RbCl 1 mg/kg 72 hours for 21 days, and then subjected to the behaviour protocol in operation for the consumption of the bait (still under treatment with RbCl) , have shown a serious learning deficit (Fig. 2) . The RbCl administered chronically induces, therefore, a state of anedonia. In Fig. 1 the number of successes is shown on the ordinates axis, whereas the X-axis indicates the test carried out (one every three days) . In the second figure, the black rectangles refer to the control group, and it is obvious from Fig. 2 that the number of successes during each "training" session increases for untreated rats, whereas it remains more or less constant for rats treated with RbCl both before and during teaching. Industrial application What is extremely interesting is that the depressant and antimanic effects of Rb work and continue to work for very low doses compared to those used both experimentally and in the clinic to test the antidepressant activities of the same. According to the invention it will therefore be possible to make a drug available with antimanic action, based on Rb, and in particular RbCl, in which the quantity of RbCl, in relation to the excipients is very low, so as not to bring about absolutely toxic effects . The effectiveness of the drug in the animals used for the experiment was also extensively tested from the above-mentioned results. LITERATURE ON THE SUBJECT • Burch, G.E., S.A., Threefoot and C.T. Ray, 1995, The rate of disappearance of Rb 8S from the plasma, the biological decay of Rb 86 , and the applicability of Rb 86 as a tracer of potassium in man with and without heart failure, J. Lab. Clin. Med 45.371. • Love, V.D. and G.E., Burch 1953, A comparison of potassium 4 , rubidium 86 and cesium 134 as tracers of potassium in the study of cation metabolism of human erythrocytes in vitro, J. Lab. Clin. Med.41, 351. • Meltzer, H.L., 1974, human and animal metabolism of rubidium Psychopharmacol , Bull. 10,43 • Meltzer, H.L., 1993, Biochemical and physiological guidelines for long-term rubidium therapy. In: Recurrent mood disorders: new perspectives in therapy. Eds: G.F., Placidi, L., Dell'Osso, G. Nistico and H.S. Akistal. Springer-Verlag, 214. • Placidi, G.A., Lenzi F., Lazzerini, L., Dell'Osso, G.B., Cassano and H.S., Akistal 1998. Exploration of the clinical profile of rubidium chloride in depression: a systemic open trial, J. Clin PPsychopharmacol . 8,184. • De Montis, M.G., C, Gambarana, 0., Ghiglieri and a., Tagliamonte, 1995, Reversal of stable behavioural modifications through NMDA receptor inhibition in rats. Behav. Pharmacol. 6,562. • Gambaran, C, 0., Ghiglieri I., Taddei, A., Tagliamonte and M.G., De Montis, 1995 Imipramine and fluoxetine prevent the stress-induced escape deficits in rats through a distinct mechanism of action. Behav. Pharmacol. 6,66. • Gambarana, C, 0., Ghiglieri, A., Tagliamonte, N. D'Alessandro and M.G., De Montis, 1995 Crucial role of D, dopamine receptors in mediating the antidepressant effect of imipramine . Pharmacol, Rinchem. Behav. 50,147. • Ghiglieri, 0., Gambarana, C, Scheggi, S., Tagliamonte, A., Willner, P., and M.G. De Montis, 1997 Palatable food induces an appetitive behaviour in satiated rats which can be inhibited by chronic stress. Behav. Pharmacol. 619-628.

Claims: CLAIMS 1. Use of rubidium and in particular rubidium chloride (RbCl) in the manufacture of a medicament for use as antimanic agent and mood stabilizer. 2. Use of rubidium and in particular rubidium chloride (RbCl) according to claim 1, in which the quantity of active principle administered, including Rb, in the form of RbCl, does not exceed the daily dose of 2 mg/kg. 3. Use of rubidium and in particular rubidium chloride, according to claim 2, characterised by the fact that in lengthy treatments a depressant and antimanic effect can be achieved even with a posological dose of 1 mg/kg every 3 days.

Inventors: PLATMAN STANLEY, TAGLIAMONTE ALLESANDRO, PLATMAN, STANLEY, TAGLIAMONTE, ALLESANDRO
Applicants: PLATMAN STANLEY, TAGLIAMONTE ALLESANDRO, UNIHART CORP, PLATMAN, STANLEY, TAGLIAMONTE, ALLESANDRO, UNIHART CORPORATION
Application year: 2000
Main classification: A61K33
IPC codes: A61K33, A61P25