MXPA97005856A - Use of melatonine in the manufacture of unmedicament to deal with addiction to dro - Google Patents

Abstract

The present invention relates to the use of melatonin in the manufacture of a medicament for treating addiction to benzodiazepines in a multi-drug addict or a patient having symptoms of having become dependent on, tolerant to, or addicted to a benzodiazepine drug. or to treat a patient who has been clinically diagnosed with a condition susceptible to relief by administration of a benzodiazepine drug, while simultaneously preventing the occurrence in the patient of symptoms of dependence, tolerance, or addiction to said benzodiazepine drug, in wherein said medicament comprises at least an effective amount of melatonin for any of said treatments, said amount being adapted for a daily regimen of administration in the range of 0.01-100 mg, as long as said medicament is for treating a patient who has been clinically diagnosed with a condition susceptible to relief The administration of a benzodiazepine drug, then said medication is a pharmaceutical formulation of sustained release, which contains no more than 5 mg of melatoni

Description

USE OF MELATONIN IN MANUFACTURE OF A MEDICINAL PRODUCT TO TREAT FLUCIDINg fl DRUGS DESCRIPTIVE MEMORY The present invention relates to pharmaceuticals for use in the manufacture of a medicament to treat, or to prevent symptoms of dependence on, tolerance to, or addiction to benzod azepma drugs, to treat addicts to multiple drugs and to a formulation pharmaceutical for use in such treatments. Dependence on benzodiazepines is commonly developed in insomniacs who use them for sleep induction and in multiple drug addicts who, in the process of withdrawing narcotics, become addicted to benzodiazepines to calm anxiety and seizures. Moreover, the chronic administration of benzodiazepma (when benzodiazepines usually have long half-life values) can induce tolerance, expressed by an ineffective increase in dosage by an unknown mechanism. Moreover, the rebound or "retreat" phenomenon that is commonly the abrupt cessation of these drugs, as observed both in animals and in humans, leads to addiction (Greenblatt, DJ, and hader, RI, Drug Metab. Rev., 1978, 8: 13-28). Fn 1990 US National Household Survey of the Use of Psychotherapeutic Medications, approximately 8% of medical users of hypnotics increased a prescribed dose themselves, which is an increase of 25% compared to the previous report in 1979. Whereas the survey showed that 2.6% of the US population ingested benzodiazepine hypnotics (compared to 2.4% in 1979) the number of individuals in the United States alone that developed tolerance and dependency can be estimated at 560,000. These values do not include the use of the substance outside of the medical or social norms and the abuse of multiple drugs. No method of rapid withdrawal followed by an effective alternative treatment has been reported in patients who developed benzoliazepine dependence in hypnotics and this problem is a major obstacle to the rehabilitation and recovery of addicts to narcotic drugs. It is well known that melaton a, a hormone derived from indole produced during the night by the pineal gland, plays a very important role in mediating the circadian sleep-to-sleep cycle and in the regulation of sleep. There is also some evidence that rnelatonin can increase the efficacy of benzodiazepine, see 1, e.g., Cardinali, LD.P. et al, Adv.Bochem. Psychopharm. , 1968, 42: 155-164; Acuna Castroviejo, D., et al, 3. Pineal Res., 1986. 3: 101-102; and Ni les, L.P. et al, LL). Neural Transm. 70: 117-124]. Similarly, melatonin may improve the anxiolytic effects of diazepam in mice (Guardiola-Lernaitre,., Et al., Framma, Biochem. Behav., 1992, 41, 405-4080). On the other hand, it has been suggested that benzodiazepines could, in some species including humans, potentiate GABA-induced inhibition of rnelatonin synthesis and secretion (McIntyre, IM et al, Biol. Psych. At., 1988, 24: 105-108 ) and that the nocturnal enhancement of elatonin in plasma can be suppressed by benzodiazepines in humans, thus leading to distortion in the rnelatomine diurnal rhythm (Kabuto, M. et al, Endocr. LDapon., 1985, 33, 405-414). Moreover, it has been observed that the chronic treatment with oxazopan modified the diurnal variations in the density of nighttime receptors in the rat brain and that this effect was not observed in pneumococcal animals (Anís, Y. et al. al, J. Neural Trasm., 1992, 89: 155-166). It has surprisingly been found in relation to the present invention that the administration of rnelatomine concurrently with benzodiazepine drugs can potentially (1) remove a patient from dependence on, addiction to, or tolerance to such drugs and (2) in the case of a patient who has been diagnosed and requires a benzodiazepine drug (where such unwanted symptoms have not yet occurred), prevent the occurrence of such symptoms.

RECOGNITION OF THE PREVIOUS TECHNIQUE MENTIONED ABOVE EP-O-513702 discloses the use of elatomin and certain derivatives thereof in the therapy of sleep disorders and on pre-anesthetic medication, optionally in the presence of? Na benzodiazepi a. This document states that benzodiazepine can therefore be administered in a relatively lower dosage and thus avoid the effects (alteration of sleep rhythms, rebound effect and development of tolerance) that are said to be related to the administration of benzodiazepine. Odiazepines in high dosages or for prolonged periods. This document does not suggest that dosages of melaton to or derivatives of less than 10 mg can be used for the purpose mentioned, nor does it suggest that elatomine could be useful when a patient has already become dependent on, tolerant of, or addicted to. a benzodiazepine drug. EP-A-518468 describes controlled release pharmaceutical formulations which, briefly mentioned, release melatonin according to a profile that stimulates the profile in human plasma having a normal endogenous melatomine profile. The formulations, which optionally contain a modifier of the melatonin receptor profile such as oxazepa, are useful for treating conditions related to the deficiency or distortion of ina melato, such as sudden infant death syndrome and migraine. This document does not suggest the use of rnelatonin to prevent or treat addiction to lae benzodiazepines. DIALOG File «Supplier PHIND. AN 00302794, 03-13-92, reports that indole-3-p? Ruv.? Co (IPA) acid increases sleep time in insomniacs, eg, in the withdrawal of benzodiazepma, and that the effect of TPA in the sleep is mainly mediated pearl reversion of increased melatonma in the pineal gland. This document also does not suggest the use of rnelatomine to prevent or treat addiction to henodiazepines.

DESCRIPTION OF THE INVENTION The present invention thus provides the use of melatomine in the manufacture of a medicament for treating addiction to benzodiazepines in a multi-drug addict or a patient having symptoms of having become dependent on, tolerant of, or addicted to a drug. benzodiazepine drug or to treat a patient who has been clinically diagnosed with a condition susceptible to relief by administering a benzodiazepine drug, simultaneously preventing the occurrence in the patient of symptoms of dependence, tolerance, or addiction to said drug of benzodiazepma, wherein said medicament contains at least an amount of 10 effective melatonm for any of said ratios, said amount being adapted for a daily administration regime within the range of 0.01-100 g, provided, when said drug is to treat a patient who has been clinically diagnosed with his condition susceptible to relief by administration of a benzodiazepine drug, then said medication is a sustained-release pharmaceutical formulation, which contains no more than 5 mg of melatomine. Said medicament can be a pharmaceutical formulation adapted for oral, rectal, parenteral or transdermal administration, and which comprises at least one diluent, vehicle or adjuvant, and can be furthermore cared for by at least one of the following characteristics (i) that it is in unit dosage form, each unit dosage comprising a quantity of rnelatonm that is within the range of 0.0025-100 mg; fu) that is in the form of a controlled release formulation, wherein the anelatomine is preferably released at a predetermined controlled rate; (in) which also comprises at least one inelatoni receptor modifier and / or modulator of the elatonin profile. The medicament may also comprise, and the pharmaceutical formulation according to the invention comprises, at least one benzodiazepine drug, such as at least one of the pyrilazole, Clordiazepoxide, Clorazepate, Diazeparn, Flunitrazeparn, Flurazepain, Halazepam, Lorazepam, Oxazepam, Prazepa, Temazepam and Triazolam. The formulation comprising at least one benzodiazepine drug may also be characterized by one or more of features (i), di) and (m) as described above. To apply the present invention in the treatment of a multiple drug addict or to a patient who has symptoms of having become dependent on, tolerant of, or addicted to a benzodiazepine drug, the administration of a benzodiazepine drug to The patient is continued, at least officially, and the tumor is administered concurrently to the patient in an amount that is effective to alleviate at least one of such symptoms. In a particular embodiment of such treatment, any of the benzodiazepine drug and melatoni a may be in the form of a pharmaceutical formulation adapted for oral, rectal, parenteral or transdermal administration and comprising at least one diluent, vehicle or adjuvant. Alternatively, the benzodiazepine drug and the rnelatonm may each be administered as formulated, either separately, or may be combined into a single pharmaceutical formulation that includes both the diazepine drug and the rnelatomine. In connection with the administration of the Melatomine, whether administered separately from or together with one or more benzodiazepine drugs, the administration can be carried out at a daily dosing regimen that e.g., is within the range of 0.01-100 mg; A controlled release formulation can be administered in a fie form. Illustratively, 1-2 mg of rnelatonin in the form of a controlled release formulation can be administered overnight. Melatonin can be administered together with a meiatomine receptor modifier or a rnelatonin profile modifier. Examples of rnelatomine receptor modifiers are short-acting benzodiazepines such as Oxazeparn; Examples of modifiers of the melatonin profile are benzodiazepines, beta blockers and serotonin assimilation inhibitor. Instead, or in addition to, the use of such a profile modifier, the melatomine profile can be modified by subjecting the patient to the effect of light, before, after or during the administration of rnelaton. The benzodiazepine drugs cited herein may create symptoms of dependence, tolerance and / or addiction. Without prejudice to this generality, such drug or drugs may be one or more of eg, Alprazolam, Clordiazepoxide, Clorazepate, Diazepam, Fl? Ni razeparn, Flurazepam, Halazepan, Lorazepam, Oxazeparn, Prazeparn, Temazepam and Tpazolam, according to It was indicated above. In an alternative embodiment to apply the invention to the treatment of the aforementioned symptoms, the benzodiazepine drug (s) initially continued to be administered to the patient, concurrently with elatonin, at a regimen daily substantially equal to that received by the patient before initiating treatment with melatomine. In another alternative embodiment of the invention for the treatment of such symptoms, the benzod azepma drug (s) will adhere to the patient, concurrently with the melatonm, to a progressively disintegrating daily regimen. compared with that received by the patient before starting treatment with rnelatonin. In this embodiment, the daily administration regimen that decreases prematurely may be continued, eg, until a predetermined stabilized administration regimen is obtained, or alternatively, e.g., until the amount of benzodiazepine drug administered is of zero. During the application of the invention for preventive purposes, that is, to treat a patient who has been clinically diagnosed with a condition susceptible to relief by the administration of a benzodiazepine drug, simultaneously preventing the occurrence in the patient of symptoms of dependence of, tolerance to, or addiction to ben odiazepma drug, a benzodiazepine drug is administered in an effective amount to alleviate said condition, concurrently administering to the patient an amount of melatomine that is effective to prevent at least one of such symptoms . The different modalities described above as applicable to treat a patient having the aforementioned symptoms are also applicable correspondingly to preventive purposes, except when they are not applicable for reasons that are self-evident to a person of the art, e.g., in this In case the treatment with a benzodiazepine drug is desider tum, evidently the amount of benzodiazepine administered, although it may possibly be reduced in any particular case as determined by a physician, will not be reduced to zero. However, it will be within the scope of the preventive application of the invention, not only the administration, concurrently with elatomine, the benzodiazepine drug in the conventional daily dosage regimen to obtain a particular purpose, but in the alternative to administer simile. Such a drug will be reduced to a daily regimen that is less than that which is conventionally administered to a patient to alleviate said condition. As mentioned above, the invention also extends to a pharmaceutical formulation that includes at least one benzodiazepine and rnelatoni a drug. Since benzodiazepine drugs are commonly administered L ~ 4 times a day, at a daily regimen of 0.01-100 mg of melatomine, typically administered at night, in the same formulation as the benzodiazepine or even if it is administered separately from the same , will be obtained illusively by the administration of benzodiazepines as follows: dosage unit days of benzodiazepine within the regimen 1 0.01 - 100 rng 2 0.05 - 50 rng 3 0.033 - 33.3 rng 4 0.025 - 25 rng In such a way, when the pharmaceutical formulation of the invention is in unit dosage form, each unit dosage is preferably administered overnight and preferably comprises an amount of rnelatonin within the range of 0.0025-100 g. The following chart shows the amounts of benzodiazepine drugs used to treat the conditions mentioned in adults. For more information, eg, on reservations, half-life, forms of administration, and appropriate dosages for children or infants, see Goodman & Gilrnan's "The Pharrnacologi l Basis of T epetry" 7th Edition, 1985 (MacMillan Publishing Co.), the passages that refer to the use of benzodiazepms (eg, pp. 352, 437).

Benzodi zepine Dosing content Normal daily oral oral unit dose ing (x per day) Hypnotic Onsiolitic Hypnotic Alprazoiarn 0. "5-1.5 Chlordiazepoxide 10-100 (1-3) 50-L00 15-40 Clorazepate 3.75-15 (82-4) 15-30 30 Diazepam 5-10 (3-4) 5-10 3-40 Flurazepam 15-30 Halazeparn 60-160 Lorazepan 2-4 2-6 Oxazeparn 15-30 (3-4) 15-30 30-60 Prazepam 20-40 Ternazepam 15-30 Triazolarn 0.25-0.5 * rng; generally divided into 2-4 unit doses; for more information including parentenna dosage regimens, see Goodman% G liman, loe cit The preparation and the release profile of the formulations for s? Use according to the invention or its applications are illustrated below. (a) Compressed in a 7 mm cylindrical punch to 2540 kg (2.5 tons), after dry mixing Powdered materials, namely 2 mg / melatomine tablet (Biosynth Co., Switzerland) and ream vehicle replica (Roh Pharrna) which was Eudragit® RS100 (SR-formulation) Ms) or Eudragit "RSPO (formulation SR-Mf), apart from other components such as: SR-Ms formulation: Eudragit * RS100 48.8%, lactose 50%, rnelatomna 1.2%, formulation SR-Mf: Eudragit * RSPO 36.3%, lactose 16.7%, calcium hydrogen phosphate 41.4%, talc 1.3%, magnesium stearate 4%, elatonin 1.3% SR-Ms and SR-Mf are sustained release formulations.

A conventional dosage form (RM) was prepared similarly to the SR-Mf formulation, but using lactose instead of Eudragit® as carrier. (b) The potential release profile of the tablets prepared as described in paragraph (a) is first investigated by the in vitro dissolution of melatonin thereof in distilled water at 37 ° C. The results in the table show the percentage of the content of elatomna (average value of 6 tablets) that dissolved in the indicated time intervals.

TABLE A Time (hours) l 2 4 6 8 10 % of rnelatonin released from: SR-Ms 12 29 62 84 90 100 SR-Mf 32 51 76 88 100 RM 93 96 100 (c) The in vivo profile of the SR-Mf tablets prepared as described in paragraph (a) was investigated by oral administration twice to a healthy male (age 36) at 10 a. ., ie when circulating levels of melatonin are undetectable. The amount of nelatomine released m vivo was determined by radiommunoassay of its main etabolite, 6-s? Lfatox? Rnelaton? Na in the urine. The amount of urinary 6-sulfatox? Rnelaton? Na refl eges the level of the hormone in the blood. The results in Table B show melatom at a certain rate or a percentage of the total melatomine administered (mean value of 2 tablets).

TABLE B M liv ation of mel m a n a n a n a l a n a l Time (hours) l 2 4 6 to 10 % release at intervals 10.7 25.7 40.6 14.0 7.0 1.9 % cumulative release 10.7 36.4 77.0 91.0 98.0 99.9 It is noted that the inactivation of inactivated melato, illustrated in Table A, provides only an approximate indication of the release profile in vivo due to the known phenomenon of the active compound that is absorbed by the tissues in the early stages of release. The amount of elatomine in the sustained release formulations may change eg to 0.5, 1 or 5 rng / tablet without affecting the release pattern that was found for the tablets containing 2 mg / tablet of rnelatomine. Because the analogues of nelatonin q are substantially mimicking the function of melatonin in the human body I are known in the art, it will be appreciated that such analogs are considered obvious chemical equivalents of elatomin in the present context. According to the present invention, one or more benzodiazepines can be incorporated in the above formulations, in the amounts described herein. The invention will now be illustrated by means of the following examples.

E3EMPL0 1 The reciprocal effects of the chronic administration of benzodiazepine and elatomin in brain receptors of melatonin and benzodiazepine were studied and the ability of melatonin to reverse these effects was studied. Male rats were kept on an itinerary of 14 h of light: 10 hours of darkness (lights on OS.OOh, cold white fluorescent lighting) at 24 ± 2 ° C. Food and water were supplied ad libiturn. The animals (2 months old) were divided into 4 groups, 5 animals in each. The animals of a group (CON) were injected, i.p. daily at 4:00 p.m. with a vehicle (200 μl of saline). That in the second group (VAL) were injected daily, i.p. at 4:00 p.m. with diazepa (1 rng in a 200 ul vehicle, Roche). The animals of the third group (MEL) were injected daily to I b 4:00 p.m. with vehicle; The drinking water of this group contained rnelatonin (4 in. dissolved in LOO μl of ethanol and diluted to one liter). The animals in the fourth group (VAL / MEL) were injected daily at 4:00 p.m. with diazeparn (1 mg in a 200 μl vehicle); The drinking water of this group contained melatonin (4 mg dissolved in 100 μl of ethanol and diluted to one liter). After 21 days the treatment was stopped and the animals were weighed. It was found that the mean body weight values in the VAL (274 ± 20 g) and VAL / MEL (239 ± 30 g) groups were slightly lower than those in the CON (292 ± 30 g) or MEL groups. (285 ± 30 g). The animals were beheaded between 18-19: 00 hrs. the next day (at this time the density of 2- ^ 25 i-iodomelatonin in the Varolium bridge showed to be maximum); their brains were quickly removed and the crude smaptosomal cocks were prepared as described, and the elastomer-receptor were calculated, as described by Laudon, M. and Zisapel, N., FEBS Lett., 1986, 197: 9- 12 Benzodiazepine receptors were calculated by measuring 3 H-fl? Ni razepa (3 H-FNZ) and the binding of 3 H-0 15-1788 as described by Amip, Z. et al., Bram Res., 1991, 553; 155-158. The binding parameters were calculated from the binding equilibrium data. The Brnax values represent the specific binding of 2-12S i-iodolemmaton. 3H-FNZ or 3H-R0 15-1788 in saturation, and the Kd values are the apparent dissociation constants. The binding parameters of the different groups were compared by Vapance analysis followed by the Student-Newman-Ke? L test for multiple comparisons. The differences were considered significant if P < 0.05. Daily injections of diazepam (1 mg ip to 16:00 h) into male rats for 3 weeks markedly reduced the density of 2-i2Si-y0domelatomna binding sites in the Varolium bridge (Table 1), whereas the union of benzodiazep na was not significantly affected (four 2). If the elatonin receptors are related to the control of the sleep-wake cycle, the results suggest that the chronic benzodiazepine administration results in the decrease of nelatonin response mechanisms and in the consequent physiological activities. The rnelatomine, given orally by means of water to drink for 3 weeks, significantly improved the binding of 3H-R0 15-1788 in the tle Varolio bridge (tables 2,3), whereas the union of 2 -i25- was not affected. yodomelaton? na The increase in density of benzodiazepine binding site and apparent Kd in the varolium bridge induced by the treatment with melatonin, is compatible with the previously observed increase in the rat cortex and showed to be mediated by opioid peptides (Gomar, MD and other Neuroendocrinology 1993, 4: 987-990). The fact that this improvement persists even in animals treated with diazepam can rule out competition between melatonin and benzodiazepines over benzodiazepine binding sites.

Daily administration of both diazepam and rnelatomine improved the binding of 3H-RO 15-1788 in the pons and reversed the diazepam-induced suppression of the binding of 2-i2sI-iodine elatom na in this area (tables 1, 2). These results were surprising, since it was previously shown (Anís, Y. and others), in rnelatomna binding sites in the hamster brain; impact of rnelatonin. Molec, Cell, Endocnnol; 1989, 67: 121-128: Oakin-Bendahan, S. and others 3. Basic Clin. Physiol, Pha rrna co 1; 199 ?, 3: 253-268) and also confirmed in the present study, the administration of elatonin by morning or evening injections, or orally by drinking water, does not affect the density or diurnal variations at the sites of melatonin binding in most areas of the brain including the pons. Furthermore, La pineal ectorní does not suppress diurnal variations in binding sites of 2- i25i-iododnelatonin, although it does affect its phase position (Oaknin-Bendahan et al., 1992, ibid). In this way, changes in densities of the elatonin binding site may not be due to autoregulation of the receptor by the melatomine. In the cerebral cortex, melatonin slightly reduced the binding of 3H-R0 15-1788 and 3H-FNZ. The treatment with diazepam did not significantly affect the binding of 3H-R0 15-178B and 3H-F Z but prevented the decrease mediated by rnelatonin (tables 2,3). These data suggest first that the effects of rnelatom a on benzodiazepine binding sites are localized, rather than the suppression or general facilitation of the occurrence of binding, and second, that the melatonin replacement therapy can counteract some harmful effects of chronic treatment with benzodiazep a. Table 1 shows equilibrium binding parameters of 2-1 5] - iodomelatonin binding sites in Smaptosomal preparations from the area of the Varolium bridge of rats treated and not treated with rnelatomine and / or diazepam in terms of S.D. values. and means of kd (in nM) and Bmax (in μmol / rng protein). The values denoted by the same character in Table 1 do not differ significantly. (Codes that have the same significance are also used in Tables 2 and 3 below).

TABLE 1 GRUPO Kd ± sd Brnax ± sd WITH 0.8 + 0.2 to 7.9 ± 1.0 to MEL 1.16 ± 0.3 to 7.7 ± 1.0 a VAL 0.98 ± 0.21 to 5.1 + 0.5 b VAL / MEL 2.27 ± 0.75 b 12.5 ± 2.0 c Table 2 shows the equilibrium binding parameters of binding sites of 3H-R0 15-1788 in einaptosomal preparations from the area of the pneumonia of rats treated and not treated with diazepa and / or rnelatom a, in terms of values of k means and SD (in nM) and Brnax (in μrnol / ng protein).

TABLE 2 GRUPO Kd + sd Brna ± sd WITH 2.3 ± 0.4 to 310 + 22 a MEL 2.8 ± 0.2 to 476 + 26 b VAL 2.5 ± 0.4 to 295134 a VAL / MEL 2.6 ± 0.5 to 375 + 87 b Table 3 shows the effect of diazepam or rnelatonin in the binding of 3H-FNZ and 3H-R0 15-1788 in the rat neurons of the rat cerebral cortex in terms of mean values and S.D. (in μrnol / mg protein).

TABLE 3 GRUPO Kd ± sd Buiax ± sd WITH 935 ± 31 to L354 + 48 a MEL 765 ± 78 b 1060+ 26 b VAL 870 ± 22 to 1264 ± 99 a VAL / MEL 980 + 16 to 1362+ 1.55 a EXAMPLE 2 This example illustrates the surprising action of mela tomna to facilitate the very rapid withdrawal of tolerance to the benzodiazepine drug. A woman of 34 years of age, married and with 2 children has suffered from insomnia for the past 10 years accompanied by frequent and severe migraine attacks. A meticulous neological calculation was negative. Psychiatric or organic problems were also ruled out. Throughout those years she was treated with benzodiazepines, tricyclic antidepressants and neuroleptic drugs, as well as biofeedback and relaxation methods without any apparent improvement. Dur-faced the last year has been using 4-8 ing of Lorazepain every night. A meticulous physiological calculation in the Sleep Laboratory of Tel Aviv University does not describe any significant pathology. The sleep quality was calculated by means of an active pattern that automatically modulates the sleep pattern - awakening by means of a small device fixed to the wrist. The plot was recorded for 3 consecutive days and showed a disordered sleep pattern: reduced efficiency, long sleep latency and multiple episodes of awakening. Urine samples were taken every 3 hours (for 36 hours) and tested to verify the main melatonin etobolite: 6-s? Lfatox? Melaton? Na, as an indicator for diurnal plasma rnelatomine secretion. The results showed that the secretion levels of 6-s? Lfatoxirnelatonina were lower than those of the individuals selected according to age and lacked the typical circadian rhythm (table 4).

Oral administration of a controlled release formulation of rnelatomine in the form of tablets containing 1 mg of elatomine (Neurirn Pharnaceuticals, Israel) was initiated to correct the deficiency and distortion of the rnelatonin rhythm. One tablet was administered daily at 8:30 p.m. The patient was instructed to gradually reduce the number of benzodiazepine tablets taken each night.

Surprisingly, within 2 days the patient stopped the use of benzodiazepine hypotonics all at once and ensured that his insomnia had improved markedly. In addition, her headaches also gradually decreased. A repeated actigraphic plot after 3 weeks of treatment showed a marked improvement in the sleep pattern. The treatment was stopped and 2 weeks later a urine sample was returned every 3 hours (for 36 hours) and tested to verify 6-sulfatox? Melatonin. The results (table 4) indicated an increase in quantity and a clear nocturnal peak of urinary 6-sulfatox? Melatonin. A follow-up of 5 months has confirmed that the patient still maintains his quality of sleep and hardly suffers from headaches. After 5 months without treatment, sleep quality began to deteriorate and melatomine therapy was remitted. This case-report indicates potentially a breakthrough in the relief of many patients whose quality of life has been impaired by the hypnotic addiction of benzodiazepine. The administration of exogenous elatomin can also serve as a means of rapid withdrawal and without symptoms of benzodiazepines in patient tolerant.

TABLE 4 6-S? Lfatox urinary irnelatonin in benzodiazepine-dependent patient before and after elatonin therapy (ug / hours) Time Before Treating Treatment After Treatment . 00 0.3 0.11 18.00 0.16 0.45 21.00 0.18 0.11 24.00 0.L3 1.24 3.00 0.23 0.74 6.00 0.23 0.36 9.00 0.22 0. 1 12.00 0.13 0.01 15.00 0.22 0.04 EXAMPLE 3 This example illustrates the effects of long-term administration of elatonin in the treatment of insomnia in patients who depend on a benzodiazepine drug. Two volunteers, YL, an 80-year-old male and EL, a 73-year-old female, suffered from insomnia and / or frequent awakenings each for a number of years during the night, accompanied by the difficulty to return to sleep later. . It was found that both had a low secretion of rnelatonin, by determining the amount of rnetabolite 6-sulfatox? Melatonin in the urine. Both patients have been taking 1-2 mg of fl? Nitrazepam orally before retiring every evening. Each patient released from fl? Ni razepan by gradually reducing the dose and administering melatonin simultaneously orally (2 ng of nelatomna daily in controlled release form). ) for a period of two months. Since the end of that period, each patient has continued to return the elatomin in the same way and in the same dosing regimen for approximately two years. Each patient has subjectively reported good sleep induction and a substantial improvement in sleep quality. Specifically, the patient E.L. noticed an improvement in sleep quality at the start of the release period and Y.L. He noticed a similar effect about a few weeks after the period of release. Each patient reported reduced fatigue during the day several days after the start of the release period and also indicated that the melatomine did not cause any feeling of residual tiredness in the morning, nor any hangover sensation. No side effects were reported by any patient.

EXAMPLE 4 This example, designed as a randomized, double-blind, crossover study, illustrates the ability of elatonin replacement therapy to improve sleep maintenance in chronically elderly patients who use benzodiazepine drugs. The group, of average age of 78 (SD = 9.7) consisted of eight men and five women, all of whom complained of long-term insomnia and used several benzodiazepine for sleep induction. A urine sample was taken approximately every 4 hours for 15 hours and the nocturnal secretion of 6-sulfatox? Melaton? Na, the main urinary metabolite of rnelatom a, was tested in duplicate by RIA. The urine analysis of these patients showed a low and decreased 6-sulfatox? Melatomine secretion (cL4μg during the night compared to 25μg per inuto in young adults). The study protocol consisted of two treatment periods of three weeks each with a one-week clearance interval between the two treatment periods. During the treatment periods, the patients were administered orally 2mg controlled-release rnelatonin tablets, or placebo, two hours before going to bed. Five patients continued with the melatonin treatment for a period of two months beyond the initial period of experimentation.

The patients' sleep was objectively calculated at the end of each treatment period for three consecutive nights using a wrist measurement. The movement logs were analyzed using the Neurirn algorithm to determine sleep latency, sleep efficiency, total sleep time, awakening discomfort after sleep and the number of awakenings, as an average for three nights for each subject. Six Uilcoxon analyzes of selected pairs and completed ranges statistically revealed significant differences in sleep parameters between the ranges of treatment periods with melatomine and placebo. The results are shown in table 5.

TABLE 5 Effect on sleep parameters of replacement with rnelatomine of benzodiazepine drugs. Parameter after 3 weeks after +2 months of treatment with rnelato-rnelatonin placebo nina efficiency) 82% 75% 85% of sleep) (z = -2.82, p = 0.005) latency of 17 mms. 39 rnins. 7 sleep nuns (z = -2.12, p = 0.03) malaise- of awakening) 59 rnins. 76 mms. 42 rnins. after sleep) (z - -2.00, p - 0.04) no. of awakenings 11 17 10 (Z = -2.70, p = 0.007) total time 386 ins. 375 mins. 248 rnms, sleep (z = -057, p - 0.58) From the above results it is concluded that melatonin replacement therapy can improve the onset and maintenance of sleep in elderly patients who use ben? od? azep? na and have a low production of endogenous nelatonin. The benefits of treatment with rnelatomna increase over time, suggesting that the reorganization of the circadian system has drained.

Claims (9)

NOVELTY OF THE INVENTION CLAIMS

1. - Use of melatonin in the manufacture of a medicament for treating benzodiazepine addiction in a multi-drug addict or a patient having symptoms of becoming dependent on, tolerating, or being addicted to a benzodiazepine drug or treating a patient that has been clinically diagnosed with a condition susceptible to relief by the administration of a benzodi zepine drug, while simultaneously preventing the occurrence in the patient of symptoms of dependence on, tolerance to, or addiction to said benzodiazepine drug, wherein said The medicament comprises at least an effective amount of elatonin for any of said treatments, said amount being adapted for a daily regimen of administration in the range of 0.01-100 mg, as long as said medicament is for treating a patient that has been clinically diagnosed. with a condition susceptible to relief by administering a drug of benzodiazepine, then said medicament is a pharmaceutical formulation of sustained release, which contains no more than 5 mg of nelatonin.

2. Use of melatonin according to claim 1 in the manufacture of a medicament to treat addiction to benzodiazepines in a multiple drug addict or a patient who has symptoms of having become dependent on, tolerant of, or addicted to. a benzodi zepine drug.

3. The use according to claim 2, wherein said medicament is a sustained release medicament containing no more than 5 mg of nel to ina.

4. Use of the elastin according to claim 1 in the manufacture of a sustained-release medicament for treating a patient who has been clinically diagnosed with a condition susceptible to relief by administration of a benzodiazepine drug, simultaneously avoiding the occurrence in the patient of symptoms of dependence of, tolerance to, or addiction to said benzodiazepine drug, wherein said medicament contains at least an amount of elatonin effective for said treatment, which is adapted for a daily dosing regimen on the scale of 0.01-5 mg.

5. Use according to any of claims 1-4, wherein said medicament comprises a pharmaceutical formulation adapted for oral, rectal, parenteral or transdermal administration and which comprises at least one diluent, vehicle or adjuvant.

6. The use according to claim 5, wherein said pharmaceutical formulation is further characterized by one of the following characteristics: i) that is in unit dosage form, each unit dosage comprising a quantity of rnelatonma that this within the regimen of 0.0025-100 rng when said formulation is not a sustained release formulation and within the regimen of 0.0025-5 rng when said formulation is a sustained release formulation; p) when said formulation is a Sustained Release formulation that is a controlled release formulation in which the melatonin is released at a predetermined controlled rate; iii) which also comprises at least one modifier of the rnelate receptor i a and / or? melatonm profile modifier.

7. The use according to any of claims 1-d, wherein said pharmacological formulation also comprises at least one benzodiazepine drug, which preferably comprises at least one of Alprazolan, Chlordiazepoxide, Clorazepate, iazepam, Fl? Nit razeparn, Fl? Razepa, Halazepam, Lorazepam, Oxazepam, Prazepam, Temazepan and Tpazolarn.

8. The use of the membrane according to any of claims 1-7 concurrently with the (The) benzodiazepine drug (s) in the preparation of a medicament to be administered under a daily regimen of the benzodiazopi drug to be progressively decreased until a predetermined stabilized regimen of administration of benzodiazepine drug (s) is obtained.

9. The use of melatom a in accordance with any of Claims 1-7, concurrently with the benzodiazepine drug (s) in the preparation of a drug administered under a daily regimen of the benzodiazepine drug that is progressively decreased until a complete withdrawal of the patient from the benzodiazepine drug (s) is achieved.