SK103097A3 - Use of melatonin for producing drug to treat patients suffering from drug addiction - Google Patents

Abstract

Melatonin is used in the manufacture of a medicament for treating a multidrug addict, or a patient who has symptoms of having become dependent on, tolerant of, or addicted to a benzodiazepine drug, or for treating a patient who has been clinically diagnosed as having a condition susceptible to alleviation by administration of a benzodiazepine drug, while simultaneously preventing the occurrence in the patient of symptoms of dependence on, tolerance of, or addiction to said benzodiazepine drug. The invention further relates to a pharmaceutical formulation for the above-stated purposes, which comprises at least one diluent, carrier or adjuvant and as active ingredients a benzodiazepine drug and melatonin.

Description

Use of melatonin for the treatment of drug-dependent patients

Technical field.

The invention relates to the use of melatonin for the manufacture of a medicament for the treatment or prevention of symptoms of mental and physical dependence or tolerance to benzodiazepine medicaments, for the treatment of multidrug addiction and for the manufacture of a pharmaceutical composition which can be used for such types of treatment.

Dotera-iží stav.-technikY

Dependence on benzodiazepines often arises in insomnia sufferers who use these medicines to induce sleep, and in those with multidrug addiction who become addicted to benzodiazepine medicines to relieve anxiety and seizures during narcotics withdrawal. In addition, chronic administration of benzodiazepine (where benzodiisepines usually have a long half-life) may induce, by an unknown mechanism, tolerance, expressed in ineffective dose escalation. Phenomena, which are often an immediate response to rapid arrest of these drugs, as seen in humans and animals, to physical dependence (Greenblatt, DJ and Shader, RI Drugletlet. Rev., 1978, 8: 13-28). In the US report

The National Household Survey of Psychotherapeutic Medicine of 1990 reported that approximately 8% of patients using hypnotics increased the prescribed dose of their own choice, an increase of 25% compared to the previous 1979 report. whereas the survey found that 2.6% of the US population use benzodiazepine hypnotics (compared to 2.4% in 1979), the number of individuals in the US only develops tolerance and psychological dependence on the drug , about 560,000. These values do not include the case; when the medicine is used outside of medical and social standards, as well as cases of multidrug addiction. To date, rapid drug withdrawal has not been reported in patients who develop psychological dependence on benziodiazepine hypnotics. followed by effective rehabilitation and treatment of narcotics dependent patients.

It is well known that melatonin, which is a hormone whose structure is derived from indole and which is produced by the 7-night epiphysis, plays an essential role in mediating the circadian sleep-wake state and in regulating sleep. There is also some evidence that melatonin is capable of enhancing the efficacy of benziodiazepine (see, e.g., Cardinali, D.P. et al., Supra).

Biochem. Psychopharm., 1986, 42: 155-164, Acuna Castroviejo 0 et al., J. Pineal Res., 1986, 3: 101-102., And Niles, L.P. et al. .

J. Neural Transm.70: 117-124 !. Melatonin may also exacerbate the anxiolytic effects of diazepam in mice (Duardiola-Lemaitre B. et al., Pharmacol. Biochem. Behav., 1992 41: 405-408). On the other hand, however, it is believed that benziodiazepines would be useful in some species, including In humans, GABA-induced synthesis and secretion of melatonin secretion could be enhanced (McIntyre, IM et al. Biol Psychiat., 198B, 24: 105-108), and a nightly increase in plasma melatonin could be suppressed in humans by benziodiazepine, resulting in a violation of the diurnal melatonin burst (Kabuto, M. et al., Endocr. Japan., 1986, 33: 405-414). In addition, it has been observed that chronic treatment with oxazepam modified diurnal variations in melatonin receptor density after and at night in rat brain, and this effect was not observed in animals in which the pineal gland was removed <Anis, Y. et al, J Neural . Transm., 1992, 89: 155-166.

In connection with the present invention, it has been surprisingly found that the administration of melatonin concomitantly with benziodiazapine drugs can potentially (1) lead the patient to withdraw from physical and psychological dependence and tolerance to these drugs, and (2) in the patient diagnosed a condition requiring the administration of a benziodiazepine drug (in which these adverse symptoms have not previously occurred) has prevented these symptoms.

SUMMARY OF THE INVENTION

Description of the invention

The present invention encompasses the use of melatonin for the manufacture of a medicament for the treatment of benzodiazepine dependence in multidrug-dependent patients or for the treatment of patients who exhibit symptoms of tolerance or psychological and physical dependence on a benzodiazepine drug, or for the treatment of patients diagnosed with susceptibility to a condition ameliorating the administration of a benzodiazepine medicament to prevent the occurrence of symptoms of tolerance or psychological and physical dependence on said benzodiazepine medicament, wherein said medicament comprises at least 10 melatonin effective for each said treatment and said amount is adjusted to a daily administered dose of 0.01 to 100 mg provided that if said medicament is used to treat a patient who has been diagnosed with an improving clinical condition by staging a benzodiazepine medicament, then said medicament is f a sustained release pharmaceutical formulation containing no more than 5 acres of melatonin.

Said medicament is a pharmaceutical composition adapted for oral, rectal, parenteral or transdermal administration comprising at least one diluent, carrier or adjuvant, and may be further characterized by one of the following:

(i) is in unit dosage form and each unit. the dose contains an amount of melatonin in the range of 0.0025 to 100mg. (i.) is in the form of a formulation that permits controlled release of the active agent, wherein the melatonin is preferably released at a predetermined controlled rate, (iii) also comprises at least one melatonin receptor modifier or melatonin profile modifier. of the present invention also contain at least one benzodiazepine drug from the group of Alprazolam, Chlordiazepoxide, Clorazepat, Diazepam, Flunitrazepam, Flurazepam, Halazepam, Lorazepam, Ox zepam, Prazepam, Temazepam or Triazolam. likewise may be further subject to one or more of the characteristics (i), (ii) and (iii) as described above.

When using the present invention to treat multidrug addiction or to treat patients who exhibit symptoms of mental and physical dependence or tolerance to a benzodiazepine drug, the administration of the benzodiazepine drug is continued at least at an early stage and concomitantly administered with melatonin. in an amount that effectively reduces at least one of these symptoms.

In a particular embodiment of this treatment, jefen? The benzodiazepine medicines or melatonin may be in the form of a pharmaceutical composition adapted for oral, oral, parenteral or transdermal administration, and the composition comprises at least one diluent, carrier or adjuvant. Another option is that the benzodiazepine drug and melatonin u? can be administered in this form either separately or in combination as a single pharmaceutical composition comprising a diazepine drug and melatonin.

Regarding the administration of melatonin, whether administered alone or together with one or more benzodiazers (new medicines), it can be administered in the form of daily doses, for example in the range of 0.01-100 mg. For example, 1 to 2 mg of melatonin in the form of a controlled release formulation may be administered in the evening Melatonin may be delivered together with a melanin receptor modifier or a 5 melatonin profile modifier. Examples of melatonin receptor modifiers are benzodiazepines with, for example, the Oxazepamepin profile, e.g. are benzodiazepines, beta-blockers and serotonin uptake inhibitors, but instead of using such a profile modifier or, if this profile modifier is used, the melatonin profile can be modified by treating the patient with light for d Ilebo the short ^Modify: Ator effect that melatonin during administration of melatonin.

Benzodiazepine medicines for bovine can now induce symptoms of mental and physical dependence and tolerance. While not emphasizing these general properties, this drug or drugs is one or more of the following: Alprazolam, Chlordiazt poxide, Clorazepate, Diazepam, F lumi trazepam, Flurazepam, Hall: epam, Lorazepam, Oxazepam, Prazepam, Temazepam and Triazolam, tat as above.

In one alternative embodiment, when the finding is used to treat the above symptoms, the benzodiaepine drug or benzodiazepine drugs are initially and continuously administered to patients together with melatonin. In another alternative embodiment, when the invention is used to treat such features, the benzodiazepine medicament or benzodiazepine medicaments are also dispensed to the patient along with melatonin at continuously decreasing daily doses as compared to those given to patients prior to commencing treatment with melatonin. In doing so, the administration of ever-decreasing daily doses may be continued, for example, until a predetermined administration, or alternatively, of the administered benzodiazepine administered is determined by a stabilized rate, for example, until the drug reaches zero.

When the invention is used for prevention, i. · a condition where improvement of symptoms can be induced by administering a benzodiazepine drug and at the same time preventing the patient from developing symptoms of physical and psychological williness JLosti on that benzodiazepine drug or tolerance to it is a benzodiazepine drug administered in an amount to alleviate said symptoms, and at the same time the patient is administered an amount of melatine to prevent at least one of these symptoms. The various embodiments described above as useful for treating a patient suffering from said symptom or symptoms are equally adequately applicable to preventive action. except where it is not possible to be used by other experts for example, if treatment with benzodiazepine liel is required by the situation (desideratum), so that apparently the amount of benzodiazepine administered, although it may be reduced according to the physician's instructions, will not be reduced to zero.

However, within the scope of the invention for the purpose of prevention, it is not only possible to administer the benzodiazepine medicament or medicaments together with melatonin in the range of conventional daily doses to achieve the desired purpose, but also to administer the medicament or medicaments similarly in daily dosages less than are commonly conceived by patients to improve their health.

As mentioned above, the invention also relates to a pharmaceutical composition comprising at least one benzodiaze: the drug and melatonin. Because benzodiazepine drugs are generally administered 1 to 4 times daily, the daily dose will be 0.01 to 00 mg of melatonin, which is administered typically in the evening, in the same formulation as benzodiazepine or benzodiazepines (or even if melatonin is administered) separately from benzodiazepine) achieved by the following administration of benzodiazepines:

Days Unit dosage of benzodiazepines in the range

1 0,01 - 100 mg 2 0,05 - 50 mg 3 0,033 - 33.3 mg 4 0,025 - 25 mg

Thus, when the pharmaceutical composition of the present invention is in unit dosage form, each dosage unit is preferably administered at night and preferably contains an amount of melatonin in the range of 0.0025 to 100 mg.

The following table shows the amount of benzodiazepine medicines used to treat health in adult patients.

w

Additional information, such as restriction, half-life, routes of administration, and appropriate dosages for children and adults, can be obtained from Goodman and Gilman's book The Pharmacological Basic of Therapeutics, 7th Edition, 19B5 (MacMillan Publishing Co.), passages relating to use benzodiazepines (e.g., p. 352, 437).

benzodiazepine

Content per single oral dose mg <x per day) sedative hypnotic

The usual daily oral dose of anxiolic acid

alprazolam 0, 75 Ch1ordiazepoxide 10-100 (1-3) 50-100 15- 40 Clorazepate 3,75- 15 (2-4) 15-30 30 diazepam 5-10 (3-4) 5-10 4-40 flurazepam 15-30 halazepam 60-160 lorazepam 2-4 2-6 oxazepam 15-30 (3-4) 15-30 30-60 prazepam 20-40 temazepam 15-30 triazolam 0.25-0.5

- in mg usually divided into 2-4 single doses, for further information regarding the same rate of parenteral administration, see Goodman and Gilman, loc. cit.

The preparation and release profile of the formulation for use according to the present invention or method of use thereof are shown below.

(a) After dry powder mixing, i to w

2-mg tablets of melatonin (Biosynth Co., Switzerland Jak) and acrylic resin-based carriers (Rohm Farm), either Eudragit R RS100 (Preparation SR-Ms) or Eudragit R RSPO (Preparation SR-Mf) , these substances were compressed at 2540 kg (2.5 tonnes) in a cylindrical tablet punch, together with the other ingredients listed below: SE-Ms formulation: Eudragit R RS100 48.8%, lactose 50%, melatonin 1.2% , Preparation SR-Mf: Eudragit '<RSPO

36.3% lactose 16.7%, calcium hydrogen phosphate 41.4%, talc 1.3%, magnesium stearate 4%, melatonin 1.3%. SR-Ms and SR-Mf are sustained release formulations.

The ingested dosage form (RM) was prepared as a SR-Mf preparation, but lactose was used as the carrier instead of Eudragit R.

(b) The potential release profile of the active ingredient from the tablets prepared in (a) was first studied by dissolving the melatonin obtained therefrom in water in distilled water at 37 ° C. The results in Table A show the percentage of melatonin content (mean value of the six tablets that was dissolved at specified time intervals).

Table A Time (hours) 1 2 4 6 B 10

Melatonin (Z) released from:

SR-Ms SR-Mf RM 12 32 93 29 51 96 62 76 100 84 90 8B 100 100 (C) In vivo profile SR- Mf tablet prepared according to clause (a) was studied at double oral administration healthy man (36 year) ABOUT 10.00, it means at time o, when level circulating melatonin is undetectable. number melatonin released in vivo was determined by determining its

the major urinary metabolite 6-sulfatoxymelatonin by the h iA method. The amount of 6-sulfaxymelatonin in the urine closely correlates with the level of the hormone in the blood. The results in Table B show melatonin determined as a percentage of total melatonin administered (mean of 2 tablets).

Table B

Release of melatonin from SR-Mf in vivo

Time (hours)

Z released at given intervals of 10.7

25.7 40.6 14.0

7.0

1.9

Cumulative release

10.7

36,4 77,0

91.0 90.0

The in vivo release of melatonin shown in Table A provides only an approximate indication of the in vivo release profile due to the known phenomenon of tissue absorption in the early release stages.

The amount of melatonin in the sustained release tablets may be varied, e.g. to 0.5, 1 or 5 mg per tablet without altering the release pattern found for tablets containing 2 mg melatonin.

Since analogs of melatonin that mimic its function in the human body are well known in the art, it can be recognized in this context that these analogues are considered to be obvious chemical equivalents of melatonin.

In accordance with the present invention, one or more benzodiazepines may be incorporated into the above compositions in the amounts described herein.

The invention is illustrated by the following examples.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

The reciprocal effects of chronic administration of benzodiazepine and melatonin on benzodiazepine and melatonin receptors in the brain and the ability of melatonin to disrupt this effect have been studied. Male rats were maintained in daytime 14 hours of light with 10 hours of darkness (5.00 illumination start, cold white fluorescent light) at 24.2 ° C. They had unlimited access to water and abortion. Animals (2 months old) were divided into 4 groups of 5 animals each. Animals of the first group (CON) were injected intraperitoneally (i.p.) with a vehicle (200 L of saline) at 16.00 hrs. Animals in the second group (VA1) were given daily at 4 pm i.p. injected diazepam (1 mg in 200 L vehicle, Roche). Animals of the third group (MEĽ) were given daily at 4 pm i.p. injected vehicle, their n-drinking water containing melatonin (4 mg of melatonin dissolved in 100 l w

ethanol and diluted to 1 liter). The fourth group of animals (VAL / MEL) received i.p. diazepam (1 mg in 200 L vehicle) and their drinking water contained melatonin (4 mg dissolved in 100 L ethanol and diluted to 1 liter). After 21 days, treatment was discontinued and animals were weighed. The average body weight of the VAL (274.20 g) and VAL / MEL (23 ', 30 g) groups was found to be slightly lower than that of the CON (292.30 g) or MEL (285.30 g) groups.

The animals were decapitated the next day between 11.00 to 7.00 pm (at this time the density of 2-issi-iodomelatonium should be at maximum), their brains were quickly selected and the gross synaptosomal pellets prepared as described above, in which the amount of tons of new receptors as described by L. Lau'lon and N. Zisapel (FEBS Lett., 1986, 197s 9-12). Bemzodiazepine receptors were determined by measuring the binding of ³ H-flunitrazepam (H-FNZ) and ³ H-R 0 15-1788 as described by Z.Amiri et al. (Brain Res-, 1991, 553s 155-158). Binding parameters were calculated from equilibrium binding values. Bmax values for specific binding

2-125-jodomelatonínu, 3H-FNZ or ^3H-R0 15-1788 at saturation, and K values are the apparent dissociation constants. The binding parameters of the individual groups were compared by scattering analysis and subsequent Student-Newman-Keule test for multiple comparisons. Differences were considered significant when P 0.05. Daily administration of diazepam (1 mg ip at 4 pm) to male rats for 3 weeks significantly reduced the density of binding sites for 2- ^12S I-iodomelatonin in the spinal cord and ponte (Table 1), but benzodiazepine binding was not significantly affected (Table 1). 2). When comparing the density of the melatonin receptors to the sleep-wake cycle control, chronic administration of benzodiazepine results in a weakening of the melanonin-responsive mechanisms and subsequent physiological activity.

Melatonin administered orally in drinking water for 3 ^; .weeks t

significantly increased the binding of ³ H-R0 15-17BB in the elongated spinal cord · ponte (Tables 2 and 3), but the binding of 2- ^12S I-iodomelatonin was unaffected. The increase in density of benzodiazepine binding platelets and apparent Kd in the elongated spinal cord and ponte induced by melatonin treatment are compatible with the elevation previously observed in rat cerebral cortex, which is mediated by opioid peptides, reported MDGomar et al. (Neuroendocrinology 1993, 4: 987-990). The fact that this increase persists in animals treated with benzodiazepine can eliminate competition between melatonin and benzodiazepine for benzodiazepine binding sites.

Daily administration of diazepam together with melatonin resulted in increased binding of ³ H-R0 15-178B in the elongated spinal cord and ponte, and prevented diazepam-induced suppression of binding

2-12Ei-iodomelatonin in this region (Tables 1 and 2). These results are surprising because, as pointed out in previous studies (Anis, Y. et al., Melatonin binding sites in the hamster brain: impact of melatonin. Molec. Cell. Endocrinol., 1989, 67: 121-128, Oaknin-Bendahan, S. et al.,

J.Basic Clin. Physiol. Phyrmacol., 1992, 3: 253-268) and confirmed in this study, administration of melatonin, whether in the form of rannc-d or evening injection or orally in drinking water, does not affect melatonin binding site density or daily fluctuation in most areas of the brain, including elongated spinal cord and ponte. In addition, pinealoctumia (removal of the pineal gland) does not eliminate the daily variation in the 2- * 2Si-iodomelatonin binding sites, although *

it affects their phase state (Oaknin-Bendahan et al., 1992, ibid.). Thus, changes in melatonin binding site density are unlikely to be due to autoregulation of the melatonin repressor.

In the cerebral cortex, melatonin slightly reduced the binding of ³ H-R 5 '5-1788 and ³ H-FNZ. Diazepam treatment did not significantly affect the binding of ³ H-R 15-1788 and ³ H-FNZ, but prevented the melaninin-induced decline (Tables 2a and 3). These data indicate: first, that melatonin has a localized effect on benzodiazepine binding sites rather than a generally suppressing or facilitating effect, and, secondly, that melatonin replacement therapy neutralizes some of the deleterious effects of benzodiazepine treatment.

Table 1 shows the equilibrium binding parameters of the majority of sites for ^2-12 i-iodomelatonin in synaptosomal formulations from the spinal cord region and on he treated diabetic and / or melatonin treated rats and untreated animals in terms of mean (± SD) values for Ka (in nM) and Bmax (in mol / mg protein). The values indicated in Table 1 by the same letter did not differ significantly. (Codes indicating the same significance are also used in Tables 2 and 3 below.

Table 1

Group Ka + SD Bmax ± SD

CON 0.87 + 0.2A 7.9 + 1.0a Mel 1.16 + 0, 3a 7.7 + 1.0a VAL 0.98 + 0.21 5, 1 + 0,5b VAL / MEL 2.27 + 0,75b 12.5 + 2,0c

Table 2 shows the equilibrium binding parameters of most sites for ³ H-RO 15-17BB- in synaptosomal preparations from the spinal cord and pontoon clastic area of rats treated with diazepam / or melatonin and in animals not treated for mean (± SD) values for K d <v nmL) and Bmax (in mol / mg protein).

Table 2

Group

Kd t SD

Bmax ± SD

CON 2.3 + 0.4A 310 + 22 Mel 2.8 + 0.2A 476 + 26b VAL 2.5 + 0, 4a 295 + 34a VAL / MEL 2.6 + 0, 5a 375 + 87b

Table 3 shows the effect of diazepam or melathrin on the binding of ³ H-FNZ and ³ H-RO 15-1788 in cerebral cortex membranes. tissue in terms of mean (± SD) values (in mol / mg protein).

Table 3

Group ³ H-FNZ ³ H-RO 15-17B8

CON 935 j t 31a 1354 + 48a MEL 765 j t 78b 1060 + 26b VAL 870 ± 22A 1264 + 99a VAL / MEL 980 j t 16a 1362 + 155a

Example 2

This example demonstrates the surprising effect of melatoline on facilitating rapid regression of the benzodiazepine drug tolerance. A 43-year-old married patient with 2 children had sleep onset insomnia in the last 10 years, accompanied by frequent and severe migraine attacks. A minor neurological examination was negative. Psychiatric but ^: Other organic complaints were also excluded. Throughout the treatment, the patient was treated with benzodiazepines, tricyclic antidepressants and neuroleptics, as well as biofeedback and relational methods, without apparent relief. She had taken 4 to 8 mg of Lorazepam every night for the last year.

A detailed psychological examination at Sleep Latjratory of the University of Tel Aviv revealed no prominent pathology. Sleep quality was assessed from an actigraph record that automatically monitored the sleep-wake pattern at sleep time using a small wrist-mounted apparatus. The recording was recorded after 3 consecutive days and showed a disturbed sleep pattern: decreased efficacy, long sleep latency n frequent waking episodes. Every 3 hours (for 36 hours) urine was collected, in which the principal melatol was determined. melatonin 6-sulfatoxymelatonin as an indicator of daily plasma melatonin recreation. The result showed that

6-sulfatoxymelatonin excretion levels were lower if the same age and lacked a typical circadian rhythm (Table 4).

Oral administration of a controlled-release melatonin preparation in the form of tablets containing 1 mg of melatonin (Neurim Pharmaceuticals, Israel) was initiated to correct melatonin deficiency and rhythm disorders. One tablet was given each day at 8.30 am. The patient was fired to gradually reduce the number of benzodiazepine tablets. that she took every night. After 2 days to surprise, the patient stopped using benzodiazepine hypnotics completely and claimed that her insomnia had improved significantly. In addition, her headaches have also gradually subsided. Repeated actigraphic record after 3 weeks of treatment showed a visible improvement in the sleep pattern.

The treatment was terminated and urine was collected every 3 hours (for 36 hours) and determined for 2 weeks thereafter.

6sulphatoxymelatonin. The results showed an increase in the total walrus w

6-sulfatoxymelatonin peak in the urine. A further five-month follow-up confirmed that the patient still maintained sleep quality and suffered only from slight headaches. After 6 months without treatment, sleep quality began to deteriorate. melatonin treatment was re-started.

This case report suggests considerable possible progress leading to 1 relief for many patients whose quality of life has been impaired by the addiction to benzodiazepine hypnotics. Moreover, the administration of exogenous melatonin may serve as a means for r ?, this and immediate sign withdrawal from benzodiazepines in patients with tolerance .

Table 4: 6-Sulphatoxymelatonin in the urine of a patient with a benzodiazepine-dependent network before and after treatment with melatonin (g / hr).

Time Before Treatment After Treatment

15:00 0, 3 0, 11 18:00 0, 16 0.45 21:00 0, 18 0, 11 24.00 0, 13 1.24 3:00 0.23 0.74 6:00 0.23 0.36 9:00 0.22 0.21 12:00 0, 13 0.01 15:00 0.22 0.04

Example 3

This example demonstrates the effect of long-term administration of melatonin in the treatment of insomnia for a patient dependent on a benzodiazerine drug.

Two volunteers, Y.L. and a 73-year-old female E.L., suffered from years of insomnia or frequent waking up at night and the consequent inability to fall asleep again. Both were found to have low melatonin secretion by determining the amount of urinary 6-sulfatoxymelatonin metabolite. Both patients took 1 to 2 mg of flunitrazepam orally each night before bedtime.

Both patients were withdrawn from flunitrazepam by gradual dose reduction and simultaneous oral administration of melatonin (Ξ mg melatonin per day as a controlled release formulation) for 2 months. Hence, each patient is taking>. followed by melatonin in the same form and with the same dose interval for approximately 2 years.

Both patients subjected to a good appetite for sleep and a significant improvement in sleep quality. Patient E.L. reported an improvement in sleep quality at the beginning of cessation cessation, a similar effect was seen by Y.L. after 2 weeks of wasting. Both patients reported reduced fatigue during the day after a few days from the start of weaning and also reported that iatonin did not cause me any residual fatigue in the morning, either. None of the two patients have side effects.

did not mention any undesirable characters

Example 4

This example, intended as a randomized, double-blind study, demonstrates the ability of melatonin replacement therapy to improve sleep duration in elderly patients who have been chronically taking benzodiazepines.

The group consisted of B men and 5 women of average age 78 ± 9.7 (SD) years, all complaining of prolonged insomnia and taking various benzodiazepines to induce sleep. Urine was collected every 15 hours every 15 hours and the overnight excretion of 6-sulfatoxymeLatonin, which is the major metabolite of melatonin in urine, was determined in the same way by the RIA method. Analysis of these patients revealed low and delayed ex 6-sulfatoxymelatonin (14 g per night as compared to 25 g per IU of young adults). The study protocol contained a one week study was 2 hours before the placebo melatonin tablf. Po poči.

three weeks of treatment with one in between. During the treatment period to patients administered orally with 2 mg controlled release or the experimental period, 5 patients continued on melatoi treatment for an additional two months.

Patients' sleep was objectively evaluated at the end! treatment period after 3 consecutive nights using if? fastened to the wrist. The motion record was then anab using the Neurim algorithm to determine latency, sleep efficiency, total sleep time, wake-up time, and wake-up number as average values for 3 µl of each patient. Six of Wicox's paired paired signs showed statistically significant differences in sleep parar and urine crushing of the uterus and / or 2 bedtime sessions with an overnight innovation. Ankova not graphed for ethers tests between periods of treatment with melatonin or placebo. The results are shown in Table 5.

Table 5

The effect of melatonin replacement of benzodiazepine drugs on sleep parameters.

Parameter Po 3 weeks treatment After another 2 months melatonin placebo melatonin treatment Sleep Efficiency 822 75Z 85X (Z = -2, S 2 P = 0.005) Sleep latency 17 minutes 39 minutes 7 minutes (Z = -2.12 P = 0.03> Waking up after falling asleep 59 minutes 76 minutes 42 minutes (Z = -2.00 P = 0.04) Number of wakes 11 17 10 (Z = -2.70 p = 0.007> Total sleep time 386 minutes 375 minutes 348 minutes (Z = -0.57 P = 0,5B>

From the above results it can be concluded that n _e ? ^; irradiation with melatonin therapy will improve the initial phase of sleep and its maintenance in elderly patients taking benzodiazepines and having low endogenous melatonin expenditure. The benefits of melatonin treatment increase over time, probably due to a reorganization of the circadial system.

Eriemyselná usability

The invention relates to the use of melatonin for the manufacture of a medicament for the treatment or prevention of a symptom of mental and physical dependence or tolerance to benzodiazepine medicaments, for the treatment of multidrug addiction and for the manufacture of a pharmaceutical composition which can be used for such types of treatment.

Claims (9)

Use of melatonin for the manufacture of a medicament dependent on benzodiazepines in multidrug-dependent patients or for the treatment of patients who have symptoms of psychological or physical dependence or tolerance to a benzodiazepine medicament, or for the treatment of patients diagnosed with a clinical condition that is improved by administration a benzodiazepine medicament to prevent the onset of symptoms of physical and mental dependence or tolerance to the benzodiazepine medicament, wherein said medicament comprises at least an amount of melatonin that is effective for each of said treatments and said amount is adapted to be administered daily at a dose of 0.01 to 100 provided that if said medicament is for the treatment of a patient diagnosed with a clinical condition that is improved by the administration of a benzodiazepine medicament, said medicament is a sustained-release pharmaceutical composition which contains not more than 5 mg of melatonin. Use of melatonin according to claim 1 for the manufacture of a medicament for the treatment of benzodiazepine dependence in multidrug / patient patients or in patients who have symptoms of mental and physical dependence or tolerance to benzodiazepine (a novel drug). Use according to claim 2, wherein said medicament is a sustained release drug containing not more than 5 mg of melatonin. Use of melatonin according to claim 1 for the manufacture of a sustained release drug for the treatment of patients diagnosed with a condition ameliorating the administration of a benzodiezepine drug to prevent the onset of symptoms of physical and psychological dependence and tolerance to the benzodiazepine drug, wherein said drug comprises at least a sufficient amount of melatonin for said treatment, said amount being adjusted to a daily administered dose in the range of 0.01 to 5 mg. Use according to any one of claims 1 to 4, wherein said the medicament comprises a pharmaceutical composition suitable for oral, rectal, parenteral and transdermal administration and which comprises at least one diluent, carrier or adjuvant. h. The use of claim 5, wherein said pharmaceutical composition is further characterized by at least one of the following characteristics: (i) it is in unit dosage form, each unit dose containing an amount of melatonin in the range of 0.0025-100 mq, wherein said formulation is not a sustained release formulation, and in the range of 0.0025-100 mg said formulation is a sustained release formulation. (ii) wherein said formulation is a sustained release formulation, i. a controlled release formulation wherein the melatonin is a predetermined controlled rate. (iii) comprises at least one melatonin receptor modifier and / or melatonin profile modifier. Use according to any one of claims 1 to 6, wherein the pharmaceutical preparation also contains at least one benzodiazepine medicament, preferably one of the following group of prepirates: Alprazolam, Chlorodiazepoxide, Clorazepate, Dizepam, Flunitrazepam, Flurazepam, Halazepam, Lorazepam, Oxazepam, Prazepam, Temazepam, and Triazolam. ⁴ The use of any one of claims 1 to 7, wherein said treatment comprises administering a benzodiazepine medicament or medicaments concurrently with melatonin, wherein the benzodiazepine medicament or medicaments are administered at daily dosages that progressively decrease until a predetermined, stabilized rate of benzodiazepine medicament is reached. or drugs. The use according to any one of claims 1 to 7, wherein said treatment comprises administering the benzodiazepine drug or medicaments concurrently with melatonin, wherein the benzodiazepine drug or medicaments are administered at daily doses that progressively decrease until the patient is completely withdrawn from the benzodiazepine drug or drugs.