CN1172431A - Use of melatonin for treating patients suffering from drug addiction - Google Patents
Use of melatonin for treating patients suffering from drug addiction Download PDFInfo
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- CN1172431A CN1172431A CN96191750A CN96191750A CN1172431A CN 1172431 A CN1172431 A CN 1172431A CN 96191750 A CN96191750 A CN 96191750A CN 96191750 A CN96191750 A CN 96191750A CN 1172431 A CN1172431 A CN 1172431A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
- A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/20—Hypnotics; Sedatives
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious agents
- A61P39/02—Antidotes
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Abstract
Melatonin is used in the manufacture of a medicament for treating a multi-drug 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
The present invention relates to melatonin and in order to treatment or prevention benzodiazepine class medicine is produced dependency, toleration or habit-forming symptom in preparation, and the application in the medicine of treatment multiple drug addiction, also relate to the pharmaceutical composition that is used for this type of treatment.
Dependence benzodiazepine betides usually and uses them to bring out the insomniac of sleep, and becomes habit-forming with among the patient who relaxes anxiety and convulsions to benzodiazepine class in sleeping pill withdrawal process.Yet habituation is taken benzodiazepine class medicine (and benzodiazepine class medicine have usually long half-lift be worth) may bring out toleration because of the mechanism of the unknown, and it shows as the invalid increase of dosage.And, all observe in the animals and human beings apoplexy due to endogenous wind, bounce-back or " withdrawal " phenomenon that suddenly stops taking place behind these medicines of being everlasting can cause being addicted (Greenblatt, D.J. and Shader, R.I., DrugMetab.Rev., 1978,8:13-28).The U.S. uses in the family investigation of spiritual healing medicine in nineteen ninety, and about 8% sleeping pill user increases its dosage in advance voluntarily, and it is before in report increase by 25% in 1979.Consider this investigation and find that 2.6% people of the United States take benzodiazepine class sleeping pill (being compared to 1979 is 2.4%), and estimate in the U.S. toleration to take place and dependent number only is 560,000.These numerical value are not included in medicine or the outer material of the normal standard of society uses and the multiple drug abuse.Be not reported in as yet in the sufferer that generation relies on benzodiazepine sleeping pill, the method for quick withdrawal is arranged, and this problem also be a big obstacle in junker's rehabilitation with restoring after effectively changing treatment.
Known melatonin (for a kind of deutero-hormone of indole that is produced by pineal gland when night) is played the part of main role in participating in periodic sleep-wakeup cycle and aspect the adjusting sleep.Also there is some evidence to show that melatonin can increase the effect of benzodiazepine , referring to, for example, Cardinali, people such as D.P., Adv.Biochem.Psychopharm., 1986,42:155-164; Acuna Castroviejo, people such as D., J.Pineal Res., 1986,3:101-102; And Niles, people such as L.P., J.Neural Transm.70:117-124.In addition, melatonin in mouse, can increase benzene first phenodiazine class medicine separate the anxiety effect (Guardiola-Lemaitre, people such as B., Pharmacol.Biochem.Behav., 1992,41,405-4080).On the other hand, existing people proposes the inhibitory action (McIntyre that benzodiazepine class medicine (in some kind, comprising among the mankind) can strengthen and secretion synthetic to the melatonin that is brought out by GABA-, I.M. wait people, Biol.Psychiat., 1988,24:105-108), and the increase at night of blood plasma melatonin can be suppressed by benzodiazepine in the mankind, and therefore upsets melatonin periodicity (Kabuto, the people such as M. on daytime, Endocr.Japon., 1986,33,405-414).Yet, observed obtaining, chronically with the treatment of oxazepaning, can change the variation in the daytime of melatonin receptor density at night in the Medulla Leporis seu Oryctolagi, and this effect is not observed (Anis, people such as Y. in the pineal animal of excision, J.Neural Transm., 1992,89:155-166).
The present invention has made us finding uncannily that melatonin takes (1) potentially with benzodiazepine class medicine simultaneously and make sufferer break away from dependence, addiction or toleration to these medicines, and (2) prevent the generation of these symptoms for being diagnosed as the patient's (and these undesirable symptoms do not take place as yet) who needs benzodiazepine class medicine.The narration of invention
Therefore the present invention is in providing on the one hand, melatonin is preparing in order to treatment multiple drug addiction, or has a patient who benzodiazepine class medicine is produced dependency, toleration or habit-forming symptom, or to treat clinical diagnosis be to have to be easy to by the patient of administration benzodiazepine class medicine with the patient's condition of slowing down misery, prevents the patient to take place this benzodiazepine class medicine is produced purposes in the pharmaceuticals of dependency, toleration or habit-forming symptom simultaneously.
On the other hand, the invention provides a kind of multiple drug addiction that is used for the treatment of, or has a patient who benzodiazepine class medicine is produced dependency, toleration or habit-forming symptom, or to treat clinical diagnosis be to have to be easy to by the patient of administration benzodiazepine class medicine with the patient's condition of slowing down misery, prevent the patient that the pharmaceutical composition of dependency, toleration or habit-forming symptom takes place this benzodiazepine class medicine is produced simultaneously, it comprises at least a diluent, carrier or adjuvant and as the benzodiazepine class medicine and the melatonin of active ingredient.
These pharmaceuticals can be the pharmaceutical composition that is suitable for oral administration, rectum, parenteral or transdermal administration, and it comprises at least a diluent, carrier or adjuvant, and can following character be feature again: (I) it be a unit dosage form, and constituent parts dosage comprises the melatonin of scope between 0.0025-100mg; (II) it is the form of controlled release composition, and wherein melatonin preferably disengages with predetermined controlled speed; (III) it also comprises at least a melatonin receptor regulator and/or the agent of melatonin effect profile adjustment.These pharmaceuticals also can comprise, and pharmaceutical composition according to the present invention comprises, at least a benzodiazepine class medicine, as at least a ALprazolanic, chlordiazepoxide, chlorine nitrogen , stable, flunitrazepan, flurazepam, halazepam, L0, oxazepan, prazepam, temazepam, triazole benzodiazepine .The compositions that comprises at least a benzodiazepine class medicine also can further reach (III) as feature with one or more of as above-mentioned character (I), (II).
Benzodiazepine class medicine is produced aspect the patient of dependency, toleration or habit-forming symptom applying the present invention to treat the multiple drug addiction or have, to continue medication benzodiazepine class medicine (when being less than beginning) and give effectively to slow down the melatonin of at least one this type of symptom of item simultaneously to the patient of patient.
In the particular embodiment of this treatment, that benzodiazepine class medicine or melatonin can be suitable for is oral, the pharmaceutical compositions of rectum, parenteral or transdermal administration exists, and comprises at least a diluent, carrier or adjuvant.In addition, therefore benzodiazepine class medicine and the distinctly administration of melatonin that is deployed into, or be combined into the single medicine compositions that comprises benzodiazepine class medicine and melatonin.
About the administration of melatonin, though administration out of the ordinary or with one or more benzodiazepine class medicine co-administered, effective dosage can be close rate every day between (for example) 0.01～100mg scope; It can controlled release composition form administration.Illustrate, 1-2mg can be in the administration in night with the melatonin of controlled release composition form.Melatonin can with melatonin receptor regulator or melatonin effect profile adjustment agent co-administered.The example of melatonin receptor regulator is that the benzodiazepine class medicine of short distance effect is as oxazepaning; The example of melatonin effect profile adjustment agent is benzodiazepine class medicine, beta blocker and a serotonin absorption inhibitor.Except that use these effect profile adjustment agent, but the effect profile mat of melatonin makes the patient before the melatonin administration, back or during accept the illumination effect.
Benzodiazepine class medicine as referred to herein may cause the danger of dependency, toleration and/or habit-forming symptom.Any prejudice of unmatchful this outline tool, this type of medicine can be aforesaid ALprazolanic, chlordiazepoxide, chlorine nitrogen , stable, flunitrazepan, flurazepam, halazepam, L0, oxazepan, in the prazepam, temazepam, triazole benzodiazepine one or more.
Treat in the specific embodiment of above-mentioned symptom in Another Application the present invention, at first benzodiazepine class medicine is continued (with melatonin simultaneously) with in fact with being accepted identical dosed administration every day with the melatonin treatment patient and given the patient of previous suggestion.Treat in the specific embodiment of these symptoms in Another Application the present invention, benzodiazepine class medicine (with the melatonin while) is given the patient with the dosed administration that the every day of being accepted with the melatonin treatment patient compared to previous suggestion, dosage reduced gradually.In this specific embodiment, the administration every day rate sustainable (for example) that this reduces gradually is to reaching predetermined stable administration rate, or also can (for example) to the dosage of benzodiazepine class medicine be till zero.
In using the present invention aspect the prevention purpose, be to have to be easy to promptly by the patient of administration benzodiazepine class medicine with the patient's condition of slowing down misery in order to treat clinical diagnosis, when preventing the patient to take place that this benzodiazepine class medicine produced dependency, toleration or habit-forming symptom simultaneously, effectively to slow down the amount administration of this patient's condition, will effectively prevent the melatonin of the amount of at least one this type of symptom to bestow the patient simultaneously benzodiazepine class medicine.Above-mentioned every specific embodiment that can be applicable to treat patient with indication symptom, also can be applied to prevent purpose accordingly, unless those skilled in the art have self-evident its inapplicable reason, for example, is in the example that presses in this with benzodiazepine class Drug therapy, the amount of the benzodiazepine class medicine of being used significantly will can not reduce to zero, and it determines to lower by the doctor in any particular case.
Yet, close rate administration every day benzodiazepine class medicine with routine when not only using with melatonin at the same time reaches specific purpose, and similarly use this type of medicine in addition and give the patient to slow down this patient's condition, all in the scope of prophylactic use of the present invention with the amount that is less than routine dosage every day.
As above indication, the present invention also extends to the pharmaceutical composition that comprises at least a benzodiazepine class medicine and melatonin.Because common administration every day of benzodiazepine class medicine 1-4 time, so every day, rate was the melatonin (using night typically) of 0.01-100mg, in the compositions identical, or during administration out of the ordinary, reach by following administration benzodiazepine class medicine with benzodiazepine class medicine:
The unit dose scope of number of days benzodiazepine
1 0.01-100 mg
2 0.05-50 mg
3 0.033-33.3?mg
4 0.025-25 mg
Therefore, when pharmaceutical composition of the present invention was unit dosage form, each dosage unit was preferably in the administration at night, and preferably comprised the melatonin that content range is 0.0025-100mg.
Following table provides the benzodiazepine class medication amount in order to the above-mentioned patient's condition among the treatment adult.For further data, for example restrictive condition, half-life, the form of medication that is suitable for child or baby and dosage are referring to Goodman ﹠amp; Gilman ' s " treatment pharmacological basis " (The Pharmacological Basis of Therapeutics), the 7th edition, 1985 (MacMillan publishing company), about the chapters and sections that use benzodiazepine the (for example the 352nd, 437 pages), all these chapters and sections are all incorporated this paper into as a reference.Benzodiazepine unit oral agents value general every day of oral dose ※
Mg (* every day) separates anxiety
The calm amount amount of sleeping peacefully ALprazolanic 0.75-1.5 librium 10-100 (1-3) 50-100 15-40 chlorine nitrogen 3.75-15 (2-4) 15-30 30 stable 5-10 (3-4) 5-10 4-40 flurazepam 15-30 halazepam 60-160 L0 2-4 2-6 15-30 (3-4) the 15-30 30-60 prazepam 20-40 temazepam 15-30 triazole benzene phenodiazine 0.25-0.5 ※ mg that oxazepans is divided into the 2-4 UD usually; For further data (comprising the parenteral close rate) referring to the above-mentioned Goodman ﹠ amp that quotes from; Gilman.
According to preparation of compositions of the present invention and discharge profile or its applicating example is described as follows.(a) with powdered substance, it is 2mg/ tablet melatonin (Biosynth company, Switzerland) with acrylic resin carrier (Rohm Pharma), it is EudragitRS100 (prescription SR-Ms) or Eudragit RSPo (prescription SR-Mf), other compositions as follows in addition: prescription SR-Ms:Eudragit RS100 48.8%, lactose 50%, melatonin 1.2%; Prescription SR-Mf:Eudragit RSPo 35.3%; Lactose 16.7%, calcium hydrogen phosphate 41.4%, Talcum 13%, magnesium stearate 4%, melatonin 1.3%, after the dry mixed, in 7 millimeters cylindrical perforations devices in 2.5 tons of lower compression.SR-Ms and SR-Mf are for continuing to disengage prescription.
Conventional dosage form (RM) is similar to prescription SR-Mf and prepares, but uses lactose to replace Eudragit as carrier.(b) as the tablet that makes as described in (a) section may discharge profile at first with in vitro in 37 ℃ of following melatonins in distilled water solution and study, the result of Table A is shown in setting-up time dissolved melatonin levels % (being the meansigma methods of 6 tablets) at interval the time.
Table A
Time (hour) 12468 10
By the following melatonin that disengages (%)
SR-Ms 12 29 62 84 90 100
SR-Mf 32 51 76 88 100
RM 93 96 100 (c) is as the in vivo profile of the SR-Mf tablet that makes as described in (a) section, be that mat is at 10 o'clock in the morning, promptly when the circulation melatonin can't detect, to twice of oral administration of healthy man (36 years old age) and research obtains.Melatonin is measured in the radioimmunoassay, RIA of its major metabolite of amount mat 6-sulfate radical oxygen base melatonin in urine that is in vivo disengaged.6-sulfate radical oxygen base melatonin levels in the urine is reacted the haemoconcentration of this hormone closely.The result of table B lists the melatonin measured to total % (being the meansigma methods of 2 tablets) that uses melatonin.
Table B melatonin from vivo the disengaging the time of SR-Mf (hour) 12468 10 disengage the 10.7 25.7 40.6 14.0 7.9 1.9 cumulative % of disengaging 10.7 36.4 77.0 91.0 98.0 99.9 in % at interval
Notice that because reactive compound can be organized the phenomenon of absorption in the commitment that disengages, melatonin only provides the about indication that in vivo disengages profile in sv disengaging (Table A is illustrated).
The content of melatonin in continuing emitting compositions can be changed into (for example) 0.5,1 or 5mg/ tablet, and does not influence in containing the pattern of disengaging that 2mg/ tablet melatonin found.
In the present invention, the known melatonin analog as imitate the melatonin effect in fact in human body will be considered to the obvious chemical equivalent that it is a melatonin.
According to the present invention, one or more benzene phenodiazine class medicine can be incorporated in the above-mentioned composition with aforesaid amount.
The present invention will illustrate with the following example.Embodiment 1
Study habitual benzodiazepine and melatonin administration reciprocal effect, and melatonin reverses the ability of these influences to melatonin in the brain and benzodiazepine receptor.Male rat is kept illumination 14 hours every days under 24 ± 2 ℃: dark timetable (illumination: 05.00h in 10 hours; Cold white fluorescent illumination).Food and the unrestricted supply of drinking-water.With animal (2 months are big), be divided into 4 groups, respectively contain 5 animals.Wherein a treated animal (CON) is injected carrier (200 μ l saline solution) with i.p. every day when 16:00.Second treated animal (VAL) every day, stable (1mg was stored in the 200 μ l carriers with the i.p. injection when 16:00; Roche).The 3rd treated animal (MEL) every day when 16:00 with vector injection; The drinking-water of this group contains melatonin (4mg is dissolved in the 100 μ l ethanol and is diluted to 1 liter).The 4th treated animal (VAL/MEL) is injected stable (1mg is stored in the 200 μ l carriers) every day when 16:00; The drinking-water of this group contains melatonin (4mg is dissolved in the 100 μ l ethanol and is diluted to 1 liter).Termination and animal weighed after 21 days, find val (274 ± 20g) with the VAL/MEL group (239 ± 30g) average weight value than CON (292 ± 30g) or the MEL group (285 ± 30g) value is low slightly.
With animal broken end (2-in this moment medullary substance bridge when the 18-19:00 of next day
125It is maximum that I-iodine melatonin concentration should be); Rapidly its brain taking-up is also prepared thick synaptosome pill as described, and as Laudon, M. and Zisapel, N., BEBS Lett., 1986, the described analysis melatonin receptor of 197:9-12.Mat such as Amiri, people such as Z., Brain Res., 1991, the described measurement of 553:155-158
3The H-flunitrazepan (
3H-FNZ) with
3Benzodiazepine receptor is analyzed in the combination of H-RO15-1788.From balance in conjunction with the data computation incorporating parametric.The Bmax value is represented 2-
125I-iodine melatonin,
3H-FNZ or
3Single-minded combination under H-RO 15-1788 is saturated, and the Kd value is the performance dissociation constant.Then make the variance of multiple ratio than Student-Newman-Keul ' s test, the relatively incorporating parametric of each group by analyzing.If the tool significant difference item is thought in P＜0.05.Be injected to 3 weeks of male rat with stable (1mg i.p was at 16.00 o'clock), obviously lower 2-in the medullary substance bridge
125The density (table 1) of I-iodine melatonin binding site, and the combination of benzodiazepine not obviously influenced (table 2).If melatonin receptor is relevant with sleep-wakeup cycle, these results hint that habitual administration benzodiazepine class medicine causes the mechanism of melatonin-reaction and follow-up physiologically active to lower.
Melatonin by drinking-water 3 weeks of oral administration, significantly strengthens
3The combination (table 2,3) of H-RO15-1788 in the medullary substance bridge, and 2-
125I-iodine melatonin in conjunction with unaffected.Handle benzodiazepine binding site density and apparent Kd increase in the medullary substance bridge that is brought out by melatonin, conform to previous increase observed in rat cortex, and demonstration participates in (Gomar, people such as M.D. between two parties by OPIOIDS peptide class, neuroendocrinology 1993,4:987-990).Even the fact that this increase still keeps in the animal that is subjected to stable treatment may be got rid of melatonin and the benzodiazepine competition effect on benzodiazepine binding site.
Stable and the melatonin of administration every day strengthens
3The combination of H-RO 15-1788 in the medullary substance bridge, and reverse by stable bring out to 2-
125I-iodine melatonin is in this regional bonded suppression (table 1,2).These results are as indicated previously to be unexpected (Anis, people such as Y., the melatonin binding site in the hamster brain: the impact of melatonin.Molec.Cell.Endocrinol, 1989,67:121-128; Oaknin-Bendahhan, S. wait the people, J.Basic Clin.Physiol.Pharmacol., 1992,3:253-268), and also in this research, prove conclusively, by morning or injection at dusk, or, can not influence melatonin and comprise the medullary substance bridge in most brain zone via drinking-water oral administration melatonin) in the density of melatonin or variation in the daytime.Yet the pineal gland excision is not abrogated 2-
125I-iodine melatonin binding site is in variation in the daytime, though it influences their phase place (people such as Oaknin-Bendahan, 1992, existing together).Therefore, the change of melatonin binding site density may not be the receptor self regulation effect that causes owing to because of melatonin.
In cerebral cortex, melatonin lowers a little
3H-RO 15-1788 with
3The combination of H-FNZ.With not appreciable impact of stable treatment
3H-RO 15-1788 with
3The combination of H-FNZ, but prevent the attenuating (table 2,3) that participates in by melatonin.These data at first hint, melatonin is circumscribed to acting as of benzodiazepine binding site, but not take place bonded generally compacting or promotion, and the second, melatonin replaces therapy can resist the illeffects that some chronic benzodiazepine treatment is produced.
Table 1 is shown in 2-in the synaptosome prepared product that is obtained by the medullary substance bridge zone through stable and/or melatonin processing and undressed rat with the terms such as average and S.D. value of Kd (nM of unit) and Bmax (the μ mol/mg of unit protein)
125The balance incorporating parametric of I-iodine melatonin binding site.There is not significant difference with the value of same-sign indication in the table 1.(symbol with same meaning also is used for table 2 and table 3, and is as follows.)
Table 1 group Kd ± sd Bmax ± sdCON 0.87 ± 0.2a 7.9+1.0aMEL 1.16 ± 0.3a 7.7 ± 1.0aVAL 0.98 ± 0.21a 5.1 ± 0.5bvAL/MEL 2.27 ± 0.75b 12.5 ± 2.0c
Table 2 is shown in the synaptosome prepared product that is obtained by the medullary substance bridge zone through stable and/or melatonin processing and undressed rat with the terms such as average and S.D. value of Kd (nM of unit) and Bmax (the μ mol/mg of unit protein)
3The average incorporating parametric of H-RO15-1788 binding site.
Table 2 group Kd ± sd Bmax ± sdCON 2.3 ± 0.4a 310 ± 22aMEL 2.8 ± 0.2a 476 ± 26aVAL 2.5 ± 0.4a 295 ± 34bVAL/MEL 2.6 ± 0.5b 375 ± 87b
Table 3 lists with average term (the μ mol/mg of unit protein) with S.D. value to be stabilized or melatonin reaches 3H-FNZ
3The bonded influence of H-RO15-1788 in rat cerebral cortex.
Table 3 group
3H-FNZ
3H-RO15-1788CON 935 ± 31a 1354 ± 48aMEL 765 ± 78b 1060 ± 26bVAL 870 ± 22a 1264 ± 99aVAL/MEL 980 ± 16a 1362 ± 155a embodiment 2
This embodiment illustrates that melatonin is in the surprised effect that promotes from benzodiazepine class Drug tolerance withdrawal aspect very fast.Position year 43 years old married women that two children are arranged arranged, suffered from the insomnia 10 years and had regular serious migraine.Its completely neurological be evaluated as negative value.The problem of spirit or other organs also is excluded.Through she has accepted benzodiazepine class medicine, tricyclic antidepressants antidepressant drug and neuroleptics these years, and with biological feedback and alleviate the treatment of method etc., do not improve but have obviously.Nearest this year, she took the 4-8mg L0 every night.
The complete mentalics assessment of (Tel Aviv) university's sleep laboratory in the Tel Aviv does not disclose any tangible condition of illness.The quality of sleeping is followed the trail of by the active force spectrum and is assessed, and described active force spectrum is followed the trail of by the automatic monitoring of the midget plant that the is connected to wrist pattern of sleeping soundly-revive in bed.This followed the trail of continuous record 3 days, and showed the sleep pattern of upsetting: efficient lowers, and long sleep is hidden and repeatedly waken insertion up.Collect urines (totally 36 hours) in per 3 hours and also analyze main melatonin metabolite: 6-sulfate radical oxygen base melatonin, as blood plasma melatonin secretory action index thing in the daytime.The result shows that 6-sulfate radical oxygen base melatonin excretion is low with the age individual, and lacks typical periodic law (table 4).
Beginning contains the controlled release melatonin compositions of 1mg melatonin (Neurim drugmaker, Israel) tablet form with oral administration, to proofread and correct the defective and the distortion in melatonin cycle.Every day in the morning, 8:30 bestowed a tablet.The benzodiazepine class medicine sheet number that requires this patient to decrease in gradually to take every night.Unexpectedly, in 2 days, this patient stops using benzodiazepine class sleeping pill fully, and declares that its insomnia obviously improves.In addition, its headache also dies away.The tracking of repeat function collection of illustrative plates shows that its sleep pattern is significantly improved after the treatment of 3 weeks.
Stop treatment, and after 2 weeks, collected urines (totally 36 hours) and analyzed 6-sulfate radical oxygen base melatonin in per once again 3 hours.Result's (table 4) indicates the 6-sulfate radical oxygen base melatonin amount of urine to increase and has peak at tangible night.5 months follow-up tracking determines that this patient still keeps its sleep character and suffering from headaches seldom again.In not having treatment after 6 months, sleep character begins to worsen and give melatonin treatment.
This case report may indicate many its life character of releasing to be subjected to benzodiazepine sleeping pill addiction and destructive patient suffering's breakthrough.The method that the exogenous melatonin of administration more can be used as fast and gives up from the patient who benzodiazepine class medicine is had toleration asymptomatically.
Table 4: in benzodiazepine * -dependent patients in the front of melatonin treatment method and after urine in 15.00 0.3 0.1118.00,0.16 0.4521.00,0.18 0.1124.00,0.13 1.24 3.00 0.23 0.74 6.00 0.23 0.36 9.00 0.22 0.2112.00,0.13 0.0115.00 0.22 0.04 after the treatment before 6-sulfate radical oxygen base melatonin (the μ g/ hour) chronotherapy
Embodiment 3
This embodiment illustrate the long term administration melatonin in treatment to the influence aspect the patient's of benzodiazepine drug dependence the insomnia.
Two volunteers, Y.L. (80 years old male) and E.L. (73 years old women) have been suffered from the insomnia and have often been awakened for many years and/or night, and back be difficult to again sleeping.This two all find the low melatonin secretion of tool (by the amount of measuring metabolite 6-sulfate radical oxygen base melatonin in the urine).Two patients all oral 1-2mg flunitrazepan before going to bed every night.
Every patient arranges it to remove to reduce flunitrazepan dosage gradually.And while oral administration melatonin (every day, 2mg was with controlled release forms) period of greater than two months.After finishing in this, the melatonin that every patient continues to take same form and same dose rate reaches about 2 years in period.
Every patient all report subjectively has good sleep derivation and in the tangible improvement of sleep properties.Especially, patient E.L. records improvement in the sleep properties during beginning during arranging, and Y.L. records similar effect during about two weeks during entering arrangement.Every patient back during beginning arrangement all is reported in tired minimizing the on daytime in a couple of days, and it is not residual tired also to point out that melatonin was made morning, or does not have any sensation of being still drank after a night.Two patients do not report that all any side effect is arranged.Embodiment 4
This embodiment is designed to randomization, double blinding, crossing research, illustrates that melatonin replaces therapy and improves the sleep function of persistence of the habitual older patient who uses benzodiazepine class medicine.
One group of average age is that 78 years old (SD=9.7) is made up of eight male and five women, and it is all suffered from long-term insomnia and uses various benzodiazepine class medicines to bring out sleep.In approximately collecting urine totally 15 hours in per 4 hours, and with the main melatonin urine metabolite of RIA replicate analysis 6-at night sulfate radical oxygen base melatonin) discharge.These patients' urinalysis shows low amount and the 6-sulfate radical oxygen base melatonin discharge (＜14 μ g are 25 μ g per minutes compared to Young Adults every night) that postpones.It respectively is for twice in treatment period in three weeks that project comprises, and the flush away that a week wherein arranged during two treatments at interval.The patient is in per os hora somni administration 2mg controlled release melatonin tablet, or placebo.Five patients continue melatonin treatment and reach 2 months beyond initial experimental period.
Continuous three nights of sleep of when each treatment finishes period, using the effect collection of illustrative plates objective analysis patient of wrist prestowage.Use Neurim algorithm analysis motion record sleep hidden to measure, reviving and the awakening number of times behind the Sleep efficiency, the length of one's sleep of determining, sleep beginning, average as three evenings of individual.Six pairing tag arrangement analyses be shown in melatonin and placebo treatment period arrangement between sleep parameters have statistically significant difference.The result is shown in the table 5.Table 5: replace of the effect of benzodiazepine class medicine to sleep parameters with melatonin.Back 2 months melatonins of the treatment in several 3 weeks
Sleep 82% 75% 85% efficient behind the melatonin placebo treatment (z=-2.82, p=0.005) hid 17 minutes 39 minutes 7 minutes by sleep
(z=-2.12, p=0.03) sleep beginning back 59 minutes 76 minutes 42 minutes revive (z=-2.00, p=0.04) awakening number of times 11 17 10
(z=-2.70, p=0.007) total sleep time is 386 minutes 375 minutes 348 minutes
(z＝-0.57，p＝0.58)
Can be obtained to draw a conclusion by The above results: the sleep initiation that melatonin replacement therapy can be improved the older patient of the use benzodiazepine medicine with low endogenous melatonin reaches lasting.Benefiting in time of melatonin treatment increases, and shows periodic system is reorganized.
Claims (8)
1, the application of melatonin, it is to be used for preparation treatment multiple drug addiction, or has a patient who benzodiazepine class medicine is produced dependency, toleration or habit-forming symptom, or to treat clinical diagnosis be to have to be easy to by the patient of administration benzodiazepine class medicine with the patient's condition of slowing down misery, prevents the patient that the pharmaceuticals of dependency, toleration or habit-forming symptom take place this benzodiazepine class medicine is produced simultaneously.
2, according to the application of claim 1, wherein, described pharmaceuticals comprise the pharmaceutical composition that is suitable for oral, rectum, parenteral or transdermal administration and comprises at least a diluent, carrier or adjuvant.
3, according to the application of claim 2, wherein, described pharmaceutical composition is a feature with following at least one character again:
(i) it is a unit dosage form, and constituent parts dosage comprises the melatonin of content range between 0.0025-100mg;
(ii) it is the form of controlled release composition, and wherein melatonin is preferably with predetermined control speed and disengages;
(iii) it also comprises at least a melatonin receptor regulator and/or the agent of melatonin effect profile adjustment.
4, according to the application of claim 2 or 3, wherein, this pharmaceutical composition also comprises at least a benzodiazepine class medicine.
5, according to the application of claim 4, wherein, described benzodiazepine medicine comprise ALprazolanic, chlordiazepoxide, chlorine nitrogen , stable, flunitrazepan, flurazepam, halazepam, L0, oxazepan, at least a in the prazepam, temazepam, triazole benzodiazepine .
6, a kind of pharmaceutical composition, it is to be used for the treatment of the multiple drug addiction, or has a patient who benzodiazepine class medicine is produced dependency, toleration or habit-forming symptom, or to treat clinical diagnosis be to have to be easy to by the patient of administration benzodiazepine class medicine with the patient's condition of slowing down misery, prevent the patient to take place this benzodiazepine medicine is produced dependency, toleration or habit-forming symptom simultaneously, said composition comprises at least a diluent, carrier or adjuvant and as the benzodiazepine class medicine and the melatonin of active ingredient.
7, according to the pharmaceutical composition of claim 6, it is suitable for oral, rectum, parenteral or transdermal administration, and is feature with following at least one character further:
(i) it is a unit dosage form, and constituent parts dosage comprises the melatonin of content range between 0.0025-100mg;
(ii) it is the form of controlled release composition, and wherein melatonin is preferably with predetermined controlled speed and disengages;
(iii) it also comprises at least a melatonin receptor regulator and/or the agent of melatonin effect profile adjustment.
8, according to the pharmaceutical composition of claim 6 or 7, wherein this benzodiazepine class medicine comprise ALprazolanic, chlordiazepoxide, chlorine nitrogen , stable, flunitrazepan, flurazepam, halazepam, L0, oxazepan, at least a in the prazepam, temazepam, triazole benzodiazepine .
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US08/381,535 US6469044B1 (en) | 1995-02-01 | 1995-02-01 | Method for treating patients suffering from drug dependencies which lead to plasma melationin deficiencies |
| US381,535 | 1995-02-01 | ||
| EP95303853A EP0724878B1 (en) | 1995-02-01 | 1995-06-06 | Use of melatonin for treating patients suffering from drug dependencies |
| EP95303853.6 | 1995-06-06 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1172431A true CN1172431A (en) | 1998-02-04 |
| CN1083263C CN1083263C (en) | 2002-04-24 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN96191750A Expired - Lifetime CN1083263C (en) | 1995-02-01 | 1996-01-29 | Use of melatonin for treating patients suffering from drug addiction |
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| Country | Link |
|---|---|
| JP (1) | JP4516159B2 (en) |
| CN (1) | CN1083263C (en) |
| AT (1) | AT408188B (en) |
| AU (1) | AU695366B2 (en) |
| BG (1) | BG62876B1 (en) |
| BR (1) | BR9607169A (en) |
| CZ (1) | CZ291349B6 (en) |
| DK (1) | DK176081B1 (en) |
| EE (1) | EE03384B1 (en) |
| FI (1) | FI119586B (en) |
| IS (1) | IS1980B (en) |
| LU (1) | LU90118B1 (en) |
| LV (1) | LV11940B (en) |
| MD (1) | MD1716C2 (en) |
| NO (1) | NO312814B1 (en) |
| NZ (1) | NZ298878A (en) |
| PL (1) | PL183148B1 (en) |
| SI (1) | SI9620022A (en) |
| SK (1) | SK284521B6 (en) |
| TR (1) | TR199700723T1 (en) |
| TW (1) | TW483757B (en) |
| WO (1) | WO1996023496A1 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100386070C (en) * | 2002-04-08 | 2008-05-07 | 纽里姆药品(1991)有限公司 | Pharmaceutical formulation comprising melatonin |
| CN109922795A (en) * | 2016-10-31 | 2019-06-21 | 纽里姆药物有限公司 | Epiphysin tabloid and preparation method thereof |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| BR0016918A (en) | 2000-01-05 | 2004-03-23 | Neurim Pharma 1991 | Process and formulation for treating antihypertensive resistance and related conditions |
| IL155666A (en) | 2003-04-29 | 2013-12-31 | Neurim Pharma 1991 | Composition for treating insomnia |
| US9119846B2 (en) | 2003-04-29 | 2015-09-01 | Neurim Pharmaceuticals (1991) Ltd. | Method and composition for enhancing cognition in alzheimer's patients |
| JP2015509106A (en) | 2012-01-26 | 2015-03-26 | ヴァンダ ファーマシューティカルズ インコーポレイテッ | Treatment of circadian rhythm disorders |
| US11918557B2 (en) | 2012-01-26 | 2024-03-05 | Vanda Pharmaceuticals Inc. | Treatment of circadian rhythm disorders |
| ES2805376T3 (en) | 2012-12-18 | 2021-02-11 | Vanda Pharmaceuticals Inc | Tasimelteon for treating circadian rhythm disorders |
| US11090285B2 (en) | 2013-11-12 | 2021-08-17 | Vanda Pharmaceuticals Inc | Treatment of circadian rhythm disorders |
| US10376487B2 (en) | 2013-11-12 | 2019-08-13 | Vanda Pharmaceuticals Inc. | Method of treatment |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DK0518468T3 (en) * | 1991-05-09 | 2000-01-31 | Neurim Pharma 1991 | Melatonin-containing compositions |
| IT1251544B (en) * | 1991-05-13 | 1995-05-17 | Gabriele Biella | PHARMACEUTICAL COMPOSITIONS ACTIVE IN THE THERAPY OF SLEEP DISORDERS INCLUDING MELATONIN OR A DERIVATIVE IN ASSOCIATION WITH A BENZODIAZEPINE DERIVATIVE |
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1996
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- 1996-01-29 WO PCT/IB1996/000082 patent/WO1996023496A1/en active IP Right Grant
- 1996-01-29 CZ CZ19972405A patent/CZ291349B6/en not_active IP Right Cessation
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1997
- 1997-07-24 LV LVP-97-144A patent/LV11940B/en unknown
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100386070C (en) * | 2002-04-08 | 2008-05-07 | 纽里姆药品(1991)有限公司 | Pharmaceutical formulation comprising melatonin |
| CN109922795A (en) * | 2016-10-31 | 2019-06-21 | 纽里姆药物有限公司 | Epiphysin tabloid and preparation method thereof |
| CN109922795B (en) * | 2016-10-31 | 2021-10-08 | 纽里姆药物有限公司 | Melatonin small tablet and preparation method thereof |
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