Patent Application: US-201414760431-A

Abstract:
a prophylactic or therapeutic agent is provided for depression or anxiety by increasing the levels of serotonin in the brain includes administration of glycyl - glutamine or cyclo glycyl - glutamine , a derivative that could cross the blood - brain barrier and could be used in peripheral applications .

Description:
in this detailed description , the preferred structuring of subject matter glycyl - glutamine while using against depression and anxiety disorder are described solely for making you understand the subject better in a way , which will not establish any restricting effects . the invention is related with the use of glycyl - glutamine ( gly - gln ) molecule with very little adverse effects and no toxic impacts , which can be synthesized endogenously in our body for treatment of depression and anxiety disorders . in the preferred structuring of the invention , the above - mentioned glycyl - glutamine is used for treatment purposes as 100 nmol / 10 μl ( 100 nano moles / 10 microliters ). however , these doses selected for laboratory animals ( in this case rats ) and have used into the brain directly . of course the dose will be different in different species and the dose depends the administration route ( oral , parenteral and all of other known routes in medicine ) of drug . the aim of the drug administration is to achieve minimum therapeutic plasma levels and not to reach minimum toxic consantrion . thus the dose depends of the patients &# 39 ; age , gender , body weight , liver and kidney functionality and the genetic factors . as a result , the dose of gly - gln in the treatment and / or prophylaxis of depression and / or anxiety should be chosen to achieve therapeutic concentration in the plasma . additionally , intracerebroventricular route ( into the lateral ventricles of brain directly ) is a very helpful in experimental models for to show investigators drugs &# 39 ; central effects but it is an unacceptable route for human beings in normal medical conditions . therefore , gly - gln should be use with regular routes in medical applications such as intravenously , intramuscular , intra - arterial , etc . but when administered peripherally gly - gln could not across the blood - brain barrier . as a result of that could not generate central effects in the brain . to achieve therapeutic effects against depression and / or anxiety cyclo gly - gln , which is a derivative of gly - gln , should be use to generate central effects in the brain . cyclo gly - gln could be across blood - brain barrier and generate central effects . subject matter glycyl - glutamine ( gly - gln ) comes off while β - endorphin is being burned in the body . molecules , which are smaller than beta - endorphin , are developed as a result of proteolytic disintegration ( ng et al . 1981 ). these are beta - endorphin 1 - 26 , beta - endorphin 1 - 27 and gly - gln . antagonization of effects of beta - endorphin by means of beta - endorphin 1 - 27 has made us think that gly - gln as another breakdown product might show similar effects . in the following studies , it has been shown that gly - gln , which has been applied on the brainstem of rodents iontophoretically , had an inhibiting effect on cell ignition and this breakdown product might be a peptide with inhibiting characteristics ( parish et al ., 1983 ). continuing studies especially focus on pomc and beta - endorphin . it has been indicated that gly - gln antagonized the thermogenesis caused by alpha - msh as one of the breakdown products of pomc ( resch and millington , 1993 ) and eliminated the cardiorespiratory depression caused by beta - endorphin ( unal et al ., 1997 ). similarly , it has been indicated that gly - gln and its cyclic form , which can penetrate and pass through blood brain barrier cyclo gly - gln eliminated the cardiorespiratory depression caused by beta - endorphin and morphine ( unal et al ., 1997 ). it is very important for the therapeutic potential of gly - gln as a dipeptide reproduced from beta - endorphin to eliminate the adverse effects arising after use of morphine without altering its analgesic effects ( owen et al ., 2000 ). the studies performed on use of alcohol can be given as examples for other significant studies by gly - gln . it has been found that beta - endorphin administered centrally increased use of alcohol while gly - gln decreased such use ( resch et al ., 2005 ; resch and simpson , 2008a and 2008b ; simpson et al ., 1998 ). it has been shown in the studies performed by nicotine and morphine , which have additive side effects , that gly - gln has prevented the conferment and deprivation symptoms against these materials ( cavun et al ., 2005 ; goktalay et al ., 2006 ). it has been shown in the studies which have been firstly performed by morphine that gly - gln has prevented the conditioned place preference caused by morphine , inhibited addition and tolerance developments and decreased deprivation symptoms ( cavun et al ., 2005 ). in the studies performed by nicotine , it has been found that gly - gln has prevented conditioned place preference and deprivation syndrome ( goktalay et al ., 2006 ). subject matter glycly - glutamine is a molecule in our body . therefore , in terms of adverse effects and toxicological characteristics , it has an edge over other chemicals used in current technique in medical use . it has been proven as a result of the tests performed on animals that glycyl - glutamine is therapeutic on depression and anxiety disorders . these aforementioned studies have been performed by means of “ the forced swimming test ” method , which is the most applied animal model , used in antidepressant treatment surveys . the forced swimming test had been developed by porsolt et al ., ( 1978 ) and it is the most applied animal model in depression surveys especially the antidepressant treatment surveys . a rodent or a mouse is placed inside a cylinder tank filled with water and then the time passed until the animal is inactive and how much the animal becomes inactive in a particular period of time are measured . after the same animal is placed in the same tank twenty - four hours after the first time , it is observed that the time passes until inactivity reduces . inactivity is expressed as losing behaviors of trying to escape in other words “ behavioral helplessness ”. the forced swimming test is a similar response to learned helplessness . the efforts spent for an escape comes to an end for the animal , which understands it is exposed to a stress it will not be able to escape . thus , it can be understood by that test model whether the antidepressant medications , which are administered before the second administration , show antidepressant effects or not . in practice , the post - treatment behaviors of the animal change for reducing behavioral helplessness . the time passed until inactivity is extended by means of acute or short - term antidepressant treatments and total time of inactivity is decreased . this result is expressed as that the antidepressant medications increase the active coping response of swimming stress ( basar and ertugrul , 2005 ). because , it is an easy to apply practice , this model is used extensively ( cryan et al ., 2002 ). in fig1 , the effect of intracerebroventricular gly - gln injection on the first term of inactivity . when , gly - gln has been administered centrally , it has extended the time passed until first inactivity compared to the control animals . while , the time passed until first inactivity of the rodents which have been centrally administered saline ( 10 μl ) has been 14 . 9 ± 2 . 8 seconds ( n = 14 ), the time passed until first inactivity of the rodent which have been applied gly - gln ( 100 nmol / 10 μl ) by that same way has been increased to 28 . 1 ± 6 . 1 seconds ( n = 12 ), ( p & lt ; 0 . 05 ). this finding shows us that gly - gin increases the active coping response of rodents against swimming stress . in fig2 , the effect of intracerebroventricular gly - gln injection on the total term of inactivity . when , gly - gln has been administered centrally , it has reduced the total time of inactivity compared to the control animals . while , the total inactivity time of the rodents which have been centrally administered saline ( 10 μl ) has been 229 . 4 ± 8 . 9 seconds ( n = 14 ), the time passed until first inactivity of the rodent which have been applied gly - gln ( 100 nmol / 10 μl ) by the same way has been increased to 172 . 5 ± 12 . 8 seconds ( n = 12 ), ( p & lt ; 0 . 001 ). this finding shows us that gly - gln increases the active coping response of rodents against swimming stress . in fig3 , the effect of intracerebroventricular gly - gln injection on the escalation and swimming times . as the control group , the escalation and swimming times of the rodents which have been centrally administered saline ( 10 μl ) have been respectively 43 . 9 ± 7 . 0 and 26 . 7 ± 2 . 9 seconds , ( n = 14 ) these escalation and swimming times for the rodents which have been administered gly - gln ( 100 nmol / 10 μl ) by the same way have been respectively 90 . 8 ± 11 . 4 and 36 . 8 ± 4 . 3 seconds ( n = 12 ). this findings statistically shows that there is not any statistical difference between the control and medication groups in terms of total time of swimming activities throughout the experiment ( p & gt ; 0 . 05 ), while the total escalation activities are more in the medication group ( p & gt ; 0 . 001 ). this finding shows us that gly - gln increases the active coping response of rodents against swimming stress . shortly , statistically significant differences between the rodents , which have been centrally saline , and gly - gln have been found . as , it is clearly indicated in the descriptions of the figures , it can be said that gly - gln increases active coping response against swimming stress of rodents . this result is important for considering gly - gln as a potential antidepressant . the source of the antidepressant effects of gly - gln , which is mentioned in the figure descriptions above , have been analyzed and shown in fig4 and 5 . in fig4 and 5 ; the effect of gly - gin on the serotonin output at the nucleus accumbency section of the brain upon intracerebroventricular gly - gln injection can be seen . as a result of the studies performed by means of brain micro - dialysis , it has been recognized that glycyl - glutamine which is centrally and singly ( intracerebroventricular ; isv ) administered in 100 nmol dose has extremely increased the serotonin output at the nucleus accumbency section of the brain ( p & lt ; 0 . 001 ). an increase in serotonin outputs can be observed in all time intervals throughout 2 hours of monitoring period following the gly - gln injection ; however , no serotonin output could be observed from the rodents in the control group who had been administered saline injections by the same way . serotonin , which is structurally a monoamine neurotransmitter , is a hormone , which makes people feel happy , energetic and lively . when , the subject matter hormone serotonin is deficient in people , they feel depressive , tired and boring . in this respect , significant increases observed on serotonin levels by means of glycyl - glutamine administrations show that subject matter glycyl - glutamine is effective on ones suffering from depressing and anxiety . furthermore , the word “ saline ” indicated in fig4 and 5 means salty water . it is used for comparing with the tested medication by administering on the control group . the non - diluted form of glycyl - glutamine can be stored in a refrigerator at − 20 ° c . for a very long period of time . after , it is diluted by saline ; 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