quiet roar
Bluelighter
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Amazing thread.
Thanks for the bump Pinkanga
Thanks for the bump Pinkanga
Selegiline (l-deprenyl) - too good to be true?
- Thread starter phase_dancer
- Start date
nanobrain
Bluelighter
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pinkanga, i KNEW you were going to ask that ;-) btw, its mgs, not gms.
my reason for not supplementing with deprenyl, as well as with anything, on a continuous basis is eventual and inevitable tolerance.
i am quite happy to do a couple courses a year to achieve the cognition enhancement i desire.
i have taken it up to 20 mg p/d, at this dose, w/l-phenylalanine, the peripheral stimulation effects were enhanced to the point of discomfort while no further increase in telepathic ability was noted.
preferred dose is still 5 mg/day, morning, after the phenyl/coffee combo and a light breakkie.
my reason for not supplementing with deprenyl, as well as with anything, on a continuous basis is eventual and inevitable tolerance.
i am quite happy to do a couple courses a year to achieve the cognition enhancement i desire.
i have taken it up to 20 mg p/d, at this dose, w/l-phenylalanine, the peripheral stimulation effects were enhanced to the point of discomfort while no further increase in telepathic ability was noted.
preferred dose is still 5 mg/day, morning, after the phenyl/coffee combo and a light breakkie.
nanobrain
Bluelighter
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^ I NEVER SAID THIS!
yes, i have combined the 2 substances, but i never suggested anyone else should do this. selegeleine is not meant to be used as an MDMA potentiator.
as has been said before, the combination can be potentially very dangerous because selegeline is a cumulative and irreversible MAO-B inhibitor.
with a caveat that there is a growing body of evidence suggesting neuroprotective effects of selegeline with concurrant MDMA administration via prevention of lipid peroxidation,
YOU can potentially DIE from the combo.
UTSE.
yes, i have combined the 2 substances, but i never suggested anyone else should do this. selegeleine is not meant to be used as an MDMA potentiator.
as has been said before, the combination can be potentially very dangerous because selegeline is a cumulative and irreversible MAO-B inhibitor.
with a caveat that there is a growing body of evidence suggesting neuroprotective effects of selegeline with concurrant MDMA administration via prevention of lipid peroxidation,
YOU can potentially DIE from the combo.
UTSE.
Last edited:
Nano, sorry to keep bringing this up but regarding the telepathy you experience(d?) - what exactly were you taking at the time? Just the selegeline? In other words, do you believe the telepathy you were feeling was from the selegeline exclusively?
streetsurfer
Ex-Bluelighter
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- Feb 18, 2004
- Messages
- 623
bump, this is very intresting stuff
nanobrain said:
like what others?
this is really interesting :D ...i remember desperately trying to read people's minds as a kid...and learning to be sceptical...i've never bothered thinking about it since lol.
am i understanding wrong, or are people saying that once you have learnt this telepathic skill that you hold onto it, whether you're taking deprenyl/other or not? Or have you got to be taking deprenyl to have it?
BigTrancer
Bluelight Crew
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- Mar 12, 2000
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- 7,339
Hehehe some people stop taking drugs when they start hearing voices in their head...
BT
BT
VelocideX
Bluelighter
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- May 26, 2003
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Bump: Wrote a mini-FAQ... may add to it
http://www.bluelight.ru/vb/showthread.php?s=&threadid=125323&r=2
http://www.bluelight.ru/vb/showthread.php?s=&threadid=125323&r=2
VelocideX
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Going to be trying deprenyl soon... had major issues getting it due to unwillingness of Australian GPs prescribing 
I'm curious - has anyone on deprenyl noticed a general increase in overall alertness/activation. Rephrased, do you feel less tired throughout the day?
I've had a problem for some t ime with being overly tired.... I've tried holding myself to anywhere from 11 to 6 hrs sleep a night. I find 8 the best, but still find myself, on the whole, tired throughout the day...
Melatonin seems to improve the quality of sleep, but I still remain tired.
(This is one of the reasons I'm going to try deprenyl)
I'm curious - has anyone on deprenyl noticed a general increase in overall alertness/activation. Rephrased, do you feel less tired throughout the day?
I've had a problem for some t ime with being overly tired.... I've tried holding myself to anywhere from 11 to 6 hrs sleep a night. I find 8 the best, but still find myself, on the whole, tired throughout the day...
Melatonin seems to improve the quality of sleep, but I still remain tired.
(This is one of the reasons I'm going to try deprenyl)
streetsurfer
Ex-Bluelighter
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I tried the other day too and the crusty old prick wouldn't give it to me. Maybe I will go to my shrink I havn't seen in years.
Has anybody had any experience with it regarding anxiety? Either causeing or releaving?
Has anybody had any experience with it regarding anxiety? Either causeing or releaving?
smileyfish
Ex-Bluelighter
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- Aug 8, 2002
- Messages
- 1,091
VelocideX said:
I too have problems with this. Would be interested to hear how you go with deprenyl - I've been tired for 12 years
Interesting thread - may actually get motivated to do some further research!
Smiley
VelocideX
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I have now seen FOUR GPs, none are willing to prescribe it.
The first three cited legal reasons... namely if something went wrong, they'd be liable as it wasn't being prescribed for the intended result (namely parkinsons)
Interestingly the fourth one told me that I could get it if I was depressed, but then I'd have to get a psychiatrist to do it.
And even then, there are much better first-line treatments for it.
It's such a pain... Including shipping, I've looked through ten or so overseas pharmacies and the best I can do is about $1.37 per tablet.
Do it in Australia with a prescription and you can get it as low as 50c or thereabouts per tablet. And the difference isn't just shipping costs... you can get 100 tablets here for cheaper than 60 overseas.
At least I'm not in Canada, where it seems to bea bout $150 for 60 tablets. sucks to be there
The first three cited legal reasons... namely if something went wrong, they'd be liable as it wasn't being prescribed for the intended result (namely parkinsons)
Interestingly the fourth one told me that I could get it if I was depressed, but then I'd have to get a psychiatrist to do it.
And even then, there are much better first-line treatments for it.
It's such a pain... Including shipping, I've looked through ten or so overseas pharmacies and the best I can do is about $1.37 per tablet.
Do it in Australia with a prescription and you can get it as low as 50c or thereabouts per tablet.
And the difference isn't just shipping costs... you can get 100 tablets here for cheaper than 60 overseas.At least I'm not in Canada, where it seems to bea bout $150 for 60 tablets. sucks to be there
streetsurfer
Ex-Bluelighter
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- Messages
- 623
The DR I went to told me it isn't covered under PBS. Is that true?
streetsurfer
Ex-Bluelighter
- Joined
- Feb 18, 2004
- Messages
- 623
Nope, load of shit, it is available under PBS but with an authority script.
Here is a little bit more info.
Actions Pharmacology. Selegiline is an irreversible inhibitor of monoamine oxidase (MAO), an intracellular enzyme associated with the outer membrane of mitochondria. Selegiline acts as a `suicide' substrate for the MAO, i.e. it is converted by MAO to an active moiety which combines irreversibly with the active site of the enzyme and/or the enzyme's essential flavine adenine dinucleotide (FAD) cofactor. MAOs are currently subclassified into two types, A and B. MAO type A (MAO-A) and MAO type B (MAO-B) differ in their substrate specificity and tissue distribution. In humans, most of the MAO in the brain is type B while intestinal MAO is predominantly type A. At the recommended dose, selegiline's affinity for type B active sites is greater than for type A, and it serves as a selective inhibitor of MAO-B. However, this selectivity is dose dependent and may be lost at higher than recommended doses (> 20 mg/day), resulting in increased inhibition of MAO-A. The precise dose at which selegiline becomes a nonselective inhibitor of all MAO is unknown.
The rate of MAO-B regeneration following discontinuation of selegiline treatment is dependent upon de novo protein synthesis. This rate, which has not been quantified, seems likely to determine how fast normal MAO-B activity can be restored.
MAO plays an important role in the catabolism of catecholamines (dopamine, noradrenaline and adrenaline) and serotonin in CNS neurones. MAOs are also important in the catabolism of various exogenous amines found in a variety of foods and drugs. For example, it is believed that MAO in the gastrointestinal tract and liver (primarily type A) provides essential protection from exogenous amines (e.g. tyramine). If absorbed intact, these amines can cause a hypertensive crisis, the so-called `cheese reaction'. This has been documented with nonselective MAOIs.
To date, there have been no reports of `cheese reactions' in patients treated with selegiline. However, the pathophysiology of the `cheese reaction' is complicated and is not fully understood. Selegiline's apparent freedom from this reaction has also been ascribed to its selective inhibition of MAO-B at clinically used doses (less than or equal to 10 mg/day) and its ability to prevent noradrenaline from being displaced from adrenergic neurones by tyramine and other indirect acting sympathomimetics.
Selegiline may have pharmacological effects unrelated to MAO-B inhibition. There is some evidence that it may increase dopaminergic activity by other mechanisms, including interfering with dopamine reuptake at the synapse. Selegiline's effects may also be mediated through its metabolites, with three of its principal metabolites possibly having their own pharmacological actions. Two metabolites, l-amphetamine and l-methamphetamine interfere with neuronal uptake and enhance release of several neurotransmitters (e.g. noradrenaline, dopamine, serotonin). However, l-amphetamine and l-methamphetamine have significantly less activity than the corresponding d-isomers. The third metabolite, N-desmethylselegiline, appears to act as a selective inhibitor of MAO-B in animal studies. The extent to which each of these metabolites contributes to the effects of selegiline is unknown.
Clinical trials. Selegiline as monotherapy in the early phase of Parkinson's disease. Four randomised, double blind, placebo controlled, parallel group studies, involving 501 patients treated with selegiline and 498 patients treated with placebo have been conducted to the end of 1994 where the primary outcome measure was time to initiation of levodopa. The largest trial, the DATATOP study, randomised 800 patients to four different treatment regimens. These regimens were selegiline (10 mg once daily); vitamin E; a combination of selegiline with vitamin E; and placebo. The primary outcome measure was time to requirement for levodopa as additional therapy. An analysis of the primary endpoint at 12 months into the trial showed that, of those patients who were treated with selegiline, 97/399 (24.3%) had progressed to the point of requiring additional therapy (levodopa). Of those patients who had received vitamin E or placebo, 176/401 (43.9%) required the addition of levodopa. The results demonstrated that selegiline delayed onset of the stage where levodopa was required, the delay in commencement of levodopa being approximately seven to nine months in the particular group studied. Overall, selegiline was shown in these four studies to significantly delay the need to introduce levodopa by five to nine months, compared to the placebo group. Evidence was less clear as to whether selegiline exerted a symptomatic effect.
Selegiline as adjunctive therapy in the early and middle phases of Parkinson's disease. Six randomised, double blind, placebo controlled, parallel or crossover studies involving 157 patients treated with selegiline in combination with levodopa and 157 patients treated with placebo in combination with levodopa have been conducted in patients in the early and middle phases of Parkinson's disease to the end of 1995. When levodopa was added to selegiline therapy, or both drugs were given together, to de novo patients with Parkinson's disease, optimal clinical conditions, in terms of disability, were maintained with levodopa doses 50 to 80% lower than if selegiline was not coadministered. Increases in daily levodopa dosage were significantly smaller in the selegiline and levodopa group, compared to the placebo and levodopa group, over time (up to five years). Levodopa dosing frequency was significantly in favour of patients on selegiline and levodopa compared to those on placebo and levodopa (i.e. less levodopa doses/day in the former group). Additionally, patients treated with selegiline and levodopa had attenuated deterioration in their disability scores, compared to the placebo and levodopa group. The conclusions from these studies were that the need to increase levodopa dose was slowed down.
Pharmacokinetics. General characteristics. Selegiline is readily absorbed from the gastrointestinal tract. The maximum concentrations are reached in 0.5 hours after oral administration. The bioavailability is low, on average 9.4 +/- 5.9% of unchanged selegiline from a 10 mg oral dose reaches the systemic circulation. A substantial increase in selegiline bioavailability (up to threefold) occurs when selegiline is administered with food high in fat.
Selegiline is a lipophilic, slightly basic compound which quickly penetrates into tissues, including the brain. It is rapidly distributed throughout the body, with the apparent volume of distribution being 508 +/- 182 L after a 10 mg intravenous dose. Selegiline is strongly bound to plasma proteins, especially to macroglobulins and, to a lesser extent, to albumin.
Selegiline is rapidly metabolised, mainly in the liver, into N-desmethylselegiline (the major metabolite), l-methamphetamine and l-amphetamine. In humans, these three metabolites have been identified in plasma and urine after single and multiple doses of selegiline. Following the oral administration of a single dose of selegiline hydrochloride 10 mg for example, N-desmethylselegiline (mean t1/2 two hours); l-amphetamine (mean t1/2 17.7 hours); and l-methamphetamine (mean t1/2 20.5 hours) were found in the serum and urine. Metabolites of selegiline are excreted mainly via the urine, with about 15% occurring in the faeces. Over a period of 48 hours, urinary excretion of these metabolites accounted for 45% of the dose administered. The mean elimination half-life of a 10 mg intravenous dose of selegiline is 1.6 +/- 0.3 hours. The total body clearance of selegiline is about 240 L/hour. The half-life of a 10 mg oral dose of selegiline is 1.2 to 1.8 hours.
Characteristics in patients. Selegiline is metabolised quickly, but due to irreversible MAO-B inhibition, the duration of clinical effect does not depend on the elimination time of selegiline, and therefore once daily dosing can be applied.
No information is available yet concerning polymorphic metabolism or the effect of renal or hepatic insufficiency on the metabolism of selegiline. Preliminary information on the pharmacokinetics of selegiline and its metabolites is available.
Indications Treatment of patients with Parkinson's disease. It can be used as monotherapy in the early phases of the disease and as adjunctive therapy with levodopa (with or without a peripheral decarboxylase inhibitor).
Contraindications Known hypersensitivity to selegiline or any of the other ingredients of this product, and whenever levodopa therapy is contraindicated.
Selective serotonin reuptake inhibitors (SSRIs). The combination of SSRIs with selegiline is contraindicated because of reports of serious, sometimes fatal, reactions in patients receiving this combination and in patients who have recently discontinued SSRIs and are then started on an MAOI. Agitation, ataxia, cold sweats, hypertension, mania, pseudophaeochromocytoma, `serotonergic reaction' and shivers have been reported with the concomitant use of selegiline and SSRIs. The mechanism of action between SSRIs and MAOIs is not fully understood.
At least five weeks should be allowed between discontinuation of, for example, fluoxetine, sertraline or paroxetine and initiating selegiline therapy, due to the long half-life of these SSRI drugs and/or their active metabolites. A period of two weeks between stopping selegiline and starting SSRIs is sufficient, because of the short half-life of selegiline and its active metabolites.
Pethidine. The combination of pethidine and MAOIs is contraindicated because of reports of serious, sometimes fatal, reactions in patients receiving this combination. These reactions have also been reported in patients who have been started on pethidine within two weeks of discontinuing an MAOI. (This warning is often extended to other opioids.) Agitation, delirium, hyperpyrexia, irritability, restlessness, rigidity, stupor and sweating have been reported with the concomitant use of selegiline and pethidine. The mechanism of the interaction is not fully understood.
Precautions Daily doses of selegiline HCl exceeding those recommended (10 mg/day) should not be used because of the risks associated with nonselective inhibition of MAO (see Pharmacology).
In higher doses (> 20 mg/day), the selectivity of selegiline starts to diminish, resulting in increased inhibition of MAO-A. The possibility of a hypertensive reaction at higher doses (> 20 mg/day) of selegiline after ingestion of food or drugs rich in various exogenous amines has to be taken into account.
Even at the recommended dose of 10 mg per day, the selectivity of selegiline for MAO-B may not be absolute. The precise dose at which selegiline becomes a nonselective inhibitor of all MAO is unknown.
Exacerbation of levodopa associated side effects may occur in some patients given selegiline. This presumably occurs because of the increased amount of dopamine reacting with supersensitive postsynaptic receptors. Reducing the dose of levodopa by approximately 10 to 30% often mitigates these effects.
Selegiline should be given cautiously to patients with severe angina pectoris, cardiac arrhythmias, labile hypertension, peptic or duodenal ulcer, severe liver or kidney dysfunction or psychosis, as selegiline may exacerbate these conditions.
Interactions Selective serotonin reuptake inhibitors. The use of SSRIs in combination with selegiline is contraindicated.
Pethidine. The use of pethidine in combination with selegiline is contraindicated (see Contraindications).
Moclobemide. No tolerability problems have been reported when selegiline and moclobemide, a reversible inhibitor of MAO-A, have been used in combination. However, when used together the exogenous amine sensitivity factor may increase. A diet low in exogenous amines such as tyramine is recommended for patients taking the combination.
Monoamine oxidase inhibitors. Nonselective, irreversible MAOIs, in combination with selegiline, may cause severe hypotension.
Serotonergic drugs. Treatment with heterogenous serotonergic drugs in patients primarily with psychiatric illness, taken alone or in combination with other drugs such as MAOIs, has been uncommonly associated with symptoms of myoclonus, tremor, confusion, restlessness, ataxia and hyperreflexia. While usually short lived, this syndrome can lead to intensive care admissions and is potentially fatal. The occurrence of the serotonin syndrome may occur after use of SSRIs, tricyclic antidepressants, tetracyclic antidepressants, 3-4-methylenedioxy-metamphetamine (MDMA or ecstasy) and other 5-HT potentiating agents, and the antipsychotic drug, clozapine. The treatment of choice is cessation of the drugs responsible. Treatment with the 5-HT receptor antagonists cyproheptadine, methysergide and propranolol may shorten the syndrome duration.
Tricyclic antidepressants. Severe CNS toxicity has been reported in patients when a combination of tricyclic antidepressants and selegiline has been used. In one patient receiving amitriptyline and selegiline this included hyperpyrexia and death; another patient receiving protriptyline and selegiline experienced tremor, agitation and restlessness, followed by unresponsiveness and death two weeks after selegiline was added. Other adverse reactions occasionally reported in patients receiving a combination of selegiline and various tricyclic antidepressants include hypertension/ hypotension, dizziness, diaphoresis, tremor, seizures and changes in behavioural and mental status. Since the mechanisms of these reactions are not fully understood, concomitant use of selegiline with tricyclic antidepressants is not recommended.
At least two weeks should be allowed between discontinuation of a tricyclic antidepressant and initiation of selegiline therapy, due to the long t1/2 of some tricyclics and their active metabolite(s). A two week period between selegiline discontinuation and tricyclic antidepressant initiation would be sufficient, because of the short t1/2 of selegiline and its active metabolites.
Oral contraceptives. Concomitant use of oral contraceptives (tablets containing the combination of gestodene/ ethinyloestradiol or levonorgestrel/ ethinyloestradiol) and selegiline may cause an increase in the oral bioavailability of selegiline. Thus, caution should be used during the concomitant administration of selegiline and oral contraceptives.
Other. In clinical trials, interactions between dopamine and selegiline have been reported occasionally resulting in a hypertensive reaction.
There have also been reports that concomitant use of tramadol with selegiline may adversely interact.
During selegiline treatment, the possibility of a hypertensive reaction as a result of an interaction with indirect sympathomimetic drugs has to be taken into account. Foods containing various exogenous amines such as tyramine have not been reported to induce hypertensive reactions during selegiline treatment at doses used in the treatment of Parkinson's disease.
Overdosage No specific information is available about clinically significant overdoses with selegiline. However, experience gained during selegiline's development reveals that some individuals exposed to doses of selegiline 600 mg/day suffered severe hypotension and psychomotor agitation.
Since the selective inhibition of MAO-B by selegiline is achieved at doses in the range recommended for the treatment of Parkinson's disease (e.g. 10 mg/day), overdoses are likely to cause significant inhibition of both MAO-A and MAO-B. The signs and symptoms of overdose may therefore resemble those observed with nonselective MAOIs (e.g. tranylcypromine, isocarboxazide and phenelzine), particularly disorders of the central nervous and cardiovascular systems (e.g. drowsiness, dizziness, faintness, irritability, hyperactivity, agitation, severe headaches, hallucination, hypertension, hypotension, vascular collapse, rapid and irregular pulse, praecordial pain, respiratory depression and failure, hyperpyrexia, diaphoresis).
Treatment. There is no specific antidote and the treatment is symptomatic.
Dosage and Administration Parkinson's disease. Selegiline is administered as monotherapy in the early phase of the disease, or as adjunctive therapy with levodopa (with or without a peripheral dopa decarboxylase inhibitor). In each case the initial dose is 5 mg taken at breakfast and lunch. There is no evidence that additional benefit will result from the administration of higher doses. Moreover, higher doses should ordinarily be avoided because of the increased risk of side effects.
After two to three days of adjunctive treatment, an attempt may be made to reduce the dose of levodopa (10 to 30%) if levodopa related adverse reactions occur. During continued selegiline therapy further reductions of levodopa may be possible.
Double blind studies on early phase parkinsonian patients showed that patients receiving selegiline monotherapy manage significantly longer without levodopa therapy than controls receiving placebo. These patients could also maintain their ability to work longer.
After the initiation of levodopa therapy, selegiline potentiates and extends the effect of levodopa, and thus a reduction of levodopa dosage is possible. By adding selegiline to levodopa therapy the fluctuations in disability, e.g. end-of-dose type fluctuations, can be reduced.
Here is a little bit more info.
Actions Pharmacology. Selegiline is an irreversible inhibitor of monoamine oxidase (MAO), an intracellular enzyme associated with the outer membrane of mitochondria. Selegiline acts as a `suicide' substrate for the MAO, i.e. it is converted by MAO to an active moiety which combines irreversibly with the active site of the enzyme and/or the enzyme's essential flavine adenine dinucleotide (FAD) cofactor. MAOs are currently subclassified into two types, A and B. MAO type A (MAO-A) and MAO type B (MAO-B) differ in their substrate specificity and tissue distribution. In humans, most of the MAO in the brain is type B while intestinal MAO is predominantly type A. At the recommended dose, selegiline's affinity for type B active sites is greater than for type A, and it serves as a selective inhibitor of MAO-B. However, this selectivity is dose dependent and may be lost at higher than recommended doses (> 20 mg/day), resulting in increased inhibition of MAO-A. The precise dose at which selegiline becomes a nonselective inhibitor of all MAO is unknown.
The rate of MAO-B regeneration following discontinuation of selegiline treatment is dependent upon de novo protein synthesis. This rate, which has not been quantified, seems likely to determine how fast normal MAO-B activity can be restored.
MAO plays an important role in the catabolism of catecholamines (dopamine, noradrenaline and adrenaline) and serotonin in CNS neurones. MAOs are also important in the catabolism of various exogenous amines found in a variety of foods and drugs. For example, it is believed that MAO in the gastrointestinal tract and liver (primarily type A) provides essential protection from exogenous amines (e.g. tyramine). If absorbed intact, these amines can cause a hypertensive crisis, the so-called `cheese reaction'. This has been documented with nonselective MAOIs.
To date, there have been no reports of `cheese reactions' in patients treated with selegiline. However, the pathophysiology of the `cheese reaction' is complicated and is not fully understood. Selegiline's apparent freedom from this reaction has also been ascribed to its selective inhibition of MAO-B at clinically used doses (less than or equal to 10 mg/day) and its ability to prevent noradrenaline from being displaced from adrenergic neurones by tyramine and other indirect acting sympathomimetics.
Selegiline may have pharmacological effects unrelated to MAO-B inhibition. There is some evidence that it may increase dopaminergic activity by other mechanisms, including interfering with dopamine reuptake at the synapse. Selegiline's effects may also be mediated through its metabolites, with three of its principal metabolites possibly having their own pharmacological actions. Two metabolites, l-amphetamine and l-methamphetamine interfere with neuronal uptake and enhance release of several neurotransmitters (e.g. noradrenaline, dopamine, serotonin). However, l-amphetamine and l-methamphetamine have significantly less activity than the corresponding d-isomers. The third metabolite, N-desmethylselegiline, appears to act as a selective inhibitor of MAO-B in animal studies. The extent to which each of these metabolites contributes to the effects of selegiline is unknown.
Clinical trials. Selegiline as monotherapy in the early phase of Parkinson's disease. Four randomised, double blind, placebo controlled, parallel group studies, involving 501 patients treated with selegiline and 498 patients treated with placebo have been conducted to the end of 1994 where the primary outcome measure was time to initiation of levodopa. The largest trial, the DATATOP study, randomised 800 patients to four different treatment regimens. These regimens were selegiline (10 mg once daily); vitamin E; a combination of selegiline with vitamin E; and placebo. The primary outcome measure was time to requirement for levodopa as additional therapy. An analysis of the primary endpoint at 12 months into the trial showed that, of those patients who were treated with selegiline, 97/399 (24.3%) had progressed to the point of requiring additional therapy (levodopa). Of those patients who had received vitamin E or placebo, 176/401 (43.9%) required the addition of levodopa. The results demonstrated that selegiline delayed onset of the stage where levodopa was required, the delay in commencement of levodopa being approximately seven to nine months in the particular group studied. Overall, selegiline was shown in these four studies to significantly delay the need to introduce levodopa by five to nine months, compared to the placebo group. Evidence was less clear as to whether selegiline exerted a symptomatic effect.
Selegiline as adjunctive therapy in the early and middle phases of Parkinson's disease. Six randomised, double blind, placebo controlled, parallel or crossover studies involving 157 patients treated with selegiline in combination with levodopa and 157 patients treated with placebo in combination with levodopa have been conducted in patients in the early and middle phases of Parkinson's disease to the end of 1995. When levodopa was added to selegiline therapy, or both drugs were given together, to de novo patients with Parkinson's disease, optimal clinical conditions, in terms of disability, were maintained with levodopa doses 50 to 80% lower than if selegiline was not coadministered. Increases in daily levodopa dosage were significantly smaller in the selegiline and levodopa group, compared to the placebo and levodopa group, over time (up to five years). Levodopa dosing frequency was significantly in favour of patients on selegiline and levodopa compared to those on placebo and levodopa (i.e. less levodopa doses/day in the former group). Additionally, patients treated with selegiline and levodopa had attenuated deterioration in their disability scores, compared to the placebo and levodopa group. The conclusions from these studies were that the need to increase levodopa dose was slowed down.
Pharmacokinetics. General characteristics. Selegiline is readily absorbed from the gastrointestinal tract. The maximum concentrations are reached in 0.5 hours after oral administration. The bioavailability is low, on average 9.4 +/- 5.9% of unchanged selegiline from a 10 mg oral dose reaches the systemic circulation. A substantial increase in selegiline bioavailability (up to threefold) occurs when selegiline is administered with food high in fat.
Selegiline is a lipophilic, slightly basic compound which quickly penetrates into tissues, including the brain. It is rapidly distributed throughout the body, with the apparent volume of distribution being 508 +/- 182 L after a 10 mg intravenous dose. Selegiline is strongly bound to plasma proteins, especially to macroglobulins and, to a lesser extent, to albumin.
Selegiline is rapidly metabolised, mainly in the liver, into N-desmethylselegiline (the major metabolite), l-methamphetamine and l-amphetamine. In humans, these three metabolites have been identified in plasma and urine after single and multiple doses of selegiline. Following the oral administration of a single dose of selegiline hydrochloride 10 mg for example, N-desmethylselegiline (mean t1/2 two hours); l-amphetamine (mean t1/2 17.7 hours); and l-methamphetamine (mean t1/2 20.5 hours) were found in the serum and urine. Metabolites of selegiline are excreted mainly via the urine, with about 15% occurring in the faeces. Over a period of 48 hours, urinary excretion of these metabolites accounted for 45% of the dose administered. The mean elimination half-life of a 10 mg intravenous dose of selegiline is 1.6 +/- 0.3 hours. The total body clearance of selegiline is about 240 L/hour. The half-life of a 10 mg oral dose of selegiline is 1.2 to 1.8 hours.
Characteristics in patients. Selegiline is metabolised quickly, but due to irreversible MAO-B inhibition, the duration of clinical effect does not depend on the elimination time of selegiline, and therefore once daily dosing can be applied.
No information is available yet concerning polymorphic metabolism or the effect of renal or hepatic insufficiency on the metabolism of selegiline. Preliminary information on the pharmacokinetics of selegiline and its metabolites is available.
Indications Treatment of patients with Parkinson's disease. It can be used as monotherapy in the early phases of the disease and as adjunctive therapy with levodopa (with or without a peripheral decarboxylase inhibitor).
Contraindications Known hypersensitivity to selegiline or any of the other ingredients of this product, and whenever levodopa therapy is contraindicated.
Selective serotonin reuptake inhibitors (SSRIs). The combination of SSRIs with selegiline is contraindicated because of reports of serious, sometimes fatal, reactions in patients receiving this combination and in patients who have recently discontinued SSRIs and are then started on an MAOI. Agitation, ataxia, cold sweats, hypertension, mania, pseudophaeochromocytoma, `serotonergic reaction' and shivers have been reported with the concomitant use of selegiline and SSRIs. The mechanism of action between SSRIs and MAOIs is not fully understood.
At least five weeks should be allowed between discontinuation of, for example, fluoxetine, sertraline or paroxetine and initiating selegiline therapy, due to the long half-life of these SSRI drugs and/or their active metabolites. A period of two weeks between stopping selegiline and starting SSRIs is sufficient, because of the short half-life of selegiline and its active metabolites.
Pethidine. The combination of pethidine and MAOIs is contraindicated because of reports of serious, sometimes fatal, reactions in patients receiving this combination. These reactions have also been reported in patients who have been started on pethidine within two weeks of discontinuing an MAOI. (This warning is often extended to other opioids.) Agitation, delirium, hyperpyrexia, irritability, restlessness, rigidity, stupor and sweating have been reported with the concomitant use of selegiline and pethidine. The mechanism of the interaction is not fully understood.
Precautions Daily doses of selegiline HCl exceeding those recommended (10 mg/day) should not be used because of the risks associated with nonselective inhibition of MAO (see Pharmacology).
In higher doses (> 20 mg/day), the selectivity of selegiline starts to diminish, resulting in increased inhibition of MAO-A. The possibility of a hypertensive reaction at higher doses (> 20 mg/day) of selegiline after ingestion of food or drugs rich in various exogenous amines has to be taken into account.
Even at the recommended dose of 10 mg per day, the selectivity of selegiline for MAO-B may not be absolute. The precise dose at which selegiline becomes a nonselective inhibitor of all MAO is unknown.
Exacerbation of levodopa associated side effects may occur in some patients given selegiline. This presumably occurs because of the increased amount of dopamine reacting with supersensitive postsynaptic receptors. Reducing the dose of levodopa by approximately 10 to 30% often mitigates these effects.
Selegiline should be given cautiously to patients with severe angina pectoris, cardiac arrhythmias, labile hypertension, peptic or duodenal ulcer, severe liver or kidney dysfunction or psychosis, as selegiline may exacerbate these conditions.
Interactions Selective serotonin reuptake inhibitors. The use of SSRIs in combination with selegiline is contraindicated.
Pethidine. The use of pethidine in combination with selegiline is contraindicated (see Contraindications).
Moclobemide. No tolerability problems have been reported when selegiline and moclobemide, a reversible inhibitor of MAO-A, have been used in combination. However, when used together the exogenous amine sensitivity factor may increase. A diet low in exogenous amines such as tyramine is recommended for patients taking the combination.
Monoamine oxidase inhibitors. Nonselective, irreversible MAOIs, in combination with selegiline, may cause severe hypotension.
Serotonergic drugs. Treatment with heterogenous serotonergic drugs in patients primarily with psychiatric illness, taken alone or in combination with other drugs such as MAOIs, has been uncommonly associated with symptoms of myoclonus, tremor, confusion, restlessness, ataxia and hyperreflexia. While usually short lived, this syndrome can lead to intensive care admissions and is potentially fatal. The occurrence of the serotonin syndrome may occur after use of SSRIs, tricyclic antidepressants, tetracyclic antidepressants, 3-4-methylenedioxy-metamphetamine (MDMA or ecstasy) and other 5-HT potentiating agents, and the antipsychotic drug, clozapine. The treatment of choice is cessation of the drugs responsible. Treatment with the 5-HT receptor antagonists cyproheptadine, methysergide and propranolol may shorten the syndrome duration.
Tricyclic antidepressants. Severe CNS toxicity has been reported in patients when a combination of tricyclic antidepressants and selegiline has been used. In one patient receiving amitriptyline and selegiline this included hyperpyrexia and death; another patient receiving protriptyline and selegiline experienced tremor, agitation and restlessness, followed by unresponsiveness and death two weeks after selegiline was added. Other adverse reactions occasionally reported in patients receiving a combination of selegiline and various tricyclic antidepressants include hypertension/ hypotension, dizziness, diaphoresis, tremor, seizures and changes in behavioural and mental status. Since the mechanisms of these reactions are not fully understood, concomitant use of selegiline with tricyclic antidepressants is not recommended.
At least two weeks should be allowed between discontinuation of a tricyclic antidepressant and initiation of selegiline therapy, due to the long t1/2 of some tricyclics and their active metabolite(s). A two week period between selegiline discontinuation and tricyclic antidepressant initiation would be sufficient, because of the short t1/2 of selegiline and its active metabolites.
Oral contraceptives. Concomitant use of oral contraceptives (tablets containing the combination of gestodene/ ethinyloestradiol or levonorgestrel/ ethinyloestradiol) and selegiline may cause an increase in the oral bioavailability of selegiline. Thus, caution should be used during the concomitant administration of selegiline and oral contraceptives.
Other. In clinical trials, interactions between dopamine and selegiline have been reported occasionally resulting in a hypertensive reaction.
There have also been reports that concomitant use of tramadol with selegiline may adversely interact.
During selegiline treatment, the possibility of a hypertensive reaction as a result of an interaction with indirect sympathomimetic drugs has to be taken into account. Foods containing various exogenous amines such as tyramine have not been reported to induce hypertensive reactions during selegiline treatment at doses used in the treatment of Parkinson's disease.
Overdosage No specific information is available about clinically significant overdoses with selegiline. However, experience gained during selegiline's development reveals that some individuals exposed to doses of selegiline 600 mg/day suffered severe hypotension and psychomotor agitation.
Since the selective inhibition of MAO-B by selegiline is achieved at doses in the range recommended for the treatment of Parkinson's disease (e.g. 10 mg/day), overdoses are likely to cause significant inhibition of both MAO-A and MAO-B. The signs and symptoms of overdose may therefore resemble those observed with nonselective MAOIs (e.g. tranylcypromine, isocarboxazide and phenelzine), particularly disorders of the central nervous and cardiovascular systems (e.g. drowsiness, dizziness, faintness, irritability, hyperactivity, agitation, severe headaches, hallucination, hypertension, hypotension, vascular collapse, rapid and irregular pulse, praecordial pain, respiratory depression and failure, hyperpyrexia, diaphoresis).
Treatment. There is no specific antidote and the treatment is symptomatic.
Dosage and Administration Parkinson's disease. Selegiline is administered as monotherapy in the early phase of the disease, or as adjunctive therapy with levodopa (with or without a peripheral dopa decarboxylase inhibitor). In each case the initial dose is 5 mg taken at breakfast and lunch. There is no evidence that additional benefit will result from the administration of higher doses. Moreover, higher doses should ordinarily be avoided because of the increased risk of side effects.
After two to three days of adjunctive treatment, an attempt may be made to reduce the dose of levodopa (10 to 30%) if levodopa related adverse reactions occur. During continued selegiline therapy further reductions of levodopa may be possible.
Double blind studies on early phase parkinsonian patients showed that patients receiving selegiline monotherapy manage significantly longer without levodopa therapy than controls receiving placebo. These patients could also maintain their ability to work longer.
After the initiation of levodopa therapy, selegiline potentiates and extends the effect of levodopa, and thus a reduction of levodopa dosage is possible. By adding selegiline to levodopa therapy the fluctuations in disability, e.g. end-of-dose type fluctuations, can be reduced.
BigTrancer
Bluelight Crew
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Thanks very much for the large info post, streetsurfer. Was this referenced from an online source of selegiline prescribing information, or elsewhere?
Edit: Thanks p_d, just wanted the ref in the thread.
BigTrancer
Edit: Thanks p_d, just wanted the ref in the thread.
BigTrancer
Last edited:
phase_dancer
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Seems pretty much word for word as the MIMS entry for eldepryl, a generic brand of selegiline