04-27-04 21:08
No 503354
ONE
I had heard rumors of pharmaceutical braggarts crowing about the imminent inclusion of some nasty foilant so effective as to blow the cottage clandestine industry out the side door.
"Ha! Fat chance," sez I: "I can clean anything, and I can keep giving it to Marvin for whatever the hell he does with it, in pursuit of his low-life self indulgent behavior patterns.
Well, I ain't so cocky as I usta be: the reason is below. But on the other hand, all y'all are fer shure interested in cognitive enhancement, aren't you?
Hey, who cares if you get high: it's more important to be clear, focused, and live a long time..
Ain't it?
+++++++++++++++++++++
Check it out:
Some of you may have heard of a legal easily obtained drug which metabolizes readily to methamphetamine:
(R)-(-)-N,2-dimethyl-N-2- propynylphenethylamine hydrochloride:
AKA . Selegiline, Jumex, L-Deprenyl, and other brand names. It's a MAO-B selective inhibitor.
(What? How can you buy something which endogenously becomes the <gasp!> Devil's Drug??)
Selegiline enters into the picture because of hints contained in the following references. See, it can enhance your experience of the really really low-test goods you are likely to encounter with increasing frequency.
You say your last batch was low-energy, Homey? You don't know what happened but it was hardly worth the effort? Take a little MAO-B inhibitor: feel your neurons being protected. Get a bright outlook on live. Protect your limited supply of dopaminergic receptors.
Wow! ??great stuff?
First, the bad news:
FIELD OF THE INVENTION
The present application provides pharmaceutical compositions and methods of using the sympathomimetic composition of (-)-pseudoephedrine as a decongestant, bronchodilator, and the like. The present compositions of (-)-pseudoephedrine are substantially-free of (+)-pseudoephedrine. According to the present invention, at similar doses, (-)-pseudoephedrine binds .alpha..sub.1 - and .alpha..sub.2 adrenergic receptors better than (+)-pseudoephedrine and yet has less adverse effects upon blood pressure and fewer drug interactions.
BACKGROUND OF THE INVENTION
Sympathomimetic drugs are structurally and pharmacologically related to amphetamine. They generally act by binding to or activating .alpha.- and .beta.-adrenergic receptors, resulting in vascular constriction, reduced blood flow and/or reduced secretion of fluids into the surrounding tissues. Such receptor binding generally decreases swelling of nasal membranes and the amount of mucous secreted into nasal passages. Sympathomimetic drugs are therefore used to treat nasal congestion, allergies and colds. In addition, they are used as appetite suppressants and mydriatic agents.
At the present time, some drugs are sold as racemic mixtures. Alternatively, the most easily isolated stereoisomer is sold, even though another stereoisomer may have greater activity or fewer side effects because that stereoisomer interacts more selectively with the receptors involved in sympathomimetic action. Isolation and use of the more selective stereoisomer may therefore reduce not only the required dosage, but many unwanted side effects.
Many organic compounds exist in optically active forms. This means that they have the ability to rotate the plane of plane-polarized light. An optically active compound is often described as a chiral compound. Such a chiral compound has at least one asymmetric carbon which can exist in two different, mirror image configurations. Compounds which have the same composition but are mirror images of each other are called enantiomer. The prefixes d and l, or (+) and (-), identify the direction in which an enantiomer rotates light. The d or (+) steroisomer, or enantiomer, is dextrorotatory. In contrast, the l or (-) enantiomer is levorotatory. A mixture of (+) and (-) enantiomers is called a racemic mixture.
An alternative classification system for stereoisomers exists where prefixes (S) and (R) are used. This classification system is based on the structure of the compound.
(+)-Pseudoephedrine is known to be sympathomimetic amine which binds to .alpha.-adrenergic receptors. It is sold under the tradename SUDAFED.RTM.. However, (+)-pseudoephedrine has undesirable side effects, including central nervous system stimulation, lightheadedness, nervousness, anxiety, paranoia, heart arrhythmia, atrial fibrillations and premature ventricular contractions. 95 American Hospital Formulatory Service 847-48.
Moreover, (+)-pseudoephedrine can easily be converted into the controlled drug, (S)-methamphetamine, by simply converting the hydroxyl in (+)-pseudoephedrine to a hydrogen.
Hence, a need exists for a composition having the beneficial decongestant activities of (+)-pseudoephedrine, without its adverse side effects, and without its (S)-methamphetamine-conversion problem.
dwarfer
(esoteric)
04-27-04 21:12
No 503355
TWO
SUMMARY OF THE INVENTION
The present invention is directed to a pharmaceutical composition containing (-)-pseudoephedrine and a pharmaceutically acceptable carrier, wherein the pharmaceutical composition is substantially-free of (+)-pseudoephedrine. Suprisingly, the present (-)-pseudoephedrine compositions bind to .alpha.-adrenergic receptors with greater affinity than do (+)-pseudoephedrine compositions while causing less adverse effects on blood pressure. Moreover, (-)-pseudoephedrine has decongestant activity which is similar to several known decongestants. The pharmaceutical composition has (-)-pseudoephedrine in a therapeutic dosage suitable for treating nasal or bronchial congestion, counteracting the physiological effects of histamine, dilating the pupil, suppressing the appetite, treating attention deficit hyperactivity disorder and treating other conditions typically treated with sympathomimetic drugs. Upon administration to a mammal in a therapeutically effect amount, the present compositions may have reduced side effects relative to administration of (+)-pseudoephedrine, for example, interactions with drugs such as antihistamines. Moreover, (-)-pseudoephedrine reduces the (S)-methamphetamine conversion problem of (+)-pseudoephedrine, because reduction of the hydroxyl in (-)-pseudoephedrine results in (R)-methamphetamine with substantially less psychoactivity than (S)-methamphetamine.
The present invention is also directed to a method of relieving nasal and bronchial congestion which includes administering a therapeutically effective amount of (-)-pseudoephedrine to a mammal, wherein such (-)-pseudoephedrine is substantially-free of (+)-pseudoephedrine. This method has less side effects than a method which includes administration of a racemic pseudoephedrine mixture or a composition of (+)-pseudoephedrine. In this embodiment, a therapeutically effective amount of (-)-pseudoephedrine is a dosage suitable for treating nasal and/or bronchial congestion.
The present invention is also directed to a method of antagonizing the physiological effects of histamine which includes administering a therapeutically effective amount of (-)-pseudoephedrine to a mammal, wherein such (-)-pseudoephedrine is substantially-free of (+)-pseudoephedrine. According to the present invention, (-)-pseudoephedrine surprisingly is a physiological antagonist of histamine. This method has fewer side effects than a method which includes administration of a composition including (+)-pseudoephedrine. It is also believed that this method has less side effects than administration of a racemic mixture of (+)- and (-)-pseudoephedrine. In this embodiment, a therapeutically effective amount of (-)-pseudoephedrine is a dosage suitable for relieving the physiological effects of histamine, for example, nasal congestion, inflammation, and other allergic responses.
The present invention is also directed to a method of treating conditions typically treated with sympathomimetic drugs, which includes administering a therapeutically effective amount of (-)-pseudoephedrine to a mammal, wherein such (-)-pseudoephedrine is substantially-free of (+)-pseudoephedrine. This method may have fewer side effects than a method which includes administration of a composition of (+)-pseudoephedrine alone. It is also believed to have fewer side effects than administration of a racemic mixture of (+)- and (-)-pseudoephedrine. In this embodiment, a therapeutically effective amount of (+)-phenylephrine is a dosage suitable for treating the condition typically treated with a sympathomimetic drug.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides pharmaceutical compositions of (-)-pseudoephedrine that are substantially free of (+)-pseudoephedrine. The present invention also provides methods of using such (-)-pseudoephedrine compositions for treating colds, treating nasal congestion, treating allergies, treating histamine-related inflammations, treating obesity, dilating the pupil, and treating other conditions typically treated with sympathomimetic drugs. According to the present invention, the structures of (+)-pseudoephedrine and (-)-pseudoephedrine are: ##STR1##
(+)-Pseudoephedrine is known as a decongestant, but it can readily be converted into the psychoactive drug, (S)-methamphetamine, by reduction of the hydroxyl group to hydrogen. Reduction of the hydroxyl in (-)-pseudoephedrine yields a compound with only one-tenth the psychoactivity of (S)-methamphetamine. Hence, the present compositions and methods avoid this problem.
The term "substantially free of (+)-pseudoephedrine" means that the composition contains at least 90% (-)-pseudoephedrine and 10% or less (+)-pseudoephedrine. In a more preferred embodiment, "substantially free of (+)-pseudoephedrine" means that the composition contains at least 95% (-)-pseudoephedrine and 5% or less (+)-pseudoephedrine. Still more preferred is an embodiment wherein the pharmaceutical composition contains 99% or more (-)-pseudoephedrine and 1% or less (+)-pseudoephedrine.
According to the present invention, compositions of (-)-pseudoephedrine which are substantially free of (+)-pseudoephedrine are also substantially free of the adverse side effects related to administration of (+)-pseudoephedrine. Such adverse side effects include but are not limited to interactions with other drugs such as antihistamines. Moreover, when similar amounts of (+)- and (-)-pseudoephedrine are administered, (-)-pseudoephedrine causes fewer cardiovascular side effects. In particular, (-)-pseudoephedrine does not adversely effect blood pressure at the doses of (+)-pseudoephedrine which are normally administered, whereas (+)-pseudoephedrine can adversely increase blood pressure. As a result, administration of the present compositions of (-)-pseudoephedrine produce reduced side effects relative to the administration of the (+)-stereoisomer of pseudoephedrine. It is also believed that administration of the present (-)-pseudoephedrine compositions has fewer side effects relative to the administration of a racemic mixture of (+)- and (-)-pseudoephedrine.
The (-)-pseudoephedrine of this invention may be prepared by known procedures. Methods for separating the stereoisomers in a racemic mixture are well-known to the skilled artisan.
The present invention also provides pharmaceutically acceptable salts of (-)-pseudoephedrine. For example, (-)-pseudoephedrine can be provided as a hydrochloride, bitartrate, tannate, sulfate, stearate, citrate or other pharmaceutically acceptable salt. Methods of making such pharmaceutical salts of (-)-pseudoephedrine are readily available to one of ordinary skill in the art.
The pharmaceutical compositions of the present invention contain (-)-pseudoephedrine with a pharmaceutically acceptable carrier. As used herein, "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, isotonic and absorption delaying agents, sweeteners and the like. The pharmaceutically acceptable carriers may be prepared from a wide range of materials including, but not limited to, diluents, binders and adhesives, lubricants, disintegrants, coloring agents, bulking agents, flavoring agents, sweetening agents and miscellaneous materials such as buffers and adsorbents that may be needed in order to prepare a particular therapeutic composition. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated.
According to the present invention, (-)-pseudoephedrine does not interact with other drugs, for example, with antihistamines. This is one advantage that the present compositions and methods of using (-)-pseudoephedrine have over compositions and methods of using (+)-pseudoephedrine: (-)-pseudoephedrine does interact with HI antihistamines such as triprolidine, whereas (+)-pseudoephedrine does interact with H.sub.1 antihistamines. Due to the lack of such drug interaction, supplementary active ingredients, such as additional antihistamines and decongestants, can be incorporated into the present (-)-pseudoephedrine compositions. The amount of the added antihistamine or decongestant present in the pharmaceutical composition will depend upon the particular drug used. Typical antihistamines include: diphenhydramine; chlorpheniramine; astemizole; terfenadine; terfenadine carboxylate; brompheniramine; triprolidine; acrivastine; and loratadine.
The present invention further contemplates a method of relieving nasal and/or bronchial congestion which comprises administering a therapeutically effective amount of (-)-pseudoephedrine which is substantially free of (+)-pseudoephedrine. Administration of (-)-pseudoephedrine avoids many of the side effects related to administering (+)-pseudoephedrine including drug interactions.
According to the present invention, (-)-pseudoephedrine is surprisingly effective as a physiological antagonist of histamine. This means (-)-pseudoephedrine counteracts the physiological effects of histamine. Histamine can cause nasal congestion, bronchial congestion, inflammation and the like. This present invention contemplates (-)-pseudoephedrine to counteract all of these histamine-related physiological responses. Moreover, according to the present invention (-)-pseudoephedrine can be combined with antihistamines, for example, antihistamines that bind to H.sub.1 antihistamine receptors.
The present invention also contemplates a method of treating inflammation and/or sinus congestion which comprises administering a therapeutically effective amount of (-)-pseudoephedrine. The pharmaceutical compositions of (-)-pseudoephedrine used for this method are substantially-free of (+)-pseudoephedrine and induce less side effects than does administration of a composition containing (+)-pseudoephedrine.
According to the present invention, a therapeutically effective amount of (-)-pseudoephedrine is an amount sufficient to relieve the symptoms of a condition which can be treated by a sympathomimetic drug. In one embodiment, an amount sufficient to reduce the symptoms of a condition which can be treated by a sympathomimetic drug is an amount of (-)-pseudoephedrine sufficient to bind or activate an adrenergic receptor, for example, and .alpha.- or a .beta.-adrenergic receptor. When the condition is nasal congestion the therapeutically effective amount is the amount needed to reduce nasal congestion. When bronchial congestion is the condition, the therapeutically effective amount is the amount needed to reduce bronchial congestion or provide bronchodilation. When inflammation and/or allergic reaction is the condition, the therapeutically effective amount is the amount needed to counteract the physiological effects of histamine. When eye pupil dilation is the desired, such as therapeutically effective amount of (-)-pseudoephedrine is an amount of (-)-pseudoephedrine sufficient to dilate the pupil. Preferably, such a pharmaceutically effective amount also produces less side effects than are observed upon administration of (+)-pseudoephedrine, or a racemic mixture of (+)- and (-)-pseudoephedrine. The skilled artisan can readily determine the necessary therapeutically effective amounts for treating these conditions, particularly in light of the teachings provided herein.
OK OK now find a bright side? You can now avoid that nasty (S)-methamphetamine
crap that has been keeping you awake and horny for lo these many years, and now make directly the stuff that Selegiline metabolizes into, l-methamphetamine,
and feel really good about yourself.
My test monkey notes that the MAOI-B action of Selegiline enhances the experience of the friendly and socially acceptable l-methamphetamine.
Get used to it.
":<)
For your edification and reading enjoyment, the following references are provided...
dwarfer
(esoteric)
04-27-04 21:16
No 503356
THREE
"At normally used clinical dosages (10-15 mg/day), deprenyl is a selective MAO-B inhibitor, so it doesn't prevent intestinal MAO-A from digesting dietary tyramine. (1) In addition, deprenyl has the unique ability to prevent tyramine from getting into noradrenalin-using nerve calls, and it's only when tyramine enters noradrenalin nerve cells that control arterial blood pressure that it triggers the "cheese effect.""
"In addition to its potential as a life-extending drug, Deprenyl also appears to have a number of other beneficial effects. One of the most significant is its libido promoting/aphrodisiac effects, in both men and women. . . . Deprenyl has also been found to protect neurons from toxic substances, act as an anti-oxidant, and as an inducer of the anti-oxidant enzymes superoxide dismutase (SOD) and catalase (CAT)"
"Selegiline is a MAO-B inhibitor that has been shown to have a significant antidepressant effect at oral doses of 30-60 mg/day. But at this level, the drug also inhibits MAO-A and requires the restriction of dietary tyramine and sympathomimetic amines"
J Neural Transm. 2003 Nov;110(11):1273-8.
A new formulation of selegiline: improved bioavailability and selectivity for MAO-B inhibition.
Clarke A, Brewer F, Johnson ES, Mallard N, Hartig F, Taylor S, Corn TH.
Scherer DDS, Swindon, United Kingdom. aclarke@cephalon.com
Seven randomised comparative studies were conducted in healthy volunteers to compare the pharmacokinetic and pharmacodynamic profiles of selegiline hydrochloride in a new formulation designed for buccal absorption "Zydis Selegiline" (1.25-10 mg) with conventional selegiline hydrochloride tablets "conventional selegiline tablets" (10 mg). A total of 156 healthy volunteers participated in these studies.
Plasma concentrations of selegiline and its primary metabolites, N-desmethylselegiline (DMS), l-amphetamine (AMT), and l-methamphetamine (MET) were measured using Gas Chromatography Mass Spectrometry (GCMS) and gas liquid chromatography (GLC) assays.
Inhibition of monoamine-oxidase type B (MAO-B) and monoamine oxidase type A (MAO-A) activity was determined by measurement of as beta-phenylethylamine (PEA) by GCMS and 5-hydroxyindoleacetic acid (5-HIAA) by High Performance Liquid Chromatography (HPLC) assays. Almost a third (2.96 mg) of a 10 mg selegiline dose in Zydis Selegiline was absorbed pre-gastrically (predominantly buccally) within 1 minute. Mean [SD] area-under-the curve (AUC(0- infinity)) values following Zydis Selegiline 10 mg (5.85 [7.31] ng.h/mL) were approximately five times higher than those following conventional selegiline tablets 10 mg (1.16 [1.05] ng.h/mL). In contrast, plasma concentrations of metabolites were significantly ( p<0.001) lower following Zydis Selegiline 10 mg than following conventional selegiline tablets 10 mg. Plasma concentrations of selegiline and its metabolites increased in a dose-dependent manner over the dose-range Zydis Selegiline 1.25-5 mg. Bioavailability was determined using AUC and peak plasma concentrations (C(max)). The C(max) of selegiline was similar following administration of Zydis Selegiline 1.25 mg (1.52 ng/mL) or conventional selegiline tablets 10 mg (1.14 mg/mL). The range of values for AUC(0- infinity) and C(max) following Zydis Selegiline 1.25 mg were entirely contained within the range following conventional selegiline tablets 10 mg, with a much higher variability of plasma selegiline concentrations occurring after conventional selegiline tablets than after Zydis Selegiline. As expected, peak plasma concentrations for DMS, AMT and MET were consistently lower after Zydis Selegiline 1.25 mg (1.19, 0.34, 0.93 ng/ml, respectively) than after conventional selegiline tablets 10 mg (18.37, 3.60, 12.92 ng/ml, respectively). A significant (r=0.0001) correlation between daily PEA excretion (a measure of brain MAO-B inhibition) and the log-transformed AUC((0-t)) for selegiline was demonstrated. Mean daily PEA excretion was similar following Zydis Selegiline 1.25 mg and conventional selegiline tablets 10 mg (13.0 microg versus 17.6 microg). In contrast, there was no correlation between PEA excretion and selegiline metabolites, indicating that selegiline metabolites do not significantly inhibit MAO-B. Urinary excretion of 5-HIAA (used as a marker for MAO-A inhibition) was unrelated to plasma concentrations of selegiline or DMS following single or repeat dosing of Zydis Selegiline 1.25 mg or conventional selegiline tablets 10 mg. However, comparison of treatment groups revealed a significantly lower excretion of 5-HIAA in the conventional selegiline tablets 10 mg group than in the Zydis Selegiline 1.25 mg group after repeated administration over 13 days. In summary, by reducing the opportunity for first-pass metabolism, the absorption of selegiline from Zydis Selegiline was more efficient and less variable than from conventional selegiline tablets. Compared with conventional selegiline tablets 10 mg, Zydis Selegiline 1.25 mg yielded similar plasma concentrations of selegiline and degree of MAO-B inhibition, but markedly reduced concentrations of the principal metabolites. Thus, the lower but equally MAO-B inhibitory dose of selegiline in Zydis Selegiline 1.25 mg, which is associated with lower concentrations of potentially harmful metabolites, could offer a safer and more predictable treatment in the management of patients with Parkinson's disease.
Cell Mol Neurobiol. 2004 Feb;24(1):87-100.
l-Deprenyl prevents lipid peroxidation and memory deficits produced by cerebral ischemia in rats.
Maia FD, Pitombeira BS, Araujo DT, Cunha GM, Viana GS.
Laboratory of Neuropharmacology, Department of Physiology and Pharmacology, Federal University of Ceara, Fortaleza, Brazil.
1. The present work shows the results on behavior and on biochemical parameters of l-deprenyl (0.1, 5, and 10 mg/kg, p.o.) administered daily for 5 days to rats submitted to global cerebral ischemia. 2. The transient global ischemia was carried out by clamping the animals bilateral common carotid arteries for 20 min. The parameters studied were memory acquisition and memory retention, locomotor activity and thiobarbituric acid reactive substances, as an index of lipid peroxidation. 3. l-Deprenyl treatment significantly improved memory deficits as compared to the ischemic group as measured by the elevated T maze test. A similar result was observed on the passive avoidance test where l-deprenyl improved late but not early memory as compared to the ischemic group. Except for an increased locomotor activity observed in the group treated with 5 mg/kg, no other alteration was detected in this behavioral test. Rats submitted to transient global ischemia (and without l-deprenyl) showed an increase in MDA levels in the hippocampus and the treatment with l-deprenyl (5 or 10 mg/kg) significantly reversed this effect bringing values close to those of the sham-operated controls. A similar profile was observed with nitrite levels. 4. In conclusion, the work showed a significant protective effect of l-deprenyl on memory deficits and lipid hyperperoxidation observed after cerebral ischemia. Possibly, the drug is acting at least in part through its antioxidant activity.
PMID: 15049513 [PubMed - in process]
Nucl Med Biol. 2004 Apr;31(3):313-9.
Comparison of the binding of the irreversible monoamine oxidase tracers, [(11)C]clorgyline and [(11)C]l-deprenyl in brain and peripheral organs in humans.
Fowler JS, Logan J, Wang GJ, Volkow ND, Telang F, Schlyer D, Zhu W, John Gatley S.
Brookhaven National Laboratory, Chemistry Department, Bldg 555, Upton, NY 11973, USA. fowler@bnl.gov
The monoamine oxidase A and B (MAO A and B) radiotracers [(11)C]clorgyline (CLG) and [(11)C]L-deprenyl (DEP) and their deuterium labeled counterparts (CLG-D and DEP-D) were compared to determine whether their distribution and kinetics in humans are consistent with their physical, chemical and pharmacological properties and the reported ratios of MAO A:MAO B in post-mortem human tissues. Irreversible binding was consistently higher for DEP in brain, heart, kidneys and spleen but not lung where CLG >DEP and not in thyroid where there is no DEP binding. The generally higher DEP binding is consistent with its higher enzyme affinity and larger free fraction in plasma while differences in regional distribution for CLG and DEP in brain, heart, thyroid and lungs are consistent with different relative ratios of MAO A and B in humans.
Neurosci Lett. 2004 Jan 16;354(3):225-8.
Positive effects of deprenyl and estradiol on spatial memory and oxidant stress in aged female rat brains.
Kiray M, Uysal N, Sonmez A, Acikgoz O, Gonenc S.
Department of Physiology, Dokuz Eylul University Medical School, Balcova, Izmir 35340, Turkey.
Increasing age decreases spatial learning and memory. Spatial learning is coordinated with different brain regions. Since the oxidative damage may play a role in the aging process, including the associated cognitive decline, age-related impairment in spatial learning and memory may be alleviated by antioxidant treatment. The present study examined the effects of the monoamine oxidase B inhibitor L-deprenyl, alone and in combination with estradiol, on spatial memory using the Morris water maze and oxidant stress in aged female rat brains. We demonstrated that co-administration of deprenyl and estradiol caused a synergistic effect on spatial memory. However, use of either deprenyl or estradiol alone increased antioxidant enzyme activities in brain and reduced lipid peroxidation. Therefore, positive effects of deprenyl and estradiol on spatial memory may occur due not only to their antioxidant activities but also to the different actions.
Neurotoxicology. 2004 Jan;25(1-2):243-50. Related Articles, Links
Therapeutic applications of selective and non-selective inhibitors of monoamine oxidase A and B that do not cause significant tyramine potentiation.
Youdim MB, Weinstock M.
Department of Pharmacology, Bruce Rappaport Faculty of Medicine-Technion, Eve Topf and National Parkinson Foundation Centers of Excellence for Neurodegenerative Diseases Research, Efron St, PO Box 9697, Haifa 31096, Israel. youdim@tx.technion.ac.il
The major side effect with the use of first generation of non selective monoamine oxidase (MAO) inhibitors as neuropsychiatric drugs was what became known as the "cheese reaction". Namely, potentiation of sympathomimetic activity of ingested tyramine present in cheese and other food stuff, resulting from its ability to release noradrenaline, when prevented from metabolism by MAO. The identification of two forms of MAO, termed types A and B and their selective irreversible inhibitors resolved some of this problems. However irreversible MAO-A inhibitors continue to induce a cheese reaction, whereas MAO-B inhibitors at their selective dosage did not and led to introduction of L-deprenyl (selegiline) as an anti-Parkinson drug, since dopamine is equally well metabolized by both enzyme forms. The cheese reaction is a consequence of inhibition of MAO-A, the enzyme responsible for metabolism of noradrenaline and serotonin, located in peripheral adrenergic neurons. The consequence of these findings were the development of reversible MAO-A inhibitors (RIMA), moclobemide and brofaromin, as antidepressants and possible anti-Parkinson activity, with limited tyramine potentiation, since the amine can displace the inhibitor from its binding site on the enzyme. It has always been deemed a greater pharmacological advantage to inhibit both forms of the enzymes to get the full functional activities of the amine neurotransmitters, and without inducing a "cheese reaction". This was not possible until recently, with the development of the novel cholinesterase-brain selective MAO-AB inhibitor, TV3326 (N-propargyl-(3R)-aminoidnan-5-yl-ethyl methylcarbamate hemitartiate), a carbamate derivative of the irreversible MAO-B inhibitor anti-Parkinson drug, rasagiline. This drug is a brain selective MAO-A and B inhibitor, with little inhibition of liver and small intestine enzymes. Pharmacologically it has limited tyramine potentiation, very similar to moclobemide and being a MAO-AB inhibitor it has the antidepressant, anti-Parkinson and anti-Alzheimer activities in the respective models used to develop such drugs.
Neurotoxicology. 2004 Jan;25(1-2):233-42. Related Articles, Links
(-)-Deprenyl, a selective MAO-B inhibitor, with apoptotic and anti-apoptotic properties.
Magyar K, Szende B.
Department of Pharmacodynamics, Neurochemical Research Unit, Semmelweis University, Hungarian Academy of Sciences, PO Box 370, Budapest 1445, Hungary. magykal@net.sote.hu
(-)-Deprenyl (selegiline) is an irreversible inhibitor of monoamine oxidase (MAO) B, which was discovered in 1962 and become the "golden standard" of MAO research. Like the other MAO-B inhibitors, it was synthesized as an antidepressant, but in a selective MAO-B inhibitory dose it does not act in depression. It is used in the treatment of Parkinson's disease. (-)-Deprenyl potentiates the effect of dopamine, it has antioxidant activity and prevents the toxicity of the dopaminergic (6-OH-dopamine; 1-methyl-4-phenyl-1,2,3,6-tetrahydro-pyr
dwarfer
(Popular Author)
04-28-04 01:45
No 503388
Who are the inventors behind this patent? Would it be Nichols and Bess of Warner Lambert? I've already wrecked two of their patents, so I was hoping for a trifecta.
(Hive Addict)
04-28-04 04:00
No 503401
I still say this goes against the corporate greed that these fuckers are ALL about!
Might work for a minute, people will buy the pseudo until they succeed in getting low octane gear. As far as repeat customers are concerned (that is what most successful businesses want) they won't have any!
Once the shareholders realize a huge dip in sales and quarterly profits, they will change the formulation back again or at least keep a couple pseudo products as their bread and butter.
Don't see it happening en masse anytime soon.
They will only PRETEND to bow down under government pressure. (IMHO)
Refuse/Resist
(Wonderful Personality)
04-28-04 13:10
No 503481
Take a little MAO-B inhibitor: feel your neurons being protected. Get a bright outlook on live. Protect your limited supply of dopaminergic receptors.
I am not sure if this is true for MAO-B selective inhibitors, but generally taking MAO-blockers and amphetamine kind stimulants was told to be a not so good idea if I remember it right.
The problem is: People wont take "a little" but heaps and they wont take l-meth but heaps of d-meth in addition. From a darwinistic point of view this might be not so bad at all, its just it makes such a bad press ya know?
(Hive Addict)
04-28-04 14:27
No 503491
Ibee the Butcher needs a patent # Big D!
MMMMkay???
Didn't find one in the Edification Dept and the staff of The Reading Enjoyment Dept have AWE cum down with a sudden case of Mad Cow Disease and their judgement can no longer be considered reLYEable!
a little less conversation, a little more reaction
(esoteric)
04-28-04 21:01
No 503569
Jumex for most people up to 15 MG (3 tabs) will inhibit
maoi-b: after that maoi-a will also be inhibited, which (as I think is referenced in the 3rd post) is implicated in the hypertesive episodes which can be the Ultimate Bummer.
It should be noted that there can be large variations in individual sensitivity to these materials: one should work
up their dosages with caution.
In my test monkey's opinion the material derived from the
reduction of the double minus stuff is a huge disappointment as regards the attainment of the initially desired effect:
but it does have it's functional uses of aleretness and focus. The caution is that if a person does excessive quantities in the hope that more will get them where
they "want" to be with "elation", the "WOO wOO" effect, and
all those things associated with the amine flipped over, they will merely succeed in getting to feel like crap, with a fuzzy head, a bit dizzy, and feeling almost like motion sickness.
So, just pretend it's what you want, do a regular amount,
and appreciate the fact that it beats the shit out of coffee..
===================
Fester, the info was forwarded to me by the famously gorgeous and libidinous lover Gemini recently: I'll ask her for the source.
dwarfer
(Hive Bee)
04-29-04 00:43
No 503616
United States Patent 6,495,529
Booth , et al. December 17, 2002
----------------------------------------
(-)-Pseudoephedrine as a sympathomimetic drug
Abstract
The present invention provides pharmaceutical compositions which include (-)-pseudoephedrine and a pharmaceutically acceptable carrier, wherein the (-)-pseudoephedrine is substantially-free of (+)-pseudoephedrine. In another embodiment, the present invention provides methods of relieving nasal and bronchial congestion and of inducing pupil dilation which include administering a pharmaceutically effective amount of (-)-pseudoephedrine to a mammal. The (-)-pseudoephedrine used in the present methods is substantially free of (+)-pseudoephedrine and also substantially free of side effects caused by administration of (+)-pseudoephedrine.
----------------------------------------
Inventors: Booth; Anthony (Chester, NJ); Sherman; William T. (Hendersonville, NC); Raven; Peter (Forth Worth, TX); Caffrey; James L. (Burelson, TX); Yorio; Thomas (Burelson, TX); Forster; Michael (Fort Worth, TX); Gwirtz; Patricia (Forth Worth, TX)
Assignee: Warner-Lambert Company (Morris Plains, NJ)
Appl. No.: 743052
Filed: April 16, 2001
PCT Filed: June 8, 1999
PCT NO: PCT/US99/12692
PCT PUB.NO.: WO00/01379
PCT PUB. Date: January 13, 2000
****************************************
oxox
gemini
(Hive Bee)
04-29-04 08:36
No 503689
damn straight org... I have been told by someone who did a series of experiments with syrian rue (i think it was syrian rue) and a whole range of supposed 'bad combos' but in very very small doses (like, 1/8th) and the main effect with stimulants was 2-3x potentiation.
people are already stupidly dosing on the pure meth that is much more available than ever before... but nobody's going to die directly, but the fact is most ppl who are like this are not likely to take any proper precautions, like for example the common practise of combining alcohol and amphetamines...
it's not so much the amphetamine that would be a problem. although it would synergise with the tyramine in the alcohol, or from the cheese or aged meats they eat (note that all of these are common alcohol adjuncts)... and then you have a problem.
one of the nicer things abut good pure methamphetamine is that it's not really possible to overdose. brain damage from overheating and vasoconstriction, possibly stroke in the 2+g range where the residual ephedrines would become problematic...
however, it's not that common. Luckily, because a lot of people, when they dose this high, become psychotic, and there has been several incidents of this leading to murder or major injury to people... there are a lot of people out there who are so disconnected from themselves already, when meth locks up their whole musculature (which is the way that one instinctively blocks pain), it starts to do things similar to pcp (actually, i find it a little disturbing that ritalin also has as one of it's side effects the locking up of muscles - this is an unpleasant feeling)... they don't feel any pain, and they are so prone to become angry, everything that even slightly irritates them makes them feel extreme pain and being that they cannot any further lock their muscles to block the pain, they lash out.
now it's something that i experienced very noticably when i was coming off my first dose of IV semi-oily gak crank, i found my body reacted very intensely to my repressive thought processes, causing muscle pain ALL OVER MY BODY.
I was trying to figure out what was causing it, and it gradually dawned on me that every time i had a thought which was negating, instantly i felt pain. So i started to repeat to myself every time i would start to find myself annoyed something like 'release, accept, do not reject' and instantly i was rewarded with a blast of blissfulness which, owing to the fact it lasted for the next 18 hours or so as i continued to take advantage of this effect to give me pleasure, it shat all over the 20 minute mind numbing rush from the crank.
thou knowest
(Hive Addict)
04-29-04 14:42
No 503730
Patent US6495529
Gem: I don't know whether to jump for joy or crawl under a rock!
Seeings how I do the most good looking under unturned stones, neither jumping for joy or crawling ubder a rock are considered bad from my perspective.
Ibee and The Kidz missed ya and are glad to know yer safe.
Thankyou for doing the footwork on this latest threat.
I posted the first(-)-pseudoeph patent that claimed a 50% (+)-pseudoeph was all they could employ in combo with (-)-pfed, but that was almost a year ago.
When UTFSE® comes back UP, I'll link to it.
If the TURD-LE's pull this one off, the prophecy's will have been fulfilled regarding pulling the product from the shelf....sorta
Thanx again cutie!
ORGY!!!! HELP!!!
Got any good Yeast stories?
a little less conversation, a little more reaction
(Hive Addict)
04-29-04 14:58
No 503733
Rhodium or any other Chemistry Geniuses:
The method of claim 1 wherein said (-)-pseudoephedrine is not readily converted to (S)-methamphetamine
The key words readily converted imply to Ibee that by some means another route may exist to convert this concoction into (R)meth.
Yes Or No?
a little less conversation, a little more reaction
(Chief Bee)
04-29-04 15:20
No 503735
Yes, but seeing that (R)-Methamphetamine is the same as l-meth, the product is not of the desired optical configuration.
You will have to racemize either the (-)-pseudoephedrine (= l-pseudo) or the resulting l-meth to get racemic methamphetamine in the end, methods for this can be found in the FAQ (almost at the end). If you want pure d-meth, you will have to perform a racemate splitting procedure with tartaric acid or similar chiral acid.
The Hive - Clandestine Chemists Without Borders
(Hive Addict)
04-29-04 20:08
No 503785
Rhodium: Thank You for the reply.
It coinsides with what Ibee thought.
And to clarify some, I don't want anybee to get the impression that the use of the "genius" terminology was intended to bee condescending or sarcastic in any way!
I have a deep respect for the knowledge here and that of those with formal education.
Thanx again!
Back to work on the behemoths
a little less conversation, a little more reaction
(esoteric)
04-29-04 23:26
No 503810
Example 3
In a 100 mL round-bottomed flask, 30g l-Ephedrine was dissolved in a solution of 1 gram sodium metal in 20 mL methanol, and the solvent was distilled off. The clear residue was heated for two hours in an oil bath at 190°C, and after the solution had cooled to room temp it was neutralized with dilute hydrochloric acid and worked up as in Example 1. The yield of dl-Ephedrine was 45% and that of dl-Pseudoephedrine was 49%.
============
Rhodium, am I reading correctly in thinking this would work on changing around 50% of the l meth to d meth?
dwarfer
(Chief Bee)
04-30-04 00:54
No 503821
You cannot perform that procedure on methamphetamine, only on (pseudo)ephedrine. But regardless of which of the four possible isomers you start with, you will end up with the same product distibution as described for lEphedrine in Example 3.
The Hive - Clandestine Chemists Without Borders
(Hive Addict)
04-30-04 01:13
No 503828
At this stage, if this is implemented as planned, or at least applied for, I'm afraid that a racemic variety of pfed will have to be settled upon!
Meaning, That a bee working from the OTC platform with this compound can expect ¼ return from what they now get 70% on average.
And Sdawg, further driving UP the profits for the pharmers from just those that are willing to to BUY into the shyte to stay alive!
I'm really fixin to fix there wagons and it sux cause they covered their asses as far as public disclosure and it leaves Ibee at a loss because of the risk of hurting the collective.
Before Ibee exits this game they call freedom,they'll know they riled the natives and entered the ring several pitbulls nippin at their heel headed idiocync-grocery's!
TURD-LE's just can't keep a good bee down now can they?
a little less conversation, a little more reaction
(esoteric)
04-30-04 01:44
No 503838
everytime i think i have this straight I confuse myself. Or, rather, discover that my confusion was never not extant, but that I was confused about that fact.
1. Then, if a person was to use that technique on suspect - - pseudo before reacting, then it wold be utilizeable?
2. Could lithium be employed?
dwarfer
(Hive Bee)
04-30-04 10:05
No 503946
but could some one briefly translate some of this discussion for me?
Is it that a different type of pseudoephedrine may come out which still serves its purpose but does not reduce into the same methamphetamine that people are using now?
Please no flames
(Wonderful Personality)
04-30-04 12:32
No 503970
Dwarfer:
1. Yes. The following reduction will yield d-l-methamphetamine though.
2. dunno, maybe. Na was used for being cheap and available these days, Li was always quite expensive in comparism.
Kris_1108:
Exactly.
(esoteric)
05-12-04 22:39
No 506717
Some of my very bestest friends apparently have encountered this plague of double negativity: and unlike the usual minusX minus =+, this sux.
I believe that the Necromancers may back off some of their more noxious amendments, in favor of this apparently dead end route.
Thus do I project with perfect foresight, that Birchers may
be testing the strong alkaline nature of Na in -OH in the near future, just to counter-fuck the fuckers.
Of course talking about it will be counterproductive, as the appearance here of success stories rapidly conditions
the response of the fuckers. Thus do I also predicet that the healthy and widespread use of non-public thread webbed information distribution may be appropriate.
Those familiar with DCM know what I am referring to..
==========
Meanwhile, a "better read" on Selegiline..
History of deprenyl -
the first selective inhibitor
of monoamine oxidase type B
ABSTRACT
(-)Deprenyl (Selegiline, Jumex, Eldepryl, Movergan), a close structural relative of phenylethylamine (PEA), is a drug with a unique pharmacological spectrum. Whereas PEA and its long-lasting variants, the amphetamines, are mixed-acting stimulants of the sympathetic system in the brain, they primarily enhance the impulse propagation generated release of catecholamines (catecholamine activity enhancer, CAE, effect) and displace catecholamines in higher concentration (catecholamine releasing effect). (-)Deprenyl is the first CAE substance in clinical use devoid of catecholamine releasing activity. (-)Deprenyl is a highly potent and selective, irreversible inhibitor of B-type monoamine oxidase (MAO), a predominantly glial enzyme in the brain. The activity of this enzyme significantly increases with age.
(-)Deprenyl, the first selective inhibitor of MAO-B described in the literature, has become a universally used research tool for selectively blocking B-type MAO and is still the only selective MAO-B inhibitor in world wide clinical use. In contrast to MAO inhibitors which strongly potentiate the catecholamine releasing effect of tyramine, (-)deprenyl inhibits it and is free of the 'cheese effect', which makes it a safe drug. Because its lack of the catecholamine releasing activity (-)deprenyl is devoid of amphetamine like dependence capacity. Maintenance on (-)deprenyl selectively enhances superoxide dismutase (SOD) and catalase activity in the striatum and protects the nigrostriatal dopaminergic neurons from selective neurotoxins (6-hydroxydopamine, MPTP, DSP-4).
Maintenance of an animal on (-)deprenyl prevents the characteristic age-related morphological changes in the neuromelanin granules of the neurocytes in the substantia nigra. Many other protective effects of (-)deprenyl, denoted as 'neuroprotective', 'trophiclike neurorescue', 'apoptosis reducing', etc, have been described. All the protective actions of (-)deprenyl are thought to be primarily related to the CAE effect of the drug. All in all, (-)deprenyl increases the activity of the nigrostriatal dopaminergic system and slows its age-related decline.
Maintenance of male rats (SQUEEEK) on (-)deprenyl delays the age-related loss of their capacity to ejaculate, slows the age-related decline of their learning capacity and prolongs their life.
Parkinsonian patients on levodopa plus (-)deprenyl (10 mg daily) live significantly longer than those on levodopa alone. Parkinsonian patients maintained, after diagnosis, on (-)deprenyl, need levodopa significantly later than their placebo-treated peers. Maintenance on (-)deprenyl significantly improves the performance of patients with Alzheimer's disease. It is concluded that patients developing Parkinson's or Alzheimer's disease need to be treated daily with 10 mg (-)deprenyl from diagnosis until death, irrespective of other medication. Because of the peculiar pharmacological spectrum and safety of the drug it may be advisable to combat the age-related decline of the nigrostriatal dopaminergic neurons in man by taking 10-15 mg (-)deprenyl weekly during the postdevelopmental phase of life. Prophylactic (-)deprenyl medication may improve the quality of life in the latter decades, delaying the time of natural death and decreasing the susceptibility to age-related neurological diseases.
dwarfer
(Newbee)
05-22-04 01:52
No 508679
Where does FDA approval fall into all of this, before or after patenting? I imagine after..
What the fuck though? For all of these years the other enantiomer of pseudo was the only one that was supposed to work. How do they get off with this new formulation? And mustn't it be tested and proven for safety and efficacy by others first?
Also, if the patent is held by one company, is it reasonable to assume that other producers are not utilizing the method?
(Hive Addict)
05-22-04 03:09
No 508699
Also, if the patent is held by one company, is it reasonable to assume that other producers are not utilizing the method?
This may be the only saving grace in all this, but if (-)-pseudo's introduction is seen as a way of limiting the conversion of the product at the consumer level, it's well within the jurisdiction of the FDA to mandate it's inclusion at the manufacturer level and force all pfed makers into compliance.
I still don't see any documentation anywhere that points to what forces formulation changes across the board on all strengths, makes and models!
These gaaks are non-existant one day and a week later...BANG....everything sux!
Yeah....there's more to it than what is being disclosed to consumers!
a little less conversation, a little more reaction
(Newbee)
05-22-04 04:46
No 508712
Our receptors are stereoselective, and if both forms work, there still must be a difference in the dose response and often certain side-effects.. Just switching from (+) to (-) would suggest a few possibilities:
1) This particular chiral center is not what is bound by the receptor, or is not 'that important' in the binding..
2) They've also secretly increased the dose of (-) to compensate.
edit: Well, not necessarily "increased" the dose, but at least changed it a little to compensate for the differences in effectiveness.
Just fetching far..
05-22-04 15:12
(Rated as: misinforming)