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Ive been immersed in 'True Hallucinations' by Terrence McKenna recently and of all things, one thing that has me most curious is his mention of making a mushroom snuff, finding it very pleasant. I am curious as to what the opinions both objective and subjective are towards this preparation method. I am especially curious as to the pharmacokinetic effects via this route (onset, intensity etc). Personally i can not decide if it would make for a more intense or for a smoother experience. Obviously, intensive experimentation by oneself is out of the question so i pose it here.

Hey all,

Just thought I'd say hi.

Been AWOL for awhile, always intend to come back round but never seem to get around to it. Seems I fell down a few rabbit holes while frolicking in the forest and got turned around a few times trying to find my way out of the warren.

So how is everyone? I do miss the place, but seems i get too easily caught up in the day to day distractions (that coupled with a non-existent attention span). Have been essentially living in the lab at uni trying to get all the experimental side of my MSc (currently looking into 'upgrading' to a PhD so i can cover the full scope of the study rather than just the corner my MSc would cover. Pharmacology if anyone was wondering, tackling heart failure more specifically.

Recently uncovered some Terrance McKenna videos that i never knew existed in a torrent and have been reuniting myself with myself part tense... hopefully the merger will provide some more clarity for the way forward.
//http://thepiratebay.org/torrent/3701092/Psychedelic_Torrent

Hopefully I will stick round longer this time, but that all depends on the plan that the dragibus has for me  :smoke:3

~VB

hey guys,
jus thought id post a paper i recently had to write for uni, might be of some interest to someone..
enjoy




Mechanisms of MPTP Neurotoxicity Causative of The Production of Parkinsonian Syndromes

Parkinson’s Disease (PD) is a degenerative movement disorder. PD is characterized clinically by resting tremor, bradykinesia, postural instability and rigidity. Post mortem examinations of PD patients also show a selective decline in dopamine (DA) neurons of the substantia nigra pars compacta (SNpc) in preference to DA neurons in the ventral tegmental area (VTA) and smaller decreases in other monoamine neuron dense areas such as the locus coeruleus, intracellular proteinaceous inclusions termed lewy bodys (LBs) and extracellular α-synuclein containing aggregates (reviewed by Dauer and Przedborski, 2003). Clinically, symptoms of classical PD is termed parkinsonism until post mortem conformation of molecular patho-physiology. The remainder of this essay will focus on the induction of parkinsonism by 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP) and its metabolites.
   MPTP is a bi-product of the illicit synthesis of 1-methyl-4-phenyl-4-propionoxypiperidine (MPPP) under altered reaction conditions (Langston et al., 1983). MPTP and MPPP are meperidine analogs. Severe non-resolving parkinsonism was observed in 4 Californian drug users by Langston et al. in 1983. The drug users had injected intravenously the MPTP containing drug obtained under the guise of ‘synthetic heroin’ for approximately 1 week before onset of symptoms caused hospitalisation (Langston et al., 1983). Parkinsonism as result of MPTP intoxication shows all but 2 of the hallmark features of classical parkinsonism (Langston et al., 1983). MPTP selectively destroys DA neurons in the SNpc but leaves other monoamine rich areas intact. LBs have not been observed in any cases of MPTP intoxication in humans but, as only 4 cases have come to autopsy, it is far from conclusive (Langston et al., 1999). It is hypothesised that this may be due to the acute nature of MPTP intoxication, the degeneration being too sudden for LBs to form (Betarbet et al., 2000). MPTP has become the gold standard in animal models for the novel treatment of PD.
   MPTP is a highly lipophilic molecule that absorbs easily across the gut and blood brain barrier (BBB) (reviewed by Dauer and Przedborski, 2003). MPTP on its own is a non-toxic entity (McKinley et al., 2005; Salach et al., 1984; Singer et al., 1985). It becomes toxic when it is metabolised into 1-methyl-4-phenyl-2,3-dihydropyridinium ion (MPDP+) by mainly mono-amine oxidase type b (MAOB) and is further oxidised to the 1-methyl-4-phenylpyridinium ion (MPP+) by MAOB and by spontaneous oxidation (Salach et al., 1984; Singer et al., 1985). This is supported by the data found by Langston et al. (1984) that pargyline, a MAO inhibitor, prevented MPTP toxicity in squirrel monkeys (Saimiri sciureus). MPTP was administered by four 2mg/kg intraperitoneal injections 2 hours apart in a single day to all monkeys. Two 2 of the 3 groups also received pargyline by one of 2 dose regimes. 50mg/kg intraperitoneal (IP) injection 30min prior to MPTP administration or oral 5mg/kg/day for 4 days prior and 5mg oral 1hour before each MPTP injection. Histological examination and assays for MPTP and MPP+ were preformed. It was found that pargyline protected against chronic nerve damage with no visible neuronal loss in the areas examined. The assays revealed that blockage of MAO enzymes caused approximately a 10 fold decrease in MPP+ level in cortical areas examined. This indicates the importance of MAO in MPP+ production. More specifically, McKinley et al. (2005) showed that l-deprenyl (MAO-B inhibitor) protected against MTP induced neuronal damage in zebra fish, implicating MAO-B as the likely isoform responsible. The transport of MPP+ into the extracellular space is by an unknown mechanism but is presumed to be via a transporter protein as the charged species would be unable to diffuse across the lipid membrane unaided (reviewed by Dauer and Przedborski, 2003).  
   MPP+ has a high affinity for several mono-amine transporters including those of serotinergic, adrenergic (NET) and dopaminergic (DAT) neurons (reviewed by Dauer and Przedborski, 2003). DAT has been shown to be directly linked to sequestration of MPP+ by dopamine neurons, facilitating subsequent damage and neuronal loss (reviewed by Dauer and Przedborski, 2003; McKinley et al., 2005). McKinley et al. demonstrated the protective effect seen in DAT knockdown zebra fish. Zebra fish embryos injected with DAT morpholino (4.8 ng), or saline vehicle, and later incubated with 5 or 10 μ g/mL MPTP solutions or vehicle for 3days. The amount of MPTP damage was measure by morpholocial studies and by behavioural tests. DAT knock down fish were more responsive than MPTP only fish, showing a response to touch but not swimming away, as seen in the non MPTP treated fish. MPTP treated wild type fish were unresponsive to touch and completely immobile. Morphological quantification of the relative neuronal loss was measured as % neuronal area compared to untreated wild type embryos. The results paralleled the observed behaviors. These results emphasize the importance of DAT in MPTP induced damage.
   DAT on its own does not provided a reliable measure of sensitivity to MPP+ damage. Once MPP+ has entered DA neurons, it may be taken up into synaptosomal vesicles by vesicular monoamine transporter 2 (VMAT2) (Liu et al., 1992).Liu et al. (1992) showed that genetic transformant Chinese hamster ovarian (CHO) fibroblasts can become MPP+ resistant when they acquire VMAT2. This was achieved by transfecting a cDNA expression library from rat phenochromocytoma PC12 cells into CHO fibroblasts and incubating them in various concentrations of 3H MPP+ (up to 1000 μM). Preparations were tested in the presence of 1 μM reserpine, an inhibitor of vesicular transporters, which caused a reversion to the wild-type sensitivity levels. This showed that the resistance was dependent on reserpine-sensitive VMAT2. This means that a better predictor of MPTP sensitivity is the ratio of DAT to VMAT2 in DA neurons. This ratio has been attributed to the selectivity of MPTP for SNpc and not DA neurons of the VTA (reviewed by Dauer and Przedborski, 2003). This also has implications in the selective neuronal loss idiopathic PD (reviewed by Dauer and Przedborski, 2003).
   MPP+ may also stay in the cytosol and react with proteins that bear a negative charge (Klaidman et al., 1993). MPP+ has been shown to have strong binding interactions with neuromealanin (D'Amato et al., 1986). This interaction may act a pool of MPP+, able to dissociate and exert a toxic effect long after the initial exposure to MPTP (D'Amato et al., 1986). MPP+ has also been shown to up regulate alpha-synuclein expression and aggregate with it to form intracellular inclusions (Kalivendi et al., 2004). These aggregations may cause cellular dysfunction and apoptosis by steric hinderance to normal cellular transporters and organelles (Kalivendi et al., 2004).  
   MPP+ is quickly concentrated into the mitichondria from the cytosol in an energy dependent fashion mostly due to the membrane potential (Ramsay & Singer, 1986). Once in the mitochondria, MPP+ is an inhibitor of NADH CoQ1 reductase (complex 1 of the electron transport chain), (Bates et al., 1994; Maharaj et al., 2006). Bates et al. (1994) demonstrated the effects on mitochondrial respiration, ATP generation and radical formation, in isolated brain mitochondria, under the influence of complex 1 inhibitors. 0.5mg isolated mitochondria was incubated with either 10 â€" 100 μM MPP+, 10 μM 4’hepatyl MPP+ or 5 μM rotenone (Positive control). Preparations were incubated for 10min at 30 ºC and various assays conducted to measure O2 consumption in stage 3 and 4 respiration, adenosine triphosphate (ATP) production, complex 1 activity and Radical formation. O2 consumption in stage 3 respiration was effectively halved by 20 μM MPP+ (Approximate IC50) and 10 μM 4’hepatyl MPP+ against control. ATP production decreased by 1/3 for MPP+ (60 μM, approximate IC50) and by 2/3 for 4’hepatyl MPP+ against controls. This shows the inhibitory potential of MPP+ inside the mitochondria for complex 1 and that MPP+ can inhibit mitochondrial ATP production. If ATP production is critically inhibited, there would be a subsequent collapse of the mitochondrial membrane potential due to the inability of ATP-ase ion pumps to function (reviewed by Dauer and Przedborski, 2003). This could also lead to the formation of reactive oxygen species (ROS) due to DA leakage into the cytoplasm as VMAT2 is unable to maintain concentration gradients into synaptosomal vesicles (reviewed by Dauer and Przedborski, 2003).
   Antioxidants have been shown to attenuate ROS produced by MPP+ and complex 1 interaction (Maharaj et al., 2006). Maharaj et al. (2006) demonstrated the attenuating effects of acetaminophen (APAP) and acetylsalicylic acid (ASA) against MPP+ induced neuronal damage. APAP, ASA or APAP + ASA treatment attenuated the decrease in complex 1 activity produced by MPP+. ASA caused a significant increase in complex 1 activity compared to basal level in controls. This shows that ASA competes with MPP+ for its complex 1 binding site. ROS levels were also shown to be decreased compared to MPP+ alone, with ROS formation in the ASA only treatment group showing decreased ROS formation compared to control levels, showing a link between complex 1 inhibition and ROS generation.
   Przedborski, et al. (1992) showed that ROS contribute to the toxic effects of MPP+. Mice transgenic for Cu/Zn super oxide dismutase (Cu/Zn-SOD) were tested alongside non transgenic littermates. Mice were given three injections of 30mg/kg IP MPTP-HCl or vehicle control 24hrs apart. After 5 days, mice were sacrificed and the brain matter was analyzed. Levels of DA and its metabolites were used as a marker for MPTP toxicity. There was a 50% decrease in DA and its metabolites in non-transgenic mice compared to saline vehicle controls and no significant change in DA metabolite levels in transgenic mice. To determine if this protective effect was due to changes in the brain other than increases ROS scavenging by increases SOD, MPTP penetration across the BBB, MAOB activity, MPP+ sequestration into mitochondria and complex 1 inhibition were measured. There were no significant changes in the brain structure or MPTP metabolism compared to non transgenic littermates. Protection was thus due to increased scavenging of ROS only. ROS were presumably a product of inhibition of complex 1 by MPP+.
   Changes in energy metabolism and ROS formation peak within hours of MPTP administration, long before most neuronal death occurs (Jackson-Lewis et al., 1995). This means it is likely that these immediate effects lead to a down stream effect that ultimately kills the neurons possibly via apoptotic pathways (reviewed by Dauer and Przedborski, 2003). Mitochondrial release of cytochrome c, a mediator of programmed cell death (PCD), and activation of caspase 3 and 9 have been observed in tandem with MPP+ sequestration into the mitochondria (Viswanath et al., 2001). Teng et al. (2006) found that nucling deficient mice were resistant to MPTP toxicity. Nucling is an apoptosis related protein (Teng, 2006). Both wild type and nucling deficient mice were given four IP 15mg/kg MPTP injections 2 hours apart. At 48hrs post treatment, nucling deficient mice showed no signs of MPTP toxicity compared to wild type mice. Nucling deficient mice showed no loss of DA neurons after treatment with MPTP and were negative for apoptosis (via TUNNEL assays) compared to wild type mice. This study demonstrated that apoptotic pathways may be the cause of neuronal death.
   The studies of the complex cascade of events that contribute to the neuronal death endpoint have provided an invaluable research tool which has lead to much advancement in the treatment of PD (reviewed by Dauer and Przedborski, 2003). Two such advancements have been the discovery of the therapeutic effect of deep brain stimulation in reduction of symptoms in advanced PD (Limousin et al., 1998) and the therapeutic benefits of  glial derived neurotrophic factor (GDNF) leading to some functional recovery to previously MPTP lesioned monkeys, aswell as prevention of further degeneration (Kordower et al., 2000).















References

BATES, T.E., HEALES, S.J., DAVIES, S.E., BOAKYE, P. & CLARK, J.B. (1994). Effects of 1-methyl-4-phenylpyridinium on isolated rat brain mitochondria: evidence for a primary involvement of energy depletion. J Neurochem, 63, 640-8.
BETARBET, R., SHERER, T.B., MACKENZIE, G., GARCIA-OSUNA, M., PANOV, A.V. & GREENAMYRE, J.T. (2000). Chronic systemic pesticide exposure reproduces features of Parkinson's disease. Nat Neurosci, 3, 1301-6.
D'AMATO, R.J., LIPMAN, Z.P. & SNYDER, S.H. (1986). Selectivity of the parkinsonian neurotoxin MPTP: toxic metabolite MPP+ binds to neuromelanin. Science, 231, 987-9.
JACKSON-LEWIS, V., JAKOWEC, M., BURKE, R.E. & PRZEDBORSKI, S. (1995). Time course and morphology of dopaminergic neuronal death caused by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Neurodegeneration, 4, 257-69.
KALIVENDI, S.V., CUNNINGHAM, S., KOTAMRAJU, S., JOSEPH, J., HILLARD, C.J. & KALYANARAMAN, B. (2004). Alpha-synuclein up-regulation and aggregation during MPP+-induced apoptosis in neuroblastoma cells: intermediacy of transferrin receptor iron and hydrogen peroxide. J Biol Chem, 279, 15240-7.
KLAIDMAN, L.K., ADAMS, J.D., JR., LEUNG, A.C., KIM, S.S. & CADENAS, E. (1993). Redox cycling of MPP+: evidence for a new mechanism involving hydride transfer with xanthine oxidase, aldehyde dehydrogenase, and lipoamide dehydrogenase. Free Radic Biol Med, 15, 169-79.
KORDOWER, J.H., EMBORG, M.E., BLOCH, J., MA, S.Y., CHU, Y., LEVENTHAL, L., MCBRIDE, J., CHEN, E.Y., PALFI, S., ROITBERG, B.Z., BROWN, W.D., HOLDEN, J.E., PYZALSKI, R., TAYLOR, M.D., CARVEY, P., LING, Z., TRONO, D., HANTRAYE, P., DEGLON, N. & AEBISCHER, P. (2000). Neurodegeneration prevented by lentiviral vector delivery of GDNF in primate models of Parkinson's disease. Science, 290, 767-73.
LANGSTON, J.W., BALLARD, P., TETRUD, J.W. & IRWIN, I. (1983). Chronic Parkinsonism in humans due to a product of meperidine-analog synthesis. Science, 219, 979-80.
LANGSTON, J.W., FORNO, L.S., TETRUD, J., REEVES, A.G., KAPLAN, J.A. & KARLUK, D. (1999). Evidence of active nerve cell degeneration in the substantia nigra of humans years after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine exposure. Ann Neurol, 46, 598-605.
LIMOUSIN, P., KRACK, P., POLLAK, P., BENAZZOUZ, A., ARDOUIN, C., HOFFMANN, D. & BENABID, A.L. (1998). Electrical stimulation of the subthalamic nucleus in advanced Parkinson's disease. N Engl J Med, 339, 1105-11.
LIU, Y., ROGHANI, A. & EDWARDS, R.H. (1992). Gene transfer of a reserpine-sensitive mechanism of resistance to N-methyl-4-phenylpyridinium. Proc Natl Acad Sci U S A, 89, 9074-8.
MAHARAJ, H., MAHARAJ, D.S. & DAYA, S. (2006). Acetylsalicylic acid and acetaminophen protect against MPP(+)-induced mitochondrial damage and superoxide anion generation. Life Sci, 78, 2438-43.
MCKINLEY, E.T., BARANOWSKI, T.C., BLAVO, D.O., CATO, C., DOAN, T.N. & RUBINSTEIN, A.L. (2005). Neuroprotection of MPTP-induced toxicity in zebrafish dopaminergic neurons. Brain Res Mol Brain Res, 141, 128-37.
SALACH, J.I., SINGER, T.P., CASTAGNOLI, N., JR. & TREVOR, A. (1984). Oxidation of the neurotoxic amine 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) by monoamine oxidases A and B and suicide inactivation of the enzymes by MPTP. Biochem Biophys Res Commun, 125, 831-5.
SINGER, T.P., SALACH, J.I. & CRABTREE, D. (1985). Reversible inhibition and mechanism-based irreversible inactivation of monoamine oxidases by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Biochem Biophys Res Commun, 127, 707-12.
TENG, X., SAKAI, T., LIU, L., SAKAI R., KAJI, R., & FUKUI, K., (2006). Attenuation of MPTP-induced neurotoxicity and locomotor
dysfunction in Nucling-de ficient mice via suppression of the
apoptosome pathway.
VISWANATH, V., WU, Y., BOONPLUEANG, R., CHEN, S., STEVENSON, F.F., YANTIRI, F., YANG, L., BEAL, M.F. & ANDERSEN, J.K. (2001). Caspase-9 activation results in downstream caspase-8 activation and bid cleavage in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced Parkinson's disease. J Neurosci, 21, 9519-28.

heres a brief report i had to write (partially) for pharmacology, i didnt write all of it, i didnt write mechanism or summary 3 but can stil answer any questions on it or clarify them, its only brief so can field any other questions nd il see what ive got..

A brief overview of the therapeutic properties of bupropion HCL including three reviewed articles of interest.

Scott Smart and Sam Costelloe


Introduction
Bupropion HCL (BUP) is a novel monocyclic aminoketone (amfebutamone) that is effective in treating major depressive disorder and also as a smoking cessation aid (Daviss et al 2005, Fava et al 2005, Turpeinen et al 2005). BUP has also been proposed as a treatment for attention deficit and hyperactivity disorder (ADHD) and weight loss but only off-label (Daviss et al 2005, Fava et al 2005).
   BUP is sold under the names of Wellbutrinâ,,¢ (depression) and Zybanâ,,¢ (smoking cessation) by GlaxoSmithKline (GSK). Three preparations are available in the US: immediate release (IR), sustained release (SR) and extended release (XR)
BUP has 3 primary metabolites with varying bioactivities: hydroxybupropion (HB), threohydrobupropion (TB) and erythrohydrobupropion (EB) (Daviss et all 2005, Fava et al 2005, Turpeinen et al 2005).   CYP2B6 is responsible for metabolism of BUP into HB (Daviss et al 2005, Turpeinen et al 2005) and CYP3A4 is responsible for metabolism of BUP into TB and EB (Daviss et al 2005).
   Common side effect can include dry mouth, headaches, nausea, insomnia at a prevalence of 5% and severe side effects such as seizures and migraines have been noticed with a dose dependent nature (Fava et al 2005). Withdrawal effects noted include irritable mood, sleeplessness, headache and generalised aches and pains after abrupt discontinuation of treatment (Berigan and Harazin 1999).



Mechanism of action
BUP is a central nervous system (CNS) drug whose site of action is it’s binding to the dopamine (DA) and noradreinaline (NA) reuptake pumps (Fava et al 2005). The efficacy of BUP as both an antidepressant and as a smoking cessation aid seems to be due to this antagonistic action.
BUP by itself appears to have a low affinity for it’s targeted binding sites (Preskorn 2000), so the pharmacokinetics of BUP come into play.
BUP is metabolised into three metabolites HB, EB and TB by CYP enzymes. All of these metabolites are pharmacologically active and due to their slower clearance rate (-ie- longer t1/2) compared to BUP, accumulated in the body to a much greater extent than BUP( Fava et al 2005).
This could indicate (although not pharmacologically proven) that BUP metabolites contribute to the antidepressant effects of BUP (Fava et al 2005). Furthermore, the combined concentration of BUP and it’s metabolites, could show how BUP’s relatively low affinity is negated/increased by it’s metabolites as the total concentration of BUP plus it’s metabolites far exceeds the concentration of most other antidepressant drugs, possibly increasing it’s effectiveness (Fava et al 2005).

Summary 1 â€" Effect of clopidogrel and ticlopidine on cytochrome P450 2B6 activity as measured by bupropion hydroxylation
The study aimed to demonstrate the CYP2B6 inhibiting properties of antiplatelet aggregation thienopyridine derivatives clopidogrel (CLOP) and ticlopidine (TICL) as measured by hydroxylation of bupropion (BUP).
   The study consisted of 3 phases; the 1st phase was a control period where all subjects (12 adult males) were given single dose BUP. In phase 2 and 3, subjects were pre-treated for 4 days with either CLOP 75mg once daily or TICL 250mg twice daily. In between phases there was a 1 week and 2 week washout periods respectively. On day 4 of Phase 2 and 3 subjects were dosed with 150mg BUP. Pharmacokinetics for BUP and hydroxybupropion (HB) were measured for 72 hours after BUP administration.
   After analysis it was shown that for bupropion, AUC increased by 60% with CLOP and 85% with TICL. Cmax  increased 40% with CLOP and 38% with TICL. There were no significant changes to T1/2 or tmax. Analysis of  HB showed: AUC decreased by 52% with CLOP and 84% with TICL. Cmax decreased 50% with CLOP and 84% with TICL. There were no significant changes to T1/2 or tmax. The ratio of HB/BUP decreased by 68% with CLOP and 90% with TICL.
   These results show that both CLOP and TICL are effective CYP2B6 inhibitor, with TICL almost completely inhibiting hydroxylation. As the t1/2 and tmax were not significly differentand Cmax BUP increased as Cmax HB decreased, the CYP2B6 hydroxylation represents the distribution phase rather than the elimination phase. This implies that the CYP2B6 metabolism of BUP is primary 1st pass metabolism. When this pathway is blocked, BUP will me metabolised via a ketone reduction pathway into its other metabolites, Erythrohydrobupropion and threohydrobupropion.
   In clinical use, dose adjustment would be required when using CYP2B6 inhibiting drugs. For BUP, the risk of dose dependent effects such as seizures would be increase if this adjustment is not carried out.

Review 2 â€" Steady state pharmacokinetics of Bupropion SR in juvenile patients
This study compared the pharmacokinetics (PK) in juvenile patients aged 7 â€" 17.9 years old (mean age=15.2±1.2) to that of adults in previous studies. 19 patients completed the trial; 11 male and 8 female. Ethnicities were white (n=15), African American (n=3) and Hispanic (n=1).Patients were all previously prescribed bupropion (BUP) or were about to start taking BUP for either ADHD or depressive disorders (or both). Patients were either trialled on 100mg/day or 200mg/day for 14days or less. Blood was drawn from an intravenous port every 1-3 hours after taking the usual morning dose of BUP. The level of sexual development was also measured in all patients for comparison.
   After analysis, it was found that the PK were different in the juvenile test subjects. Mean half life (t1/2) for BUP was 12.1hrs vs. 26.3hrs in adult studies. T1/2 hydroxybupropion (HB) was 21.8 vs. 20.5, t1/2 threohydrobupropion (HB) was 26.3 vs.37 and t1/2 erythrohydrobupropion (EB) was 32.7 vs. 33. The metabolite ratios of HB:TB:EB:BUP were 7.5:6.3:1.2:1 vs. 17:7:1.5:1. All Results were compared to results of adult trials indicated by GSK product info (2002).
These results show that in juvenile patients, the half life of bupropion is decreased which would lead to a faster accumulation of metabolites than in adults which is an increased risk factor towards serious metabolite concentration related effects such as seizure. The differing ratio of metabolites in the metabolite profile also brings into question the importance of each active metabolite to the therapeutic effects of BUP as a medication. Further study into the activity of each individual metabolite is required before the true implications of the differing metabolism in juveniles vs. adults can be fully understood. In clinical use, BUP should also be dose adjusted with these considerations in mind when prescribing to juveniles.   
This study also identified possible racial differences in the African-American patients which would require a larger group study of African-American patients to confirm.

Review 3 -A Comparison of Sustained-release (SR) Bupropion and Placebo For Smoking Cessation.
 This study of Bupropion aimed to assess the efficacy of Bupropion in a SR formulation as aid in smoking cessation due to suspions that nicotine may act as an antidepressant.
Subjects were recruited through the medium of advertising and were eligible if they were over the age of 18, had smoked 15 plus cigarettes a day for at least a period of one year. Subjects were excluded if they had the predisposition to seizures, psychiatric conditions, current depression and/or dependence on other drugs, such as alcohol and so forth.
Subjects were placed into one of four groups receiving either a 100mg/day, 150mg/day, 300mg/day or placebo dosages of SR Bupropion. The treatment with the drug was for seven weeks, all subjects were to stop smoking after the first week of treatment. Of the 612 subjects enrolled in the drug trial, 219 subjects (33%) failed to complete all 12 months of the study, mainly from perceived lack of belief. There were also 15 subjects who withdrew because of adverse reactions and one death.
Of the 393 subjects who completed the 12 month trial, 12.4% of subjects in the placebo group were abstinent from smoking, 19.6% on the 100mg/day, 22.9% on the 150mg/day and 23.1% on the 300mg/day.
It was found that Bupropion was effective in increasing the rate of abstinence from smoking and was well tolerated by the subjects. There was also a recommendation that the dosage be increased as higher doses seem to be more effective.


References
DAVISS W.B., PEREL J.M.,RUDOLF G.R., ALEXSON D.A.,GILCHRIST R.,NUSS S., BIRMAHER B. AND BRENT D. (2005).A. Steady-state Pharmacokinetics of bupropion SR in juvenile patients. Journal of the American Academy of Child and Adolescent Psychiatry. 44(4),349-357

FAVA M., RUSH A.J., THASE M.E., CLAYTON A., STAHL S.M., PRADKO J.F. AND JOHNSTON J.A.(2005) 15 Years of Clinical Experience With Bupropion HCl: From Bupropion to Bupropion SR to Bupropion XL. Primary care companion to the Journal of clinical psychiatry.7(3),106-113

PRESKORN S.H. (2000). Bupropion: What Mechanism of Action?. Journal of Practical Psychiatry and Behavioral Health. Jan. 272-276

TURPEINEN M., TOLONEN A., UUSITALO J., JALONEN J., PELKONEN O. AND LAINE K.(2005) Effect of clopidogrel and ticlopidine on cytochrome P450 2B6 activity as measured by bupropion hydroxylation. Clinical Pharmacology and Therapeutics. 77(6). 553-559

BERGAIN T.R AND HARAZIN J.S. (1999). Bupropion-associated withdrawal symptoms: a case report. Primary care companion to the Journal of clinical psychiatry. 1. 2

Summaries

1. TURPEINEN M., TOLONEN A., UUSITALO J., JALONEN J., PELKONEN O. AND LAINE K.(2005) Effect of clopidogrel and ticlopidine on cytochrome P450 2B6 activity as measured by bupropion hydroxylation. Clinical Pharmacology and Therapeutics. 77(6). 553-559

2. DAVISS W.B., PEREL J.M.,RUDOLF G.R., ALEXSON D.A.,GILCHRIST R.,NUSS S., BIRMAHER B. AND BRENT D. (2005).A. Steady-state Pharmacokinetics of bupropion SR in juvenile patients. Journal of the American Academy of Child and Adolescent Psychiatry. 44(4),349-357
3. HURT R., SACHS D., GLOVER E., OFFORD K., JOHNSTON J., DALE L. AND SULLIVAN P. (1997). A comparison of sustained-release bupropion and placebo for smoking cessation. New England Journal of Medicine. 337. 1195-1202

hey guys, jus finished writing this essay for a neurobiology assignment, nice n brief on PD, jus thought id post incase anyone was interested.




An overview of Parkinson’s disease with focus on dementia and cognitive aspects

Parkinsons disease (PD) is a progressive neurodegenerative disease characterised pathologically by substantial loss of the dopaminergic neurons of the substantia nigra (SN), with lewy bodies and lewy neutrites present in surviving cells [1]. Clinical symptoms used in a differential diagnosis include: hypokinesia, muscle rigidity, resting tremor, abnormal gait and postural instability. Some patients will also experience a cognitive decline as the disease progresses[1, 2]. PD affects around 1% of the population older than 65 [1]. The majority of motor-deficits are attributed to the loss of dopaminergic neurons, and therefore decrease in striatal dopamine concentrations [2].
   
The etiology of both sporadic and familial PD is still poorly understood. Recent research has identified 5 genes that appear to have mutations leading to a predisposition of PD [1]. These genes are α-Synuclein, Parkin, UCHL1, DJ-1 and PINK-1[1].
Over expression of, or mutations in, α-Synuclein (PARK-1) promotes aggregation into oligomeric species in response to oxidative stress [1,4].
   Parkin (PARK-2) and UCHL-1 (PARK-5) are both part of the Ubiquitin-proteasome system(UPS) [1]. A loss of function will result in  cytotoxic protein build up. Parkin has been associated with autosomal recessive jouvenal parkinsons disease (AR-JPD)[1].
   PINK-1 (PARK-6) phosphorylates mitochondrial proteins to prevent mitochondrial dysfunction in the presence of oxidative stress [1].
DJ-1 (PARK-7) may act as an antioxidant protein or a sensor of oxidative stress[1].

Currently Levadopa (L-dopa) and other dopamine receptor agonists are used to treat early stage PD but is coupled with a many adverse therapy related symptoms [5,6]. Experimentally, the implantation of foetal dopaminergic cells into the SN have shown great promise, with observed regeneration of striatal dopaminergic projections[5].
Dementia assosciated with PD is not uncommon. Estimates put the occurance anywhere between 27-78% and at 6x more common than in control individuals[7].Notably, it has been observed that almost all PD patients will suffer some degree of cognitive decline, but not severe enough to warrant the diagnosis of dementia[2,6,7]. This decline has been shown to be proportional to the motor decline [7]. This link can be either a direct cause of late stage PD or an increased vulnerability to other Neurodegenerative diseases such as Alzheimer’s disease (AD)
Research has started to cast doubt over many neurodegenerative diseases being mutually exclusive [6-9]. The 2 conditions providing the greatest similarity of pathology and clinical symptoms are dementia with lewy bodies (DLB) and PD with dementia (PDD)[6,8,9]. The major clinical differentiation between them is the time of dementia onset. If dementia precedes, or occurs within 1 year of , the onset of parkinsonian symptoms, it is classed as DLB, but if it occurs >1year after initial PD onset then it is termed as PDD[6,9]. Pathologically, there will most often be more cortical lewy bodies in DLB but this can be variable and the 2 pathologies can be indistinguishable unless patient history is available[6,9]. This suggests a common pathological pathway in the Initiated by the disease process with differing start points but similar end points.

It is also interesting that AD type changes were also noted in pathological studies of some of the specimens. Notably the presence of senile plaques (SP) of neurofibrillary tangles (NFTs) [6,8,9]. In DLB and PDD, α-Synuclein positive lewy bodies are the most common pathology. [6,8,9]. This suggest that lewy bodies may play a role in normal cellular function as a protective mechanism. Faulty/misfolded/redundant proteins may aggregate if their accumulation exceeds protein degradation capacity as to remove them from cellular function as not to cause a deleterious effect. In disease states, if cellular mechanisms of degradation are compromised, or if proteins are over expressed, the accumulation of aggregates may itself have a deleterious effect as it can not be broken down or far exceeds breakdown capacity. If this build up is in structures influencing cognitive function, a decrease in functionality could be presumed. This is however an untested hypothesis and more research would be required to asses its validity.

The psychological changes seen are not thought to be only due to the loss of dopaminergic neurons of the SN, but also due to the less substantial loss of serotinergic neurons of the raphe nucleus, the loss of adrenergic neurons in the locus coeruleus and the loss of cholinergic neurons of the basal nucleus of Meynert [2]. The main cognitive deficit thought to be attributable to dopaminergic neuron loss is dysexecutive syndrome due to loss of neurons in the medial SN [2]. Noradrenergic neuron loss correlates to a decrease in alertness and attention to a task [2]. Serotinergic neuron depletion has been thought to possibly play some role in depressive states observed in some PD and PDD patients [2]. This notion of the involvement of other systems is strengthened by the findings that cognitive impairment does not respond to l-dopa treatment, leading to a non-dopamine hypothesis [2]. With the involvement of non-dopaminergic systems, new pharmacological treatments for non-motor PD symptoms can be developed. Several studies have found Acetylcholine-esterase inhibitors effective in improving cognitive and behavioural symptoms such as apathy, hallucinations, confusion, psychosis and anxiety with minimal worsening of motor symptoms [2]. This hypothesis is also strengthened by experiments showing hyoscine to cause memory impairment in no demented PD patients but not in healthy subjects, suggesting that there is a decrease in Ach in PD, but not below the threshold as seen in PDD [2]. With further understanding of how these other neural systems are affected by the progression of PD, a better understanding of the complete spectrum of the disease course can be obtained and with this new treatments can be devised. PDD patients as well as PD patients may benefit from treatments to help correct these neuro-chemical deficits. Drugs such as bupropion HCL, a weak noradrenaline and dopamine uptake inhibitor, may hold some therapeutic value. The interactions and effect in PD patients would need to be assessed, but it could also help to alleviate some of the negative symptoms of  l-dopa therapy currently used, allowing for a lower dosage for the same effect when used in combination therapy. The development of pharmacological treatments for the symptoms of PDD and PD in general will be reliant on development of more selective drugs as well as better vehicles of administration to maximise positive effect and minimise negative effects of treatment. The greatest prospects seem to be a tailored combination therapy, allowing for better management of PD symptoms and thus an increase in the quality of life for sufferers.


References

[1]    Moore D.J., West A.B., Dawson V.L., Dawson T.M. .Molecular Pathophysiology of Parkinson’s Disease. Annual Review of Neuroscience.2005.28:57-87
[2]   Emre M. Dementia associated with Parkinson’s disease. Lancet Neurology. 2003.2(4):229-237
[3]    Cookson  M.R. The biochemistry of Parkinson’s Disease. Annual Revue of Biochemistry. 2005.74:29-52
[4]   Maguire-Zeiss. K.A., Short. D.W., Federoff. H.J. Synuclein, dopamine and oxidative stress: co-conspirators in Parkinson’s Disease?. Molecular Brain Research. 2005.134:18-23
[5]    Winkler. C., Kirik. D., Björklund. A. Cell transplantation in parkinson’s disease: how can we make it work?. Trends in neuroscience. 2005.28(2)
[6]   Mori. H. Pathological substrate of dementia in Parkinson’s diseaseâ€"Its relation to DLB and DLBD. Parkinsonism and related disorders, 2005.11:41-45
[7]   Sabbagh M.N., Silverberg N., Bircea S., Majeed B., Samant S. Caviness J.N., Reisberg B., Adler C.H., Is the functional decline of Parkinson’s disease similar to functional decline of Alzheimer’s disease?. Parkinsonism and related disorders.2005.11:311-315
[8]   Tsuboi Y.,Dickson D.W. Dementia with lewy bodies and Parkinson’s disease with dementia: Are they different?. Parkinsonism and related disorders.2005.11:47-51
[9] Guo L., Itaya M., Takanashi M., Mizuno Y., Mori H. Relationship between Parkinson’s disease with dementia and dementia with lewy bodies. Parkinsonism and related disorders.2005.11:305-309

can anyone reccomend a good stream ripping program?
this is for windows., either quicktime,realplay or win media player  formats

basically i want to download and store some videos on the net that if right clicked on and save target as, it download a shortcut to the streaming file, so cant actually download the video, being on dirty dirty dial up atm, i cant really stream so downloading is preferable
anyone?

hey guys, jus a lil tidbit i saw 2day, intrested me as most ppl seem to know someone who got"fucked up" on weed, maybe a step towards better understanding amongst users..

Cannabis-pyschosis link - it's in the genes

29 April 2005

A gene linking teenage cannabis use with psychotic illnesses has been identified in an international study based on data from the University of Otago's Multidisciplinary Health & Development Study.

"What we found is those people with a particular version of this gene have almost 11 times the chance of having a diagnosis of psychosis if they used cannabis during adolescence. The strength of this association is on par with that seen for a-pack-a-day cigarette smoker and the likelihood of ending up with lung cancer," Multidisciplinary Health & Development Study director Associate Professor Richie Poulton says.

The paper comes from an international research team from the University of Otago, the Institute of Psychiatry at King's College London and the University of Wisconsin and was led by Professors Avshalom Caspi and Terrie Moffitt.

The study, which will be published in the international journal Biological Psychiatry next month, focused on the COMT gene, which was chosen because it is known to play a part in the production of dopamine, a brain-signaling chemical that is abnormal in schizophrenia, Assoc Prof Poulton says.

"The findings reinforce a growing consensus that nature and nurture are not mutually exclusive forces but combine to affect behaviour and health," he says.

"This explains why cannabis use has a devastating affect on some users but leaves most unharmed. We have suspected genetic factors are responsible for the difference but until now no gene has been identified."

The Dunedin Multidisciplinary Health & Development Study has tracked approximately 1000 men and women since they were born in Dunedin in 1972 and 1973, making it one of the longest and most detailed cohort studies in the world. Each participant was interviewed at 13, 15 and 18 years about cannabis use and tested to determine which type of COMT gene they had inherited and followed up at age 26 for signs of mental illness.


//http://www.otago.ac.nz/news/news/2005/29-04-05_press_release.html

hey all
have recently been atempting to get a dual boot between win xp and fedora 3 working on my system,
i am wanting the dual boot so i can run windows when required until i get used to linux and get it fully functional, net set up etc,

the problem i am having at the moment is getting a hdd that can be utilised by both os's, have a 200gig sata drive i use for storage of media etc, have the two os's on seperate partitions on abother hdd, however i cannot acess any partitions on the storage drive, have one set up as a test partitiopn, as FAT32, the other major partition being NTFS.
so my question is basically, should seperate partitions show up aong side file system automatically? or how do i gain access to them through linux?

hey guys
anyone have any suggestions to fix this error message?

the other day i brought a dvd rewriter,  strted getting error messages when trying to view data cds and dvds,
'file' : data error (cyclic redundancy test)
initially it came up with both video and mp3 files and when they were played from cd/dvd they became jerky, mp3's stopped and started
now it only seems tobe effecting mp3 files
i cannot play them without jerkyness or dopy them to hdd without the error message.

anyone have any ideas how to fix this error?

hey guys, was just wonmderinging on the merit of adding lemon juice to herbal teas, this is more a general question, how much would the actual extraction of alkaloids form the plant matter be effected by a squeeze of lemon juice?

i know that this is different for each chemical, but generally is it advised or not, this is especially true for mixes of herbs in teas.

would it in turn be better to let it seep for awhile in hot water then add lemon juice and let sit for longer?

i know there is lotsa chemistry involved in this, i could try find the best academic answer by looking at chem structures and pkas and such but jus wondering if there is a simple yes or no answer...

does anyone have any info on the alkaloid profile of the mexican prickley poppy?

also, which parts are toxic, is it only the seeds?