Snead OC, Gibson KM. Gamma hydroxybutyric acid. NEJM 2005; 352:2721-2732.
Benarroch EE. Y-Hydroxybutyric acid and its relevance in neurology. Neurology 2009; 72: 282-286.
GHB is formed from endogenous GABA or exogenous dosing. Its effects are modulated both by GABA-B and GHB receptors. The former, within mesocorticolimbic dopamine pathways is probably responsible for the addictive nature. Effects of exogenous drug include triggering the onset of slow wave sleep (thus its use in cataplexy), intoxication, tolerance, withdrawal and addiction. It also may be used in alcohol withdrawal and intoxication. Accumulation may underlie some signs of SSADH deficiency in humans.
The sedative properties are similar to those previously seen in gamma butyrolactone 13 years ago, because that drug is metabolized to GHB. GHB occurs naturally from GABA and resembles neurotransmitters, and is released by neuronal depolarization in a calcium dependent fashion. The high affinity receptor is probably presynaptic and G protein coupled, and is located in the hippocampus, thalamus, and neocortex. GABA A receptors (not related here) result in influx of chloride ions and the generation of a fast inhibitory post-synaptic potential, whereas the GABA B receptor mediates a slow inhibitory postsynaptic potential. GABA B receptors mediate effects through voltage dependent inhibition of high voltage activated calcium channes. GHB and GABA B receptor may be one and the same (controversial). Natural GHB is present in micromolar quantities, can activate GHB receptors but not GABA B receptors. Exogenous GHB probably acts through GABA B receptor. GHB conversion to GABA (normal metabolism) can be inhibited by valproic acid and ethosiximide.
GHB has a half life of 20-30 minutes, peak levels occur at 40 minutes, and it can be detected in urine for 12 hours. The narrow margin of safety is such that doses up to 20-30 mg/kg lead to euphoria and memory loss, drowsiness and sleep. Twice this dose leads to coma.
The clinical hallmark is rapid onset of profound coma, myoclonus, respiratory depression, hypoventilation, and bradycardia. Hupothermia, vomiting, mydriasis, or miosis also may occur. The signs persist for a short time. The rapid/uneventful recovery creates a false sense of security in users. The level of consciousness does not correlate with the serum level of GHB. It should be considered in any young man with rapid onset of coma when head trauma, metabolic disorders, CNS infection and increased intracranial pressure are excluded. It can be considered in women as well (date rape drug).
Death due to overdose can occur to respiratory compromise, aspiration, positional asphyxia, pulmonary edema, accidental trauma, or injury. Over half of abusers also use other drugs, and alcohol is synergistic in causing respiratory depression and hypotension.
Management is supportive (airway, breathing, circulation) oxygen, and atropine for persistent bradycardia. Mucosal burns can occur as illicit forms are synthesized from gamma butyrolactone and sodium hydroxide. There are no specific antidotes. Charcoal is not indicated due to short half life and risk of aspiration. Physostigmine is not indicated.
GHB and its prodrugs (gammabutyrolactone and 1,4 butanediol) are abused by bodybuilders because they were thought to stimulate the production of growth hormone. The diol prodrug is metabolized by an alchohol dehyrogenase, and is made more toxic by alcohol, possibly because of competition by two drugs for that enzyme. GHB is available by schedule one prescription. Names for illicit forms include G, liquid ecstasy, grievous bodily harm, Georgia home boy, liquid X, soap, easy lay, salty water, scoop, cherry meth, and nitro. The two prodrugs are available on internet for sale, advertised for mood enhancement, sleep induction and bodybuilding (GBL, gamma butyrolactone).
The psychic effects include reduced anxiety, euphoria, enhanced sensuality, and emotional warmth. It is common at raves. Raves are all night dance parties attended by large number sof young people with clandestine venues, hynotic music and liberal use of drugs including GHB. Circuit parties differ in that they are usually attended by homosexual/bisexual men. This is a problem, because protease inhibitors, given for HIV infection, alter the metabolism of GHB through interaction on P-450 system. Even small doses can cause coma.
Rebound insomnia after 2-3 hours of sleep can lead to repeat dosing with an additive response. Chronic users may thus take doses every 2-4 hours around the clock, and suffer withdrawal when they stop taking it with symptoms similar to those of benzodiazepine or alcohol. Once daily GHB users (for narcolepsy) do not develop withdrawal. The minimum dose for withdrawal is 18 g (10g for precursor) but doses are variable. Symptoms are mild at onset and include tremor, tachycardia, restlessness, insomnia, anxiety, or vomiting and can build up, later causing delirium, frank psychosis, diaphoresis or death. Withdrawal can last weeks or even months and patients may abuse benzodiazepines or alcohol to self-medicate symptoms. Lorazepan or diazepam often in very high doses may be needed to treat withdrawal. Antipsychotics and antiepileptic drugs are not needed. Baclofen could be considered a potential drug for weaning as it is a GABA B receptor agonist and helps in other addictive drugs by decreasing reinforcement effects in dopaminergic mesocorticolimbic pathways,
Sexual assault (date rape drug) occurs with doses of 10-20 mg/kg, as drug causes increased libido, anterograde amnesia, suggestibility and passivity. In suspected patients, early collection of blood and urine is important for detection. It is not readily measurable and may need to be sent out to a state reference lab.
Potential legitimate uses include narcolepsy, alcohol dependence and withdrawal, stimulus induced paroxysmal drop attacks in Coffin-Lowry syndrome, tardive dyskinesia and bipolar affective disorder.
See discussion of metabolic disease SSADH (related) here :
http://www.blogger.com/post-edit.g?blogID=30837446&postID=3676676890024591264
Letters to editor were published in NEJM 2005; 353: 1632-33. One writer opined that rapid diagnosis through tox screens should be detectable by urinary organic acid analysis, similar to the way succinic dehydrogenase deficiency is diagnoses. Another writer opined that GHB is approved for alcohol detoxification in Europe, as well as maintenance of long term abstinence. No abuse occurs with greater fractioning of the dose. A third writer stresses the importance of assessing agitation as a sign of co-intoxicants. They plan to publish a series on 146 deaths with GHB, including 138 CP deaths, 4 drownings, 3 MVA fatalities, and 1 death to a fire while intoxicated.
Friday, December 7, 2007
Thursday, December 6, 2007
Tale about Tau
Ashe KH. A Tale about tau. NEJM 2007;357:933-935.
The author reviews evidence suggesting that tau is an appropriate drug target for Alzheimer's disease. They cite a mouse model by Roberson ED et al (Science 2007;316:750-754)that expresses amyloid precursor protein encoded by two genes carrying two mutations for early onset familial AD. APP cleaves to form A Beta , the main component of amyloid plaques of AD, and the mice develop abnormal behaviors, memory loss and plaques. In these mice, depleting endogenous tau (from NFT's) (by crossing with mice in whom the tau gene was inactivated) , that did not result in decreased amyloid plaques in the mice, but did result in prevention of behavioral disturbance, memory loss and sudden death. Improvement occurred even with a 50 % reduction of tau. Soluble a Beta assemblies cause memory loss and bind to dendritic spines, the postsynaptic elements that house the key elements of memory formation. NFT's are not as important, as mice with neuritic plaques and tangles with reduced tau had normal behavior.
Tau joins other molecules that mediate the effects of aBeta on memory and synaptic plasticity. Tau lives in axons where it binds microtubules to polymerize and stabilize molecules. Under pathologic conditions, tau interacts with cytoskeletal component actin, mediating changes in dendritic spines and synaptic plasticity. Dendritic spines also are entry points for excitotoxicity.
Mice with low tau were resistant to excitotoxic seizures, suggesting it might potentiate excitotoxic effects of a Beta. Since tau facilitates brain dysfunction due to A Beta and excitotoxin, and even a partial low level can diminish bad effects, "propels tau to a higher spot" on list of therapeutic targets for Alzheimer's disease, and stroke and epilepsy (that involve excitotoxicity). Author cautions that TIMING of tau reduction may be important, as it may be important in development rather than in adult specimens.
The author reviews evidence suggesting that tau is an appropriate drug target for Alzheimer's disease. They cite a mouse model by Roberson ED et al (Science 2007;316:750-754)that expresses amyloid precursor protein encoded by two genes carrying two mutations for early onset familial AD. APP cleaves to form A Beta , the main component of amyloid plaques of AD, and the mice develop abnormal behaviors, memory loss and plaques. In these mice, depleting endogenous tau (from NFT's) (by crossing with mice in whom the tau gene was inactivated) , that did not result in decreased amyloid plaques in the mice, but did result in prevention of behavioral disturbance, memory loss and sudden death. Improvement occurred even with a 50 % reduction of tau. Soluble a Beta assemblies cause memory loss and bind to dendritic spines, the postsynaptic elements that house the key elements of memory formation. NFT's are not as important, as mice with neuritic plaques and tangles with reduced tau had normal behavior.
Tau joins other molecules that mediate the effects of aBeta on memory and synaptic plasticity. Tau lives in axons where it binds microtubules to polymerize and stabilize molecules. Under pathologic conditions, tau interacts with cytoskeletal component actin, mediating changes in dendritic spines and synaptic plasticity. Dendritic spines also are entry points for excitotoxicity.
Mice with low tau were resistant to excitotoxic seizures, suggesting it might potentiate excitotoxic effects of a Beta. Since tau facilitates brain dysfunction due to A Beta and excitotoxin, and even a partial low level can diminish bad effects, "propels tau to a higher spot" on list of therapeutic targets for Alzheimer's disease, and stroke and epilepsy (that involve excitotoxicity). Author cautions that TIMING of tau reduction may be important, as it may be important in development rather than in adult specimens.
Friday, July 6, 2007
Rebooting the immune system with cytoxan
Drachman et al. Annals of Neurology2003 and Lewis and Lisak editorial same issue.
Drachman et al. take advantage of the resistance of stem cells to cycophosphamide because they lack the enzyme aldehyde dehydrogenase. That makes bone marrow transplantation unneeded, with the hope that the rebooted marrow lacks the pathologic autoimmune response seen before treatment. It is not clear that rebooting is not simply effective because it is prolonged severe immunosuppression. In other AI disorders, the technique has been used producing remissions but also deaths.
Drachman et al. take advantage of the resistance of stem cells to cycophosphamide because they lack the enzyme aldehyde dehydrogenase. That makes bone marrow transplantation unneeded, with the hope that the rebooted marrow lacks the pathologic autoimmune response seen before treatment. It is not clear that rebooting is not simply effective because it is prolonged severe immunosuppression. In other AI disorders, the technique has been used producing remissions but also deaths.
Saturday, May 5, 2007
Do Bone Marrow Cells Generate Neurons?
Hess DC et al. Arch Neurol 2004;61:483-485. Neurological Review.
Bone marrow cells can evolve into hepatocytes, endothelial, muscle, cardiac muscle or neuronal cells, in vitro and in vivo. Method used is transplanting genetically marked bone marrow in mice that have received lethal radiation. The "radiation chimera" is often a sex mismatch, eg. a y chromosome in a female. Many neurologic structures received marked cells including cells expressing GFP and NS proteins, in olfactory bulb, cortex, hypothalamus, hippocampus, amygdala, PAG, striatum, Purkinje cells of cerebellum but not spinal cord or brainstem. This also has been shown in several humans who received transgender bone marrow transplants . Some evidence suggests this is due to cell fusion. It is not yet clear whether these cells express normal function.
Bone marrow cells can evolve into hepatocytes, endothelial, muscle, cardiac muscle or neuronal cells, in vitro and in vivo. Method used is transplanting genetically marked bone marrow in mice that have received lethal radiation. The "radiation chimera" is often a sex mismatch, eg. a y chromosome in a female. Many neurologic structures received marked cells including cells expressing GFP and NS proteins, in olfactory bulb, cortex, hypothalamus, hippocampus, amygdala, PAG, striatum, Purkinje cells of cerebellum but not spinal cord or brainstem. This also has been shown in several humans who received transgender bone marrow transplants . Some evidence suggests this is due to cell fusion. It is not yet clear whether these cells express normal function.
Sunday, April 22, 2007
Apoptosis and Caspaces in neurodegenerative diseases
Friedlander RM. Mechanisms of disease. NEJM 2003; 348:1365-1375.
Caspaces (cysteine dependent, apartate specific proteases) are the executioners in the apoptotic programs for cell death. This work was originated in nematodes and has become prominent in the past fifteen years only. There are upstream or initiator caspaces and downstream executioner caspaces. Cytochrome c, a part of the electron transport chain, is intimately involved . There also are inhibitors of caspaces to prevent apoptosis gone amuk.
In acute neurologic diseases, necrotic death and apoptosis both occur. In neurodegenerative diseases, apoptosis predominates. Caspaces may be important in AD, PD, HIV related dementia. In addition, a role exists in ALS mice, in which caspace 1 and 3 are upregulated. 10 % of patients have a SOD mutation and in these it may be preordinant. In Huntington's disease, huntingten is depleted which is a substrate for caspace 1. Increased caspace mediated cleavage of huntingten leads to hgih levels of huntingten fragments and depleted wild type huntingten. Down regulation of receptors also occurs, and this is caspace dependent but not considered apoptosis.
Minocycline inhibits nitric oxide and reduces the severity of ischemia induced tissue injury. It also inhibits caspace. Neuroprotection with it has been observed in models of HD, ALS, brain injury, PD and MS. The mechanism is the direct inhibition of the release of cytochrome c, and inhibition of downstream activation of caspace 3. It is orally bioavailable, crosses the bloodbrain barrier is safe, and is being tested in HD and ALS.
Apoptosis is "contagious" as it occurs, as it releases pro-apoptotic factors causing neighborhood to all commit apoptosis It is therefore a reasonable idea for treatment of acute neurologic disease as well.
Caspaces (cysteine dependent, apartate specific proteases) are the executioners in the apoptotic programs for cell death. This work was originated in nematodes and has become prominent in the past fifteen years only. There are upstream or initiator caspaces and downstream executioner caspaces. Cytochrome c, a part of the electron transport chain, is intimately involved . There also are inhibitors of caspaces to prevent apoptosis gone amuk.
In acute neurologic diseases, necrotic death and apoptosis both occur. In neurodegenerative diseases, apoptosis predominates. Caspaces may be important in AD, PD, HIV related dementia. In addition, a role exists in ALS mice, in which caspace 1 and 3 are upregulated. 10 % of patients have a SOD mutation and in these it may be preordinant. In Huntington's disease, huntingten is depleted which is a substrate for caspace 1. Increased caspace mediated cleavage of huntingten leads to hgih levels of huntingten fragments and depleted wild type huntingten. Down regulation of receptors also occurs, and this is caspace dependent but not considered apoptosis.
Minocycline inhibits nitric oxide and reduces the severity of ischemia induced tissue injury. It also inhibits caspace. Neuroprotection with it has been observed in models of HD, ALS, brain injury, PD and MS. The mechanism is the direct inhibition of the release of cytochrome c, and inhibition of downstream activation of caspace 3. It is orally bioavailable, crosses the bloodbrain barrier is safe, and is being tested in HD and ALS.
Apoptosis is "contagious" as it occurs, as it releases pro-apoptotic factors causing neighborhood to all commit apoptosis It is therefore a reasonable idea for treatment of acute neurologic disease as well.
Friday, March 23, 2007
Neuroprotection in the peripheral nervous system
Hoke A. Neuroprtoection in the peripheral nervous system. Arch Neurol 2006; 63: 1681-1685
The authors criticise the dogma holding that there is a "dying back " neuropathy in which the axon degrades centripetally from the end. In other work (Griffin and Hoke) the concept of last field of irrigation is reversed, and neuronal body depends upon target derived growth factors for survival. Also, Raff et al proposed that the so-called dying back neuropathy is a programmed responsed similar to apoptosis. Neuroprotective activities designed for neuronal survival, such as in the brain or spinal cord, may be inappropos due to lack of significant neuronal death in many peripheral neuropathies. The author proposes research center on 2 areas: mechanisms involving distal axonal degeneration, and axon-glia mechanisms important for neuroprotection.
Unlike Wallerian degeneration, in many peripheral neuropathies there is compartmental degeneration of axons without physical compartmentalization. In HIV virus envelope gp120 involves chemokine receptors on Schwann cells. In familial ALS, mutations in the SOD 1 gene suggested initial ep abnormality was explained by axonal degeneration not neuronal loss.
In stroke literature ischemic preconditioning protects neurons and limits damage from future events. This endogenous protection may be related to astrocyte secreted erythropoietin. In sciatic transection in rats, Schwann cells in contact upregulate erythropoetin expression and DRG ensory neurons upregulate receptors for the same. The injury signal in nitric oxide, that activates hypoxia-inducible-factor 1 that induces erythropoetin changes. Exogenous erythropoietin helps in models of neuropathy due to paclitaxel, diabetic neuropathy, and cisplatinum induced PN.
The authors also note a mouse strain that is resistant to degeneration after injury, due to a Wlds gene (Wallerian degeneration-slow). Further studies of axon-glia interactions are needed.
The authors criticise the dogma holding that there is a "dying back " neuropathy in which the axon degrades centripetally from the end. In other work (Griffin and Hoke) the concept of last field of irrigation is reversed, and neuronal body depends upon target derived growth factors for survival. Also, Raff et al proposed that the so-called dying back neuropathy is a programmed responsed similar to apoptosis. Neuroprotective activities designed for neuronal survival, such as in the brain or spinal cord, may be inappropos due to lack of significant neuronal death in many peripheral neuropathies. The author proposes research center on 2 areas: mechanisms involving distal axonal degeneration, and axon-glia mechanisms important for neuroprotection.
Unlike Wallerian degeneration, in many peripheral neuropathies there is compartmental degeneration of axons without physical compartmentalization. In HIV virus envelope gp120 involves chemokine receptors on Schwann cells. In familial ALS, mutations in the SOD 1 gene suggested initial ep abnormality was explained by axonal degeneration not neuronal loss.
In stroke literature ischemic preconditioning protects neurons and limits damage from future events. This endogenous protection may be related to astrocyte secreted erythropoietin. In sciatic transection in rats, Schwann cells in contact upregulate erythropoetin expression and DRG ensory neurons upregulate receptors for the same. The injury signal in nitric oxide, that activates hypoxia-inducible-factor 1 that induces erythropoetin changes. Exogenous erythropoietin helps in models of neuropathy due to paclitaxel, diabetic neuropathy, and cisplatinum induced PN.
The authors also note a mouse strain that is resistant to degeneration after injury, due to a Wlds gene (Wallerian degeneration-slow). Further studies of axon-glia interactions are needed.
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