Monday, 23 September 2013

Huntington's Disease

Huntington's disease (HD) is a rare, hereditary, fatal (death usually occurs 10-25 years after the first symptoms appear) neurodegenerative disorder (i.e. a neurological [pertaining to the brain, spinal cord and/or nerve cells] yet progressive disorder) that can strike persons at any time in life. It causes a progressive decline in motor function (your ability to control your normally, voluntary movements), cognitive function (memory, learning, etc.), emotional stability, connection with reality (in the later stages people with the disorder can become psychotic with many of the classic symptoms of paranoid schizophrenia) and various other neurological functions. The first symptom is usually chorea (an abnormal involuntary movement disorder that often presents with involuntary flailing movements) hence the previous name of the condition, Huntington's chorea.1

It is due to the build-up of a faulty (or mutated) huntingtin protein (mHtt) which is due to a mutation in the huntingtin gene (HTT). This gene is used to create the huntingtin protein which plays a key role in various cellular processes in the brain and testes. The gene is inherited in an autosomal dominant fashion (i.e. it is inherited in a manner that is totally independent of the sex of the parent and the child. This is because we all get two autosomes [the type of chromosome on which the huntingtin gene is found; these are the non-sex chromosomes] of each variety [there's 21 different autosomes], one from our father, one from our mother. It takes just one autosome that contains a faulty huntingtin gene to cause Huntington's disease). The faulty huntingtin protein builds up and this leads to neuronal (electrically-signalling brain, spinal cord and nerve cell [in this case mostly just brain cell]) dysfunction and death (although we're not sure exactly how).1

At this point in time there are limited treatment options for people with Huntington's disease. Most treatments are aimed at making the patient as comfortable as possible as they die. Treatments that are designed to do this include neuroleptics (antidopaminergic drugs; drugs that counteract the actions of the neurotransmitter, dopamine, throughout the nervous system [brain, spinal cord and nerves] particularly in the basal ganglia -- the part of the brain that takes the biggest hit in Huntington's disease. It plays a key role in controlling our voluntary movements. Neuroleptics are basically the older antipsychotic medications [the so called "typical" antipsychotics] and some of the older antiemetics [anti-nausea and vomiting]), benzodiazepines (e.g. diazepam [VALIUM], clonazepam [RIVOTRIL]), dopamine-depleting agents (e.g. reserpine, tetrabenazine) and valproate (EPILIM, DEPAKENE, DEPAKOTE) which are designed to help with the choreas typical of HD. Likewise if symptoms include muscle rigidity and slowed movements then dopamine agonists (receptor activators; compounds that mimic dopamine's effects in the body) or levodopa (a compound the body uses to synthesise dopamine) are preferred. Depression is also common in patients with HD and is often treated standard antidepressants such as sertraline (ZOLOFT), fluoxetine (PROZAC), etc. None of these treatments are believed to be disease-modifying i.e. treatments that actually slow (or "modify") the course of the disease.1

I theorise that valproate may have disease-modifying effects in HD seeing how it is a known histone deacetylase (HDAC) inhibitor (which alter the generation of proteins from genes) and HDAC inhibitors are known to slow the progression of HD in animal models of the disease.2

Coenzyme Q10 is an enzyme that participates in the electron-transport chain that provides a significant portion of a cell's energy. Consequently it plays a pivotal role in mitochondrial (the "power house" of cells) function. When it's supplemented with dietary supplements it provides antioxidant, anti-inflammatory and neuroprotectant (neuron-protecting) effects. In animal models of HD it was found to possess diseases-modifying effects.3

Creatine, another naturally-occurring antioxidant, has been found to possess protective effects in animal models of HD.3,4


Reference List:

  1. Revilla FJ. Huntington Disease. 2013 May 14 [cited 2013 Sep 23]; Available from: http://emedicine.medscape.com/article/1150165-overview#showall
  2. Sadri-Vakili G, Cha J-H. Histone Deacetylase Inhibitors: A Novel Therapeutic Approach to Huntingtons Disease (Complex Mechanism of Neuronal Death). Current Alzheimer Research [Internet]. 2006 Sep 1 [cited 2013 Sep 23];3(4):403–8. Available from: http://www.eurekaselect.com/77042/article
  3. Yang L, Calingasan NY, Wille EJ, Cormier K, Smith K, Ferrante RJ, et al. Combination therapy with Coenzyme Q10 and creatine produces additive neuroprotective effects in models of Parkinson’s and Huntington’s Diseases. Journal of Neurochemistry [Internet]. 2009 [cited 2013 Sep 23];109(5):1427–39. Available from: http://onlinelibrary.wiley.com/doi/10.1111/j.1471-4159.2009.06074.x/abstract
  4. Dedeoglu A, Kubilus JK, Yang L, Ferrante KL, Hersch SM, Beal MF, et al. Creatine therapy provides neuroprotection after onset of clinical symptoms in Huntington’s disease transgenic mice. J Neurochem. 2003 Jun;85(6):1359–67. 

Monday, 9 September 2013

The Tuberous Sclerosis Complex

Tuberous sclerosis complex (TSC) is a disease that I learnt of today in my studies of the drug rapamycin (Sirolimus; RAPAMUNE) that's quite frankly rather sad. It is a genetic disease that causes benign (i.e. non-cancerous) tumours to arise in any and, often, every organ of the body. The way how this presents in terms of symptoms greatly depends, of course, on the location of the tumour(s). Epilepsy is common in patients with TSC and status epilepticus is not an uncommon cause of death in patients with TSC. Status epilepticus is basically either singular long, sustained seizures or a series of small seizures that occurs in short succession. Mental retardation and autism is not uncommon in patients with TSC which can result from episodes of status epilepticus or directly from the growth of tumours in the brain and the pressure this can exert on brain tissue. Many patients with TSC are also born with heart defects, many also have vision impairments.1

It is inherited in an autosomal dominant fashion, that is, there is no gender influence on how the gene is inherited and it takes just one copy (as opposed to two copies if the gene was recessive) of the gene to cause the disease. What this means is that if one parent has the disease there's a 1/4 chance one of their kids will develop the disease and if both parents have the disease then there's a 3/4 chance that their kids will inherit the disease and if one parent has two copies of the gene as opposed to the minimum of one copy that is needed to cause the disease then all their kids will have TSC.1

There are two distinct genes that, when mutated, can lead to TSC: TSC1 and TSC2. These genes are both what's known as tumour suppressor genes – (note: what follows is not the definition of a tumour suppressor gene, it's the term tumour suppressor gene applies to this case; in general it just means a gene that appears to severe as a safe-guard against cancer) they encode (used as instructions per say for the production of) proteins that in turn regulate the activity of the mammalian target of rapamycin (mTOR) and if the activity of these genes is impaired, by say a mutation (like is the case in TSC), mTOR activity increases leading to an increased propensity for uncontrolled cell growth like that seen in cancer. The place where rapamycin, the popular immunosuppressant (immune system-suppressing drug), comes in is that it inhibits mTOR, which is, as you can probably guess, the drug after which mTOR is named.1


Ironically not long ago I was reading up about the ketogenic diet (the diet that aims to induce ketogenesis [the formation of ketone bodies from dietary fats and their utilisation as an energy source of the body] by depriving the body of other energy sources like carbohydrates and, to a lesser extent, proteins) and I learnt that one of its potential mechanisms in the treatment of epilepsy (most often from non-TSC courses) is that it inhibits mTOR.2 mTOR appears to play a key role in longevity too and lately a novel class of drugs known as sirtuin activators have been in development and the way they work is by activating the sirtuin family of enzymes which includes SIRT1, an enzyme that in turn, by interacting with TSC1/2 inhibits mTOR.3 Resveratrol is a compound that occurs naturally in grapeskins and other plant sources that activates SIRT1. Hence it is conceivable that drugs like resveratrol may be of therapeutic benefit in patients with TSC. Resveratrol, however, is not exactly suited for this indication due to the fact that it has poor oral bioavailability, that is, very little of the original drug reaches circulation (in the blood) in the body after it is taken orally.3

Reference List:
  1. Franz DN. Tuberous Sclerosis [Internet]. 2013 [cited 2013 Sep 10]. Available from: http://emedicine.medscape.com/article/1177711-overview#showall
  2. Danial NN, Hartman AL, Stafstrom CE, Thio LL. How Does the Ketogenic Diet Work? Four Potential Mechanisms. J Child Neurol [Internet]. 2013 Aug 1 [cited 2013 Sep 10];28(8):1027–33. Available from: http://jcn.sagepub.com/content/28/8/1027
  3. Ghosh HS, McBurney M, Robbins PD. SIRT1 Negatively Regulates the Mammalian Target of Rapamycin. PLoS ONE [Internet]. 2010 Feb 15 [cited 2013 Sep 10];5(2):e9199. Available from: http://dx.doi.org/10.1371/journal.pone.0009199

Saturday, 24 August 2013

Valproic Acid

Valproic acid and its salts (e.g. sodium valproate [EPILIM]) are quite fascinating drugs when you get down to it. They're chemically quite simple (valproic acid's IUPAC name for those of you that understand what this means is just 2-propylpentanoic acid) were originally synthesised from a compound with a very humble source: the Valerian plant (this is because the Valerian contains valeric acid amongst hundreds of other compounds and valeric acid is also known as pentanoic acid which is quite similar to valproic acid). Valproic acid is also fascinating in that it has so many medical uses including:1
  • as an antimanic (a drug that treats the manic states often seen in patients with bipolar disorder and related psychiatric disorders)
  • as a mood stabiliser in the long-term treatment of bipolar disorder (unfortunately, however, it appears to have limited efficacy in preventing future depressive episodes in patients with bipolar disorder)
  • As an adjunctive (add-on) treatment to antipsychotic therapy in patients treatment-resistant schizophrenia2 and in the treatment of agitation in patients with schizophrenia3
  • Anticonvulsant (anti-seizure medication; this is, in fact, valproic acid's chief medical use. The great thing about valproic acid too is that it works against a broad spectrum of different seizure types. See in epileptic seizures can be divided into various different subtypes according to the parts of the brain that are affected and the symptoms of the seizure and valproic acid appears to work against all types of seizures which is not always the case with anticonvulsants)
  • As an anticancer agent (this use has only become apparent recently and isn't very well studied yet but in theory it definitely should have anticancer activity)4
  • In the prevention of migraines 
  • As an analgesic (painkiller) in patients with neuropathic (nerve injury-related) pain (ironically one type of neuropathic pain it has been tested in is neuropathic pain due to cancer and in this clinical trial it was found effective)
  • The treatment of hallucinations associated with alcohol abuse

It has also been tested as an adjunct (add-on treatment) in the treatment of HIV but in this indication it has been found to be ineffective.5

The mechanism by which valproic acid works these almost majestic effects is not entirely known but, as always, we do have our theories. Its anticonvulsant effects are believed to be mediated by its ability to do the following:
  • Block voltage-dependent sodium channels (in brain and other electrically excitable cells a message is propelled through the cell by means of ions like sodium ions. These sodium channels like other ion channels allows a particular ion [like sodium] into and out of the cell; ions are atoms that have either lost or gained an electron(s))6
  • Inhibit the activity of the enzyme GABA-T which catalyses the breakdown of the neurotransmitter, gamma-aminobutyric acid (GABA). This allows GABA levels in the brain and other tissues to rise and since seizures are due to pathological (usually pathologically excessive) electrical activity in the brain and GABA depresses neuronal [electrically-signalling cells of the brain, spinal cord and nerves] activity, this rise in GABA levels can reduce this pathologically excessive activity.7
  • Potentiating the activity of the enzyme glutamic acid decarboxylase (GAD) – an enzyme that catalyses the synthesis of GABA8

Its antimanic, anticancer and potentially its analgesic effects are probably, at least in part, due to its ability to inhibit the enzyme Histone Deacetylase (HDAC). Histone deacetylase enzymes catalyse the deacetylation of histones – proteins that package and order DNA in the nuclei (centre, almost like the "brain" of the cell) of cells and plays a key role in gene expression (i.e. the generation of proteins like receptors and enzymes from genes). By doing this HDAC inhibitors like valproic acid lead to a significant increase in the expression of certain genes and a reduction in the expression of others. In support of the role of HDAC inhibition in the antimanic effects of valproic acid the other HDAC inhibitor, butyric acid (which, interestingly, is something naturally found in our intestines as a by-product of the bacteria in our intestines metabolising dietary fibre), has been found to be efficacious in an animal model of mania.9 HDAC’s role in cancer cell proliferation (spread), differentiation, etc. is well established as is supported by the fact that the HDAC inhibitor, vorinostat, is Food and Drug Administration (FDA; the US Gov.’s regulatory administration on drugs and food) approved for certain types of cancer.

One protein that is upregulated (i.e. its gene expression is increased by valproic acid) by HDAC inhibitors that may be, in part, responsible for the antimanic and analgesic effects of valproic acid is the metabotropic glutamate receptor 2 (mGluR2).10,11 mGluR2 in turn regulates the release of the neurotransmitter glutamate in various brain and spinal cord areas including those involved in emotional processing and the perception of pain.12 It is also conceivable that mGluR2 receptors may play a role in the anticonvulsant effects of valproic acid since excess glutamatergic activity is implicated in epilepsy. Something that is often predictive of antimanic activity in animal models is antipsychotic activity (which in turn is determined in various different animal models of schizophrenia) and mGluR2 agonists (activators) and potentiators are known to possess significant antipsychotic activity, in fact, one mGluR2/3 receptor agonist (pomaglumetad methionil) was in clinical trials until recently as a potential treatment for schizophrenia. Unfortunately this drug failed phase III (the final phase of clinical testing prior to the approval of the drug) clinical testing despite displaying antipsychotic activity in phase II clinical trials. Another change in gene expression that might be involved in the antimanic effects of valproic acid is that of the brain-derived neurotrophic factor (BDNF) – a protein involved in the protection, reproduction and repair of neurons.13,14 It is also possible that the antimanic effects of valproic acid may be due to its inhibitory effects on glycogen synthase kinase 3β (GSK-3β) expression, which is supported by the fact that the antimanic agent, lithium, also inhibits GSK-3β, albeit via a different mechanism.15

How it works on cancer is very complex considering how many different genes are upregulated in cancer cells relative to their non-cancerous counterparts. The following genes are a few that may play a role in the anticancer effects of valproic acid and its salts:
  • Cyclin D216
  • Amyloid precursor protein17
  • Glycogen synthase kinase 3β (GSK-3β)15

Since the amyloid precursor protein is also involved in the pathogenesis (disease process) of Alzheimer’s disease it may be helpful there.18

However don't get me wrong valproic acid and its salts are definitely not very benign (i.e. has a limited potential to do harm) drugs and some of their side effects can leave one with permanent organ injuries and/or death. Potential life-threatening/debilitating side effects according to Micromedex includes:1
  • Hyperammonaemia (elevated blood levels of ammonia) – which can lead to permanent or temporary brain injury and coma 
  • Liver failure
  • Pancreatitis (inflammation of the pancreas)
  • Thrombocyotpaenia (reduction in the amount of platelets in your blood leading to an increased tendency to bleed) 
  • Palpitations (abnormally rapid, irregular or strong heart beat) 
  • Immune hypersensitivity reaction (a severe allergic reaction to the drug) 
  • Permanent Deafness 
  • Pleural effusion (a build-up of fluid around the lungs)

It has a number of less severe, common side effects but there’s so many that I deem it too tedious to write it out here.


Reference List:

  1. Truven Health Analytics, Inc. DRUGDEX® System (Internet) [cited 2013 Aug 24]. Greenwood Village, CO: Thomsen Healthcare; 2013.
  2. Suzuki T, Uchida H, Takeuchi H, Nakajima S, Nomura K, Tanabe A, et al. Augmentation of atypical antipsychotics with valproic acid. An open-label study for most difficult patients with schizophrenia. Human Psychopharmacology: Clinical and Experimental [Internet]. 2009 [cited 2013 Aug 24];24(8):628–38. Available from: http://onlinelibrary.wiley.com/doi/10.1002/hup.1073/abstract
  3. Yoshimura R, Shinkai K, Ueda N, Nakamura J. Valproic Acid improves Psychotic Agitation without Influencing Plasma Risperidone Levels in Schizophrenic Patients. Pharmacopsychiatry [Internet]. 2007 Jan [cited 2013 Aug 24];40(1):9–13. Available from: https://www.thieme-connect.com/DOI/DOI?10.1055/s-2007-958521
  4. Michaelis M, Doerr H, Cinatl Jr. J. Valproic Acid As Anti-Cancer Drug. Current Pharmaceutical Design [Internet]. 2007 Nov 1 [cited 2013 Aug 24];13(33):3378–93. Available from: http://www.eurekaselect.com/60121/article
  5. Routy J, Tremblay C, Angel J, Trottier B, Rouleau D, Baril J, et al. Valproic acid in association with highly active antiretroviral therapy for reducing systemic HIV-1 reservoirs: results from a multicentre randomized clinical study. HIV Medicine [Internet]. 2012 [cited 2013 Aug 24];13(5):291–6. Available from: http://onlinelibrary.wiley.com/doi/10.1111/j.1468-1293.2011.00975.x/abstract
  6. Antiepileptic drugs and agents that inhibit voltage-gated sodium channels prevent NMDA antagonist neurotoxicity. , Published online: 15 August 2002; | doi:101038/sj.mp4001087 [Internet]. 2002 Aug 15 [cited 2013 Aug 24];7(7). Available from: http://www.nature.com/mp/journal/v7/n7/full/4001087a.html
  7. Johannessen CU. Mechanisms of action of valproate: a commentatory. Neurochemistry International [Internet]. 2000 Aug 1 [cited 2013 Aug 24];37(2–3):103–10. Available from: http://www.sciencedirect.com/science/article/pii/S0197018600000139
  8. Wikinski SI, Acosta GB, Rubio MC. Valproic acid differs in its in vitro effect on glutamic acid decarboxylase activity in neonatal and adult rat brain. General Pharmacology: The Vascular System [Internet]. 1996 Jun [cited 2013 Aug 24];27(4):635–8. Available from: http://www.sciencedirect.com/science/article/pii/0306362395020926
  9. Steckert AV, Valvassori SS, Varela RB, Mina F, Resende WR, Bavaresco DV, et al. Effects of sodium butyrate on oxidative stress and behavioral changes induced by administration of d-AMPH. Neurochemistry International [Internet]. 2013 Mar [cited 2013 Aug 24];62(4):425–32. Available from: http://www.sciencedirect.com/science/article/pii/S0197018613000405
  10. Chiechio S, Zammataro M, Morales ME, Busceti CL, Drago F, Gereau RW, et al. Epigenetic Modulation of mGlu2 Receptors by Histone Deacetylase Inhibitors in the Treatment of Inflammatory Pain. Mol Pharmacol [Internet]. 2009 May 1 [cited 2013 Aug 24];75(5):1014–20. Available from: http://molpharm.aspetjournals.org/content/75/5/1014.full.pdf
  11. Chiechio S, Zammataro M, Morales ME, Busceti CL, Drago F, Gereau RW, et al. Epigenetic Modulation of mGlu2 Receptors by Histone Deacetylase Inhibitors in the Treatment of Inflammatory Pain. Mol Pharmacol [Internet]. 2009 May 1 [cited 2013 Aug 24];75(5):1014–20. Available from: http://molpharm.aspetjournals.org/content/75/5/1014.full.pdf
  12. Czapinski P, Blaszczyk B, Czuczwar S. Mechanisms of Action of Antiepileptic Drugs. Current Topics in Medicinal Chemistry [Internet]. 2005 Jan 1 [cited 2013 Aug 24];5(1):3–14. Available from: http://www.eurekaselect.com/79696/article
  13. Grande I, Fries GR, Kunz M, Kapczinski F. The Role of BDNF as a Mediator of Neuroplasticity in Bipolar Disorder. Psychiatry Investig [Internet]. 2010 Dec [cited 2013 Aug 24];7(4):243–50. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3022310/
  14. Yasuda S, Liang M-H, Marinova Z, Yahyavi A, Chuang D-M. The mood stabilizers lithium and valproate selectively activate the promoter IV of brain-derived neurotrophic factor in neurons. Mol Psychiatry [Internet]. 2007 Oct 9 [cited 2013 Aug 24];14(1):51–9. Available from: http://www.nature.com/mp/journal/v14/n1/full/4002099a.html
  15. De Sarno P, Li X, Jope RS. Regulation of Akt and glycogen synthase kinase-3β phosphorylation by sodium valproate and lithium. Neuropharmacology [Internet]. 2002 Dec [cited 2013 Aug 24];43(7):1158–64. Available from: http://www.sciencedirect.com/science/article/pii/S0028390802002150
  16. Venkataramani V, Rossner C, Iffland L, Schweyer S, Tamboli IY, Walter J, et al. Histone Deacetylase Inhibitor Valproic Acid Inhibits Cancer Cell Proliferation via Down-regulation of the Alzheimer Amyloid Precursor Protein. J Biol Chem [Internet]. 2010 Apr 2 [cited 2013 Aug 24];285(14):10678–89. Available from: http://www.jbc.org/content/285/14/10678
  17. Venkataramani V, Rossner C, Iffland L, Schweyer S, Tamboli IY, Walter J, et al. Histone Deacetylase Inhibitor Valproic Acid Inhibits Cancer Cell Proliferation via Down-regulation of the Alzheimer Amyloid Precursor Protein. J Biol Chem [Internet]. 2010 Apr 2 [cited 2013 Aug 24];285(14):10678–89. Available from: http://www.jbc.org/content/285/14/10678
  18. Zhang X-Z, Li X-J, Zhang H-Y. Valproic acid as a promising agent to combat Alzheimer’s disease. Brain Research Bulletin [Internet]. 2010 Jan 15 [cited 2013 Aug 24];81(1):3–6. Available from: http://www.sciencedirect.com/science/article/pii/S0361923009002779

Wednesday, 21 August 2013

D-cycloserine -- An Old Drug Getting A New Life

D-cycloserine is a drug that was once frequently used in the treatment of tuberculosis, nowadays it is less frequently used, probably, in part, due to how rare tuberculosis is nowadays in developed countries like Australia. Nowadays D-cycloserine is generating some interest as a potential treatment for certain psychiatric disorders such as major depressive disorder (MDD) and schizophrenia.1,2 This is because D-cycloserine, much like the non-cyclic form of this amino acid, D-serine, (the related [sort of a mirror image of D-serine] amino acid, L-serine, which is also what the body synthesises D-serine from, is found in animal and vegetable proteins) has been found to bind to the so called glycine site on the NMDA glutamate receptor. The NMDA receptor is one of the receptors for the very important amino acid neurotransmitter, glutamate (also known as glutamic acid). The NMDA receptor primarily serves as an excitatory receptor, that is, it increases the activity of the cells on which it is expressed.

This receptor has been implicated in several of the major psychiatric disorders that have plagued our society for generations such as schizophrenia, bipolar disorder, major depressive disorder and anxiety disorders. In order to be activated, however, the NMDA receptor requires two events to occur simultaneously: the neurotransmitters, glutamate or aspartate (aspartic acid) must bind to the so called glutamate site on the receptor and the neurotransmitter glycine, or similar amino acid neurotransmitters such as D-alanine or D-serine need to bind to the so called glycine site on the receptor. What's so special about D-cycloserine, however, is that it serves as a partial agonist at the glycine site on the NMDA receptor. This means that when it binds to the glycine site, provided glutamate or aspartate is already bound to the glutamate site, a smaller response is seen than if D-serine, D-alanine or glycine had bound to the same glycine site. Hence because the glycine sites on the NMDA receptor are never completely occupied by the glycine, D-serine and the D-alanine obtained from the diet (after some chemical processing) [this is because there are so many NMDA receptors found in the body that it’s impossible for these neurotransmitters to occupy them all] at lower concentrations of D-cycloserine in the blood it (D-cycloserine) occupies the non-occupied glycine sites on the NMDA receptor and hence leads to an overall increase in the activity of the NMDA receptor. At higher concentrations, however, D-cycloserine competes with glycine, D-serine and D-alanine for the binding with the glycine site on the NMDA receptor and hence it displaces some of these amino acid neurotransmitters and hence since it produces a less full response than these amino acid neurotransmitters  it causes a net reduction in NMDA receptor activity.

The way how this relates to psychiatric illnesses like schizophrenia and major depressive disorder is that it is believed that in schizophrenia the NMDA receptor is underactive and hence by potentiating its activity it is hoped that low doses of D-cycloserine (which translates to low concentrations in the blood when the drug is absorbed by the body) may be of therapeutic benefit in patients with schizophrenia. Whereas in major depressive disorder the NMDA receptor is believed to be overactive and drugs that attenuate its activity have been shown to elicit rapid and robust antidepressant effects and hence it is hoped that high doses of D-cycloserine (or high concentrations) might likewise elicit rapid and robust antidepressant effects without some of the psychotomimetic (psychosis [a state characterised by hallucinations, delusions, etc.]-mimicking) effects of NMDA antagonists (blockers) like ketamine.1,2

Its efficacy in treating schizophrenia seems to be very limited, however, probably because the difference between doses that potentiate the activity of the NMDA receptor and doses that inhibit the activity of the NMDA receptor is rather small and the maximum potentiation of NMDA receptor that D-cycloserine is capable of is significantly less than that of glycine site full agonists (compounds that manage [with the help of glutamate/aspartate binding at the glutamate site] to produce full activation of the NMDA receptor) like glycine and hence it is easy to inadvertently give a patient a dose that overall inhibits NMDA activity hence exacerbating the symptoms of schizophrenia.1 

Whereas in treating major depressive disorder D-cycloserine appears to be rather effective, even in previously treatment-resistant cases probably because it’s been discovered that not only do NMDA antagonists produce antidepressant activity but so do NMDA agonists (activators) like glycine and glutamate.2

There is some evidence in rats to suggest that D-cycloserine might be helpful in the treatment of cocaine addiction.3


Reference List:

  1. Goff DC, Cather C, Gottlieb JD, Evins AE, Walsh J, Raeke L, et al. Once-Weekly D-Cycloserine Effects on Negative Symptoms and Cognition in Schizophrenia: An Exploratory Study. Schizophr Res [Internet]. 2008 Dec [cited 2013 Aug 22];106(2-3):320–7. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2628436/
  2. Heresco-Levy U, Gelfin G, Bloch B, Levin R, Edelman S, Javitt DC, et al. A randomized add-on trial of high-dose d-cycloserine for treatment-resistant depression. The International Journal of Neuropsychopharmacology. 2013;16(03):501–6. Available from: http://journals.cambridge.org/action/displayAbstract?fromPage=online&aid=8852104
  3. Thanos PK, Bermeo C, Wang G-J, Volkow ND. D-cycloserine facilitates extinction of cocaine self-administration in rats. Synapse [Internet]. 2011 [cited 2013 Aug 22];65(9):938–44. Available from: http://onlinelibrary.wiley.com/doi/10.1002/syn.20922/abstract

Sunday, 21 July 2013

The 5-HT2C receptor

Interestingly one of the subtype of receptors that the neurotransmitter serotonin binds to and activates, the 5-HT2C receptor (which was once called the 5-HT1C receptor), is found on the X chromosome.1 What this means is that males have one copy of the gene encoding the 5-HT2C receptor, whereas women have two copies of this gene. Practically this means that if there is a defect in the gene that causes less of the 5-HT2C receptor protein (as you may or may not know all receptors are, in fact, proteins) to be synthesised and a man inherits it, he'll suffer more than a women that inherits one copy of the defective gene and one functional 5-HT2C receptor gene on their other X chromosome.

The role of the 5-HT2C receptor is complex. To the cell on which 5-HT2C receptors are expressed they are excitatory – that is, they increase the activity of the cells on which they are expressed. But because there are neurons (the electrically signalling cells of the brain, spinal cord and nerves) that, when excited, release inhibitory neurotransmitters like GABA, 5-HT2C receptors can, in some brain regions, have indirect (i.e. via these inhibitory GABAergic interneurons as they're called) inhibitory functions, that is they can reduce cellular activity in these regions.2

It appears to, via this indirect mechanism, to suppress the release of dopamine and norepinephrine in certain parts of the brain, particularly in the mesolimbic pathway.2-4 Which is a part of the brain from which the rewarding (or pleasurable) effects of recreational drugs, certain behaviours (like gambling) and even food originates from. It has hence been found that 5-HT2C antagonists (or blockers) facilitate the release of dopamine in the mesolimbic pathway induced by drugs of abuse like nicotine, cocaine, morphine and phencyclidine (PCP), hence potentially amplifying their rewarding or pleasurable effects. This is kind of ironic when you think about how patients with schizophrenia have a far higher incidence of substance abuse problems, including tobacco smoking addiction, seeing how many of the newer antipsychotics on the market that are frequently used to treat patients schizophrenia do, in fact, antagonise the 5-HT2C receptor. Albeit they also antagonise a few of the dopamine receptors that are involved in the pleasurable effects of these drugs but seeing how this effect is usually weaker than their inhibitory effects on the 5-HT2C receptor you could make the argument that they likely overall cause an increased liability to amplifying the addictive potential of recreational drugs.5,6

It has also been discovered that 5-HT2C receptors regulate feeding – 5-HT2C antagonists are known to cause an increase in appetite in humans and this can lead to obesity, as is exemplified by the fact that several of the newer antipsychotics like clozapine and olanzapine that antagonise the 5-HT2C receptors lead frequently to weight gain and obesity. Conversely 5-HT2C agonists are known to suppress appetite and the drug lorcaserin was recently approved by the US FDA for the treatment of obesity.

5-HT2C receptors also regulate mood and perception. For instance, the 5-HT2C agonist vabicaserin was being developed as a treatment for schizophrenia, until development was ceased in 2010 for a reason that escapes me. 5-HT2C antagonists display antidepressant activity, with several commercially (or clinically) available antidepressants such as fluoxetine (PROZAC), agomelatine (VALDOXAN), mirtazapine (AVANZA, REMERON), amitriptyline (ELAVIL, ENDEP) and mianserin (LUMIN, TOLVON) displaying clinically-significant affinity towards the receptor as an antagonist.7 It is possible that it is, in part, by antagonising the 5-HT2C receptor that atypical (newer) antipsychotics like olanzapine and aripiprazole that they manage to speed up and improve response rates to antidepressant therapy.7-10

Reference List:

  1. Milatovich A, Hsieh C-L, Bonaminio G, Tecott L, Francke U. Serotonin receptor 1c gene assigned to X chromosome in human (band q24) and mouse (bands D-F4). Hum Mol Genet [Internet]. 1992 Dec 1 [cited 2013 Jul 22];1(9):681–4. Available from: http://hmg.oxfordjournals.org/content/1/9/681
  2. Invernizzi RW, Pierucci M, Calcagno E, Di Giovanni G, Di Matteo V, Benigno A, et al. Selective activation of 5-HT2C receptors stimulates GABA-ergic function in the rat substantia nigra pars reticulata: A combined in vivo electrophysiological and neurochemical study. Neuroscience [Internet]. 2007 Feb 23 [cited 2013 Jul 22];144(4):1523–35. Available from: http://www.sciencedirect.com/science/article/pii/S0306452206015211
  3. Millan M, Dekeyne A, Gobert A. Serotonin (5-HT)2C receptors tonically inhibit dopamine (DA) and noradrenaline (NA), but not 5-HT, release in the frontal cortex in vivo. Neuropharmacology [Internet]. 1998 Jul [cited 2013 Jul 22];37(7):953–5. Available from: http://www.sciencedirect.com/science/article/pii/S0028390898000781
  4. Di Giovanni G, De Deurwaerdére P, Di Mascio M, Di Matteo V, Esposito E, Spampinato U. Selective blockade of serotonin-2C/2B receptors enhances mesolimbic and mesostriatal dopaminergic function: a combined in vivo electrophysiological and microdialysis study. Neuroscience [Internet]. 1999 Jun [cited 2013 Jul 22];91(2):587–97. Available from: http://www.sciencedirect.com/science/article/pii/S0306452298006551
  5. Porras G, Matteo VD, Fracasso C, Lucas G, Deurwaerdère PD, Caccia S, et al. 5-HT2A and 5-HT2C/2B Receptor Subtypes Modulate Dopamine Release Induced in Vivo by Amphetamine and Morphine in Both the Rat Nucleus Accumbens and Striatum. , Published online: 18 July 2001; | doi:101016/S0893-133X(01)00333-5 [Internet]. 2001 Jul 18 [cited 2013 Jul 22];26(3):311–24. Available from: http://www.nature.com/npp/journal/v26/n3/full/1395776a.html
  6. Navailles S, De Deurwaerdère P, Porras G, Spampinato U. In Vivo Evidence that 5-HT2C Receptor Antagonist but not Agonist Modulates Cocaine-Induced Dopamine Outflow in the Rat Nucleus Accumbens and Striatum. Neuropsychopharmacology [Internet]. 2003 Oct 15 [cited 2013 Jul 22];29(2):319–26. Available from: http://www.nature.com/npp/journal/v29/n2/full/1300329a.html
  7. Jenck F, Moreau J-L, Mutel V, Martin JR, Haefely WE. Evidence for a role of 5-HT1C receptors in the antiserotonergic properties of some antidepressant drugs. European Journal of Pharmacology [Internet]. 1993 Feb 9 [cited 2013 Jul 22];231(2):223–9. Available from: http://www.sciencedirect.com/science/article/pii/001429999390453O
  8. Dolder CR, Nelson M, Snider M. Agomelatine Treatment of Major Depressive Disorder. Annals of Pharmacotherapy. 2008 Nov 18;42(12):1822–31.
  9. Jenck F, Moreau J-L, Mutel V, Martin JR. Brain 5-HT1C receptors and antidepressants. Progress in Neuro-Psychopharmacology and Biological Psychiatry [Internet]. 1994 May [cited 2013 Jul 22];18(3):563–74. Available from: http://www.sciencedirect.com/science/article/pii/0278584694900132
  10. Jenck F, Bös M, Wichmann J, Stadler H, Martin J, Moreau J. The role of 5ht2c receptors in affective disorders. Expert Opinion on Investigational Drugs [Internet]. 1998 Oct [cited 2013 Jul 22];7(10):1587–99. Available from: http://informahealthcare.com/doi/abs/10.1517/13543784.7.10.1587


Saturday, 20 July 2013

Varenicline

Varenicline (CHANTIX, CHAMPIX) is the name of a popular, and, according to a few clinical trials, most of which were funded by Pfizer -- the pharmaceutical company sponsoring the development and profiting from the sales of the drug, an effective smoking cessation aid (i.e. a drug designed to help people quit smoking).1

A more impartial source (albeit since the bulk of the clinical trial data they would have analysed would be from Pfizer-funded trials it is impossible to say that it would get unbiased results), the Cochrane collaboration (which performs statistical analysis of available clinical trial data) demonstrated that it was more effective than a placebo and that it was more effective than the smoking cessation aid bupropion (WELLBUTRIN, ZYBAN), and while statistical significance wasn't reached there was a trend in this meta-analysis (statistical analysis) that favoured varenicline over nicotine replacement therapy (NRT; this is where attempts are made to replace the nicotine a smoker would normally get by smoking they get via less dangerous and less addicting ways like nicotine patches and gum). What this means is that the data we have comparing varenicline with NRT isn't strong enough to rule out the possibility of a coincidence occurring in the trials comparing the efficacy of NRT with that of varenicline that so happened to favour varenicline over NRT2

It works by serving as a partial agonist at the α4β2 subtype of nicotinic acetylcholine receptors (nAChR). To explain what this means I need to teach you a little bit about the nicotinic acetylcholine receptors.

nAChRs are receptors that are found throughout the central and peripheral nervous systems (explained in the sentence after next). The term acetylcholine refers to the fact that these receptors are activated by the body-synthesised neurotransmitter (chemical messenger between the electrically-signalling cells of the peripheral and central nervous systems), acetylcholine, which the body synthesises from choline – a member of the B group of essential vitamins.

In the central nervous system (CNS; brain and spinal cord) nAChRs are found in a number of places, particularly in the regions of the brain involved in reward (like where the rewarding, or pleasurable, effects of recreational drugs originate), wakefulness, sensory perception, memory, learning and mood. In the peripheral nervous system (PNS; the nerves we all use to sense pain, pressure, temperature, etc. and to control our voluntary and involuntary movements) they regulate muscular activity, both voluntary and involuntary, as is exemplified by the fact that the muscle relaxants often used to prevent twitching/shivering during surgeries and also in the lethal injection to stop breathing work by blocking certain peripheral nAChRs. Some nAChRs are also found on the vagus nerve (a nerve that goes directly from the brain down through much of the torso) where they appear to regulate immune function.3,4

Another fact about the nAChRs is that they are made out of subunits, which you could think of as the building blocks the receptor. These subunits are designated a Greek letter (e.g. α) and a number (e.g. 4), e.g. one subunit is called the α4 subunit based on this. Each receptor must contain a total of exactly five subunits in order for it to be functional (i.e. for it to actually work); for α4β2 nAChRs there are 2 α4 and 3 β2 subunits found in each receptor.

Varenicline binds to the α4β2 nAChRs and activates them, but it does so less “fully” or strongly than acetylcholine does, and this is why we call it a partial agonist at this receptor. α4β2 nAChRs are expressed solely in the CNS where they regulate the release of neurotransmitters including those involved in reward and hence the euphoric effects of many drugs (e.g. dopamine and β-endorphin would be examples of such neurotransmitters) and it is via this action that α4β2 nAChRs, when activated, produce euphoric (or rewarding) effects. It is believed that it is via these receptors that nicotine produces much of its rewarding and hence addictive effects.5 Varenicline, by serving as a partial agonist, it is able to antagonise (block or prevent) the increase in nAChR activity triggered by nicotine because it binds to the same site on the α4β2 nAChRs as nicotine hence preventing nicotine from binding to said site and hence preventing it from inducing many of its effects, including the rewarding effects it produces that leads to addiction. Simultaneously, via its ability to “partially” activate the α4β2 nAChRs it is able to reduce nicotine cravings by mimicking nicotine’s effects on dopamine and β-endorphin release, just to a lesser extent. Hence it is able to both block the rewarding effects of nicotine while simultaneously reducing cravings, and perhaps other symptoms characteristic of nicotine withdrawal.


For the past few years questions have been raised regarding the safety of varenicline, amidst reports of suicidal ideation (thinking about suicide) and cardiovascular (pertaining to the heart and blood vessels; e.g. myocardial infarctions [heart attacks]) adverse effects in patients receiving varenicline as a smoking cessation aid. The risks of both these types of adverse effects appears to be quite small, with mostly just those with pre-existing psychiatric or cardiovascular conditions, respectively, afflicted by such adverse effects.6 Despite these reports that varenicline can cause suicidality (even though depression does not strike me as a particularly unusual problem for people that by definition are trying to kick such an addictive habit) there is some evidence from tests on mice that suggests that it might have antidepressant effects, likewise, in mice, it was also found to potentiate the antidepressant effects of the popular, Therapeutic Goods Administration (TGA)-approved antidepressant, sertraline (ZOLOFT).7

Varenicline also serves as a full agonist at the α7 subtype of nAChRs, i.e. it activates the receptor to the same extent as acetylcholine, and since the α7 nAChRs appears to be heavily involved in memory and learning it may have some positive effects on the aforementioned functions. Varenicline also activates the 5-HT3 receptor,8 which might be responsible for its high propensity for causing nausea (approximately 50% of patients treated with varenicline experience nausea).6

References

  1. Jorenby DE, Hays J, Rigotti NA, et al. Efficacy of varenicline, an α4β2 nicotinic acetylcholine receptor partial agonist, vs placebo or sustained-release bupropion for smoking cessation: A randomized controlled trial. JAMA [Internet]. 2006 Jul 5 [cited 2013 Jul 21];296(1):56–63. Available from: http://dx.doi.org/10.1001/jama.296.1.56
  2. Cahill K, Stead LF, Lancaster T. Nicotine receptor partial agonists for smoking cessation. Cochrane Database of Systematic Reviews [Internet]. John Wiley & Sons, Ltd; 2013 [cited 2013 Jul 21]. Available from: http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD006103.pub6/abstract
  3. De Jonge WJ, Ulloa L. The alpha7 nicotinic acetylcholine receptor as a pharmacological target for inflammation. Br J Pharmacol [Internet]. 2007 Aug [cited 2013 Jul 21];151(7):915–29. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2042938/
  4. Van der Zanden EP, Snoek SA, Heinsbroek SE, Stanisor OI, Verseijden C, Boeckxstaens GE, et al. Vagus Nerve Activity Augments Intestinal Macrophage Phagocytosis via Nicotinic Acetylcholine Receptor α4β2. Gastroenterology [Internet]. 2009 Sep [cited 2013 Jul 21];137(3):1029–1039.e4. Available from: http://www.gastrojournal.org/article/S0016-5085(09)00737-9/abstract?referrer=http://www.ncbi.nlm.nih.gov/pubmed/19427310
  5. Albuquerque EX, Pereira EFR, Alkondon M, Rogers SW. Mammalian Nicotinic Acetylcholine Receptors: From Structure to Function. Physiol Rev [Internet]. 2009 Jan 1 [cited 2013 Jul 21];89(1):73–120. Available from: http://physrev.physiology.org/content/89/1/73.full.pdf
  6. Truven Health Analytics, Inc. DRUGDEX® System (Internet) [cited 2013 Jul 21]. Greenwood Village, CO: Thomsen Healthcare; 2013.
  7. Rollema H, Guanowsky V, Mineur YS, Shrikhande A, Coe JW, Seymour PA, et al. Varenicline has antidepressant-like activity in the forced swim test and augments sertraline’s effect. European Journal of Pharmacology [Internet]. 2009 Mar 1 [cited 2013 Jul 21];605(1–3):114–6. Available from: http://www.sciencedirect.com/science/article/pii/S0014299909000302
  8. Lummis SCR, Thompson AJ, Bencherif M, Lester HA. Varenicline Is a Potent Agonist of the Human 5-Hydroxytryptamine3 Receptor. J Pharmacol Exp Ther [Internet]. 2011 Oct [cited 2013 Jul 21];339(1):125–31. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3186289/pdf/zpt125.pdf

Sunday, 14 July 2013

PDE4 inhibitors and their potential applications in the treatment of a variety of conditions

Note: Terms that are not explained in the body are explained in a Glossary near the end (before the references) of the post.

The enzyme phosphodiesterase 4 (PDE4) is an emerging drug target in the management of psychiatric, neurologic, immune and inflammatory disorders such as major depressive disorder1 (MDD), schizophrenia1, Alzheimer’s disease1 (AD), chronic obstructive pulmonary disease2 (COPD) and multiple sclerosis (MS). The drugs being developed to target PDE4 all inhibit the aforementioned enzyme – that is they reduce the activity of the PDE4 and this is how they elicit their therapeutic effects. These drugs are called the PDE4 inhibitors. In order to explain just how PDE4 inhibition leaves these drugs open to being used in the management of the aforementioned conditions I need to first explain the role of PDE4 in cells.

PDE4 belongs to a group of enzymes called the cyclic nucleotide phosphodiesterases which catalyse (or help) the reactions involved in the breakdown of cyclic nucleotides, which includes two chemical messengers that are of particular biologic significance – cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). These messengers are also referred to as second messengers. This is because when some G protein-coupled receptors (GPCRs; which are usually expressed on a cell’s surface) are activated these second messengers relay their respective signals to the inner components of the cell. Hence drugs that inhibit cyclic nucleotide phosphodiesterases are able to produce many of the same effects as drugs that directly interact with these G protein-coupled receptors on the cell surface. Not all GPCRs transmit their signals by increasing intracellular (inside the cell) concentrations of cyclic nucleotides, some, upon activation, decrease intracellular cyclic nucleotide concentrations and these receptors include, among numerous others, the dopamine, D2, family of receptors (D2, D3, D4).1

The different phosphodiesterases, however, do have different respective affinities towards the different cyclic nucleotides and hence the cyclic nucleotide(s) that PDE4 prefers to (or has a higher affinity to) degrade is relevant and is cAMP. Hence PDE4 inhibitors increase intracellular cAMP levels and since PDE4 is found in virtually every organ system of the body it increases intracellular cAMP levels throughout the body.1

The interesting thing about PDE4 inhibitors is that they also elicit very potent anti-inflammatory effects and they also elicit antidepressant effects, which would appear to be in agreement with the inflammatory hypothesis of depression. Although this could very easily a coincidence seeing how cAMP is a very common second messenger throughout the body and it is well known that serotonin is heavily involved in mood regulation, as is glutamate (I know this one is a lesser known neurotransmitter as far as its role in depression but ketamine, the anaesthetic turned rapid-acting and robust antidepressant acts on the glutamate receptors to elicit its effects and hence this is also a popular theory for the cause of depression) and norepinephrine (noradrenaline) and a few of the receptors for all three of these neurotransmitters use cAMP as their second messengers and hence by inhibiting PDE4 and raising cAMP levels it is entirely possible that it mimics the effects of those these neurotransmitters in the central nervous system (CNS).

Another thing that PDE4 inhibitors do that they share with all other antidepressants is that they promote neurogenesis and exert neuroprotective effects – that is, they induce the formation of new neurons and have protective effects on existing neurons, respectively. They also seem to induce long-term potentiation, the process by which the signalling between two neurons is enhanced in a long-lasting fashion.

PDE4 inhibitors also possess antipsychotic activity which may be related to the fact that the D2 family of receptors – which thing all antipsychotics in clinical use block – are G­i/o protein-coupled and hence inhibit the formation of cAMP. Hence by blocking them antipsychotics increase cAMP synthesis in cells that express the D2 family of receptors. Plus they also appear to interact with the metabotropic glutamate receptors which regulate the release of the neurotransmitter glutamate, which also appears to play a key role in schizophrenia. In fact until mid-last year it appeared that soon a drug that directly acted on two types of metabotropic glutamate receptor (mGluR 2 and 3) would soon be FDA approved for the treatment of schizophrenia as it showed promise in early clinical testing in the treatment of this indication. The serotonin 5-HT1A receptor has also been found to be involved in the antipsychotic action of some TGA and FDA approved antipsychotics and it also couples to a Gi/o protein.5-6

Currently there is only one PDE4 inhibitor that has received FDA and TGA approval – Roflumilast. It received TGA approval in November 2011 (see http://www.tga.gov.au/pdf/auspar/auspar-daxas.pdf for details) for the treatment of severe COPD, specifically chronic bronchitis. Roflumilast is, from what I have read on Micromedex, a rather well-tolerated drug, that is, its side effects are rather mild and rare, for the most part at least (it has been found to cause suicidal ideation – thinking about suicide – which is its only particularly worrying side effect). According to Micromedex aside from suicidal ideation it has the following side effects:7
  • weight decreased (7% to 20% ) 
  • Decrease in appetite (2.1% ) 
  • Diarrhoea (9.5% ) 
  • Nausea (4.7% ) 
  • Influenza (2.8% ) 
  • Backache (3.2% ) 
  • Dizziness (2.1% ) 
  • Headache (4.4% ) 
  • Insomnia (2.4% )
(with their respective incidence in brackets)
The side effect of influenza is particularly worrying to me, considering the fact that patients with COPD are particularly vulnerable to respiratory infections like influenza. It is also interesting because PDE4 inhibitors have also been found to reduce innate immunity – the first line of the body’s immune defences where the second-line is the more specific (to the microbe, that is) line of immunity, which also recognises prior bugs encountered by the body’s defenses8-10 which would explain an increased susceptibility of PDE4 inhibitor-treated individuals to common infections such as the flu.

Most of the original PDE4 inhibitors to be developed, such as rolipram, had one side effect in particular that limited their clinical utility – severe emesis. Despite this side effect it turns out that some South African individuals have been using a PDE4 inhibitor-containing plant for its antidepressant effects for centuries – the kanna plant. This plant contains mesembrenone, among other alkaloids which display PDE4 inhibitory effects.

Glossary

Central Nervous System (CNS) – the brain and spinal cord.
Chronic Obstructive Pulmonary Disease (COPD) – a collection of progressive, disabling, incurable and often, with time, fatal lung diseases that cause a progressive deterioration in lung function. They include emphysema, chronic bronchitis and even some cases of asthma. They are normally associated with smoking.  
Emesis – nausea and vomiting.
Endogenous Ligand – a ligand for a particular receptor
Enzyme – an enzyme is a chemical catalyst in reactions, that is, they serve to increase the rate of a chemical reaction despite not being directly involved in the reaction. By directly it is meant that the enzyme is not transformed by the chemical reaction, or used up by the reaction.
Extracellular – outside cells.
Intracellular – inside cells.
Ligand – a compound that binds to its respective receptor (for which it is a ligand). Agonists are a type of ligand that activate the receptor whereas antagonists do not activate the receptor but rather prevent agonists from activating the receptor.
Neuron – electrically-signalling cells of the brain, spinal cord and nerves.
Receptor – receptors are proteins that, upon the binding of an agonist, cause the modulation of cellular functions. G protein-coupled receptors (GPCR) are receptors that are bound to G proteins, which in turn, upon binding by an agonist to the receptor, set off a series of chemical reactions that alter the functioning of a cell. The Gi/o protein is a G protein that when the receptor it is coupled with is activated (and hence it is too as this is the purpose of coupling between receptor and G proteins) it inhibits adenylate cyclase – the enzyme responsible for the formation of cAMP, from the energy source of cells, adenosine triphosphate (ATP). Likewise the Gs protein is a G protein that enhances adenylate cyclase activity upon its activation.

Reference List

  1. Halene TB, Siegel SJ. PDE inhibitors in psychiatry – future options for dementia, depression and schizophrenia? Drug Discovery Today [Internet]. 2007 Oct [cited 2013 Jul 12];12(19–20):870–8. Available from: http://www.sciencedirect.com/science/article/pii/S1359644607003066
  2. Spina D. PDE4 inhibitors: current status. Br J Pharmacol [Internet]. 2008 Oct [cited 2013 Jul 12];155(3):308–15. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2567892/
  3. Boswell-Smith V, Spina D, Page CP. Phosphodiesterase inhibitors. Br J Pharmacol [Internet]. 2006 Jan [cited 2013 Jul 12];147(Suppl 1):S252–S257. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1760738/
  4. Barad M, Bourtchouladze R, Winder DG, Golan H, Kandel E. Rolipram, a type IV-specific phosphodiesterase inhibitor, facilitates the establishment of long-lasting long-term potentiation and improves memory. Proc Natl Acad Sci U S A [Internet]. 1998 Dec 8 [cited 2013 Jul 12];95(25):15020–5. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC24568/
  5. Bantick RA, Deakin JFW, Grasby PM. The 5-HT1A receptor in schizophrenia: a promising target for novel atypical neuroleptics? J Psychopharmacol [Internet]. 2001 Jan 1 [cited 2013 Jul 14];15(1):37–46. Available from: http://jop.sagepub.com/content/15/1/37
  6. Ohno Y. Therapeutic Role of 5-HT1A Receptors in The Treatment of Schizophrenia and Parkinson’s Disease. CNS Neuroscience & Therapeutics [Internet]. 2011 [cited 2013 Jul 14];17(1):58–65. Available from: http://onlinelibrary.wiley.com/doi/10.1111/j.1755-5949.2010.00211.x/abstract
  7. Truven Health Analytics, Inc. DRUGDEX® System (Internet) [cited 2013 Jul 14]. Greenwood Village, CO: Thomsen Healthcare; 2013.
  8. Koo M-S, Manca C, Yang G, O’Brien P, Sung N, Tsenova L, et al. Phosphodiesterase 4 Inhibition Reduces Innate Immunity and Improves Isoniazid Clearance of Mycobacterium tuberculosis in the Lungs of Infected Mice. PLoS ONE [Internet]. 2011 Feb 25 [cited 2013 Jul 14];6(2):e17091. Available from: http://dx.doi.org/10.1371/journal.pone.0017091
  9. Sadrai Z, Stevenson W, Okanobo A, Chen Y, Dohlman TH, Hua J, et al. PDE4 Inhibition Suppresses IL-17–Associated Immunity in Dry Eye Disease. IOVS [Internet]. 2012 Jun 1 [cited 2013 Jul 14];53(7):3584–91. Available from: http://www.iovs.org/content/53/7/3584
  10. Serezani CH, Ballinger MN, Aronoff DM, Peters-Golden M. Cyclic AMP. Am J Respir Cell Mol Biol [Internet]. 2008 Aug [cited 2013 Jul 14];39(2):127–32. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2720142/

Wednesday, 10 July 2013

The Obesity Pandemic: What can be done?

The statistics on obesity are just frightening... according to the World Health Organisation (WHO) in 2010 the following is true regarding individuals over the age of 15:

Country
% Population that are Overweight (BMI>25)
% Population that are Obese (BMI>30)

Females
Males
Females
Males
Australia
66.5
75.7
29.1
28.4
Japan
16.2
29.8
1.1
2.3
South Africa
68.5
41.3
36.8
7.6
United Kingdom
63.8
67.8
26.3
23.7
United States
76.7
80.5
48.3
44.2

A healthy BMI is between 18.5 and 25. A person is usually called overweight if their BMI is >25. Usually a BMI of >30 is considered obese. However, I should probably state that this model does not take into consideration their tissue type, i.e. whether their weight is mostly due to adipose tissue (i.e. fat) or muscle.
If you would like to see more stats on the subject you can go to https://apps.who.int/infobase/Comparisons.aspx.

These statistics are worrying considering the detrimental health effects of obesity. Obese individuals are approximately 40% more likely to develop cardiovascular disease, and substantially more likely to develop a variety of cancers including oesophageal, pancreatic, colorectal, breast, endometrial, kidney, thyroid and gallbladder cancers and substantially more likely to develop type II diabetes mellitus.1-4 In one study men with a BMI of >35 had a 42 fold higher risk of developing type II diabetes mellitus.5 These risks are not all those that have come to light in recent years with dementia and multiple sclerosis, among other conditions, being more common among the obese.4,6,7

I personally see obesity as an addiction, an addiction to simple sugars like fructose, glucose, sucrose and to unhealthy fats like saturated and transunsaturated fats. Treatments for this addiction include drugs that suppress appetite (e.g. bupropion [ZYBAN], atomoxetine [STRATTERA], modafinil [PROVIGIL], naltrexone [REVIA], lorcaserin [BELVIQ], sibutramine [MERIDIA; withdrawn from the market due to safety concerns], amfepramone [BONTRIL], topiramate [TOPAMAX], phentermine [ADIPEX-P], rimonabant [ACOMPLIA; now withdrawn from the market due to safety concerns], fenfluramine [along with phentermine it formed the famous dieting medication FEN-PHEN which has now been withdrawn from the market due to safety concerns] etc.) and drugs that prevent the metabolism of dietary fats by the body (e.g. orlistat [ALLI]). Plus there is substituting unhealthy flavourings (e.g. simple sugars) with healthy flavourings like artificial sweeteners or natural sweeteners.

Of course there is the age-old technique of dieting and exercise, but in my opinion these methods are rather ineffective in the long-run due to the fact that obesity is an addiction and as with people telling an addict to change it just does not work regardless of how much knowledge of the consequences they have. I do believe that people can overcome addictions cold turkey (or via dieting and exercising in the case of obesity) if they are given real motivation to do so, perhaps by their habit threatening to harm those they care about and hence this might give them sufficient motivation for dieting and exercise to work. Since I like to talk about drugs, however, I am going to devote a great deal of this post to talking about the drugs used to combat obesity.

Bupropion, atomoxetine and modafinil are sometimes used off-label (i.e. the US FDA and the Australian TGA has not approved either drug for this use) to treat obesity, probably due to their stimulant effects. See drugs that serve as stimulants (i.e. drugs that promote wakefulness, alertness and generally stimulate brain activity. This includes illicit stimulants like methamphetamine, amphetamine, methylphenidate [RITALIN], etc) nearly always have additional appetite-supressing effects and the same is true with these three drugs. Bupropion is traditionally used to treat depression or help people quit smoking and it works by raising the levels of norepinephrine (or noradrenaline) and dopamine in the body, this includes the hypothalamus which is a part of the brain that, among other things, regulates feeding behaviour. Likewise atomoxetine is normally used to treat attention deficit hyperactivity disorder (ADHD) but it also elevates central nervous system (CNS; brain and spinal cord) levels of norepinephrine (while having minimal effects on dopamine concentrations in the CNS) including in the hypothalamus. Modafinil on the other hand is normally used to treat sleep disorders like narcolepsy and works primarily by increasing CNS concentrations of dopamine while also altering the actions of other neurotransmitters in the brain and spinal cord. These three drugs are reuptake inhibitors of these two neurotransmitters which means in effect they prevent the “leakage” of these neurotransmitters from the gap between neurons (electrically signalling brain, spinal cord and nerve cells) which is also known as the synaptic cleft, across which they are used as chemical messengers between neurons (the electrically signalling cells of the brain, spinal cord and nerves).  

Amfepramone (or diethylpropion) is also a stimulant drug but is different in that it is converted by the body into ethcathinone which is a releasing agent of norepinephrine (in contrast to reuptake inhibitors releasing agents just cause neurons to release more of the respective neurotransmitter [in this case norepinephrine] into the synaptic cleft) which is something the stimulant amphetamine does, but unlike amphetamine it has minimal effects on dopamine and serotonin release, hence limiting its potential for causing addiction (since dopamine is associated with the euphoria recreational drugs create and hence are implicated in how they cause addiction). Amfepramone is also unique compared to the aforementioned three stimulants in that it is actually FDA and TGA approved for weight loss.

Sibutramine is similar to atomoxetine in that it increases brain concentrations of norepinephrine by inhibiting its reuptake. It has been withdrawn from the market, however, amidst concerns it can cause cardiovascular disease in susceptible individuals.8

The mechanism via which topiramate manages to promote weight loss is not unclear, but it is known that it promotes satiety (i.e. not eating) by supressing appetite.9

Phentermine and fenfluramine also work via serving as stimulants hence promoting satiety.

Naltrexone on the other hand is a drug used to treat opioid dependence (i.e. addiction to opioids like heroin, oxycodone, etc.). Naltrexone is currently being investigated, when combined with bupropion that is, for its ability to reduce body weight in obese patients. Naltrexone when used by itself has inconsistently (i.e. some clinical trials have failed to demonstrate any benefit of it in the indication of weight loss) been found to cause some weight loss with some evidence indicating that the weight-loss it encourages is more prominent in females. It is believed its beneficial effects on weight are due to its ability to block the opioid receptors of the central nervous system which are involved in reward, perhaps including the rewarding effects of eating.10

Rimonabant, however, was quite a promising appetite-suppressant until it was withdrawn from the market in late 2008. It worked by blocking the first cannabinoid receptor, which is the receptor that cannabis, by stimulating, manages to elicit its appetite-stimulating effects. Unfortunately, however, by blocking this receptor it caused a number of patients to become depressed even to the point of suicide.11,12 It was promising in a number of ways, including that it managed to improve insulin sensitivity, and hence might afford protection against the metabolic consequences of obesity.

Lorcaserin is a member of a new class of weight loss medications with, hopefully, a more favourable side effect profile. It works, or so we believe, by activating the 5-HT2C receptor which, among other things, appears to regulate feeding behaviour. The 5-HT2C receptor may also be a promising as a target for drug abuse disorders like cocaine dependence. This is due to the fact that it reduces the concentrations of dopamine in the mesolimbic pathway which is also known as the “reward pathway”. Increases in dopamine in the mesolimbic pathway are directly associated with the rewarding effect of drugs of abuse like cocaine,13 and interestingly, even fructose.14 Unfortunately, however, in diabetic individuals lorcaserin has been linked to hypoglycaemia – low blood sugar, which can be fatal if not promptly treated.15 Since over-functioning of the mesolimbic pathway has also been associated with schizophrenia it was hoped that another 5-HT2C agonist (activator) vabicaserin might possess antipsychotic effects, which thing was confirmed by one clinical trial (the reason why it is no longer being pursued as a treatment for schizophrenia is a mystery to me).16

Orlistat on the other hand is a drug that inhibits pancreatic lipases which are enzymes that the body uses to metabolise dietary fats into things it can use. By inhibiting pancreatic lipases the body is left with no choice but to leave dietary fats in the stool which is why a well-known side effect of orlistat is that it causes loose, oily and foul-smelling stools. It is the only pharmaceutical weight loss drug that I am aware of that is over the counter in many countries. Orlistat also appears capable of reducing the incidence of diabetes in the obese.17

Some have also suggested that banning processed sugars from our food would reduce the incidence of obesity and while it sounds perfect on paper in practice it is less so seeing how prohibition of drugs that the public are already addicted to or accustomed to normally results in nothing of any benefit considering the fact that when America tried this in the 20s and 30s with the prohibition of alcohol and while the availability of alcohol was unchanged because alcohol production and distribution had fallen into the black market organised crime was profiting from the law and this saw the uprising of organised crime in America. Plus I personally do not see any sizeable benefit that would come from banning sugar since as is seen in countries with a high religious anti-drug presence, such as Saudi Arabia, when one (or in the case of Saudi several) substance of abuse is stamped out what remains that has a potential for abuse (in the case of Saudi this is unhealthy food, seeing how obesity is very common there) is abused more than prior to the prohibition.18 People with an addiction are born, often, with an predisposition towards addiction, sort of like a gap if you would that they feel the need to fill with something, be that drugs, be that unhealthy foods, be that alcohol, etc. and if you take away one substance of abuse they will substitute it with something else.

Reference List

  1. Hubert HB, Feinleib M, McNamara PM, Castelli WP. Obesity as an independent risk factor for cardiovascular disease: a 26-year follow-up of participants in the Framingham Heart Study. Circulation [Internet]. 1983 May 1 [cited 2013 Jul 9];67(5):968–77. Available from: http://circ.ahajournals.org/content/67/5/968
  2. Kruijsdijk RCM van, Wall E van der, Visseren FLJ. Obesity and Cancer: The Role of Dysfunctional Adipose Tissue. Cancer Epidemiol Biomarkers Prev [Internet]. 2009 Oct 1 [cited 2013 Jul 9];18(10):2569–78. Available from: http://cebp.aacrjournals.org/content/18/10/2569
  3. Mokdad AH FE. Prevalence of obesity, diabetes, and obesity-related health risk factors, 2001. JAMA [Internet]. 2003 Jan 1 [cited 2013 Jul 9];289(1):76–9. Available from: http://dx.doi.org/10.1001/jama.289.1.76
  4. Haslam DW, James WPT. Obesity. The Lancet [Internet]. 1 [cited 2013 Jul 9];366(9492):1197–209. Available from: http://www.sciencedirect.com/science/article/pii/S0140673605674831
  5. Chan JM, Rimm EB, Colditz GA, Stampfer MJ, Willett WC. Obesity, Fat Distribution, and Weight Gain as Risk Factors for Clinical Diabetes in Men. Dia Care [Internet]. 1994 Sep 1 [cited 2013 Jul 9];17(9):961–9. Available from: http://care.diabetesjournals.org/content/17/9/961
  6. Munger KL, Chitnis T, Ascherio A. Body size and risk of MS in two cohorts of US women. Neurology [Internet]. 2009 Nov 10 [cited 2013 Jul 9];73(19):1543–50. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2777074/
  7. Beydoun MA, Beydoun HA, Wang Y. Obesity and central obesity as risk factors for incident dementia and its subtypes: a systematic review and meta-analysis. Obesity Reviews [Internet]. 2008 [cited 2013 Jul 9];9(3):204–18. Available from: http://onlinelibrary.wiley.com/doi/10.1111/j.1467-789X.2008.00473.x/abstract
  8. Scheen AJ. Sibutramine on Cardiovascular Outcome. Diabetes Care [Internet]. 2011 Apr 27 [cited 2013 Jul 9];34(Supplement_2):S114–S119. Available from: http://care.diabetesjournals.org/content/34/Supplement_2/S114.full.pdf
  9. Verrotti A, Scaparrotta A, Agostinelli S, Di Pillo S, Chiarelli F, Grosso S. Topiramate-induced weight loss: A review. Epilepsy Research [Internet]. 2011 Aug [cited 2013 Jul 9];95(3):189–99. Available from: http://www.epires-journal.com/article/S0920-1211(11)00134-3/abstract
  10. Ornellas T, Chavez B. Naltrexone SR/Bupropion SR (Contrave). P T [Internet]. 2011 May [cited 2013 Jul 9];36(5):255–62. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3138366/
  11. Stapleton JA. [Commentary] TRIAL COMES TOO LATE AS PSYCHIATRIC SIDE EFFECTS END HOPE FOR RIMONABANT. Addiction [Internet]. 2009 [cited 2013 Jul 9];104(2):277–8. Available from: http://onlinelibrary.wiley.com/doi/10.1111/j.1360-0443.2008.02487.x/abstract
  12. Topol EJ, Bousser M-G, Fox KA, Creager MA, Despres J-P, Easton JD, et al. Rimonabant for prevention of cardiovascular events (CRESCENDO): a randomised, multicentre, placebo-controlled trial. The Lancet [Internet]. 14 [cited 2013 Jul 9];376(9740):517–23. Available from: http://www.sciencedirect.com/science/article/pii/S014067361060935X
  13. Bubar M, Cunningham K. Serotonin 5-HT2A and 5-HT2C Receptors as Potential Targets for Modulation of Psychostimulant Use and Dependence. Current Topics in Medicinal Chemistry [Internet]. 2006 Sep 1 [cited 2013 Jul 9];6(18):1971–85. Available from: http://www.eurekaselect.com/77101/article
  14. Bernal SY, Dostova I, Kest A, Abayev Y, Kandova E, Touzani K, et al. Role of dopamine D1 and D2 receptors in the nucleus accumbens shell on the acquisition and expression of fructose-conditioned flavor–flavor preferences in rats. Behavioural Brain Research [Internet]. 2008 Jun 26 [cited 2013 Jul 9];190(1):59–66. Available from: http://www.sciencedirect.com/science/article/pii/S0166432808000788
  15. Truven Health Analytics, Inc. DRUGDEX® System (Internet) [cited 2013 Jul 10]. Greenwood Village, CO: Thomsen Healthcare; 2013.
  16. Shen JHQ, Zhao Y, Rosenzweig-Lipson S, Popp D, Williams JBW, Giller E, Detke MJ, Kane J. A 6-week Randomized, Double-Blind, Placebo-Controlled, Comparator Referenced, Multicenter Trial of Vabicaserin in Subjects with Acute Exacerbation of Schizophrenia. Neuropsychopharmacology [Internet]. 2011 Dec 5 [cited 2013 Jul 10];36(60):S75–S197. Available from: http://www.nature.com/npp/journal/v36/n1s/full/npp2011291a.html
  17. Torgerson JS, Hauptman J, Boldrin MN, Sjöström L. XENical in the Prevention of Diabetes in Obese Subjects (XENDOS) Study A randomized study of orlistat as an adjunct to lifestyle changes for the prevention of type 2 diabetes in obese patients. Dia Care [Internet]. 2004 Jan 1 [cited 2013 Jul 10];27(1):155–61. Available from: http://care.diabetesjournals.org/content/27/1/155.full.pdf
  18. Kim KH, Sobal J, Wethington E. Religion and body weight. Int J Obes Relat Metab Disord [Internet]. 2003 [cited 2013 Jul 9];27(4):469–77. Available from: http://www.nature.com/ijo/journal/v27/n4/full/0802220a.html