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Nature reviews drug discovery august 2010 vol 9 no 8 by Prof. Yasser Alaa
Nature reviews drug discovery august 2010 vol 9 no 8 by Prof. Yasser Alaa
Nature reviews drug discovery august 2010 vol 9 no 8 by Prof. Yasser Alaa
Nature reviews drug discovery august 2010 vol 9 no 8 by Prof. Yasser Alaa
Nature reviews drug discovery august 2010 vol 9 no 8 by Prof. Yasser Alaa
Nature reviews drug discovery august 2010 vol 9 no 8 by Prof. Yasser Alaa
Nature reviews drug discovery august 2010 vol 9 no 8 by Prof. Yasser Alaa
Nature reviews drug discovery august 2010 vol 9 no 8 by Prof. Yasser Alaa
Nature reviews drug discovery august 2010 vol 9 no 8 by Prof. Yasser Alaa
Nature reviews drug discovery august 2010 vol 9 no 8 by Prof. Yasser Alaa
Nature reviews drug discovery august 2010 vol 9 no 8 by Prof. Yasser Alaa
Nature reviews drug discovery august 2010 vol 9 no 8 by Prof. Yasser Alaa
Nature reviews drug discovery august 2010 vol 9 no 8 by Prof. Yasser Alaa
Nature reviews drug discovery august 2010 vol 9 no 8 by Prof. Yasser Alaa
Nature reviews drug discovery august 2010 vol 9 no 8 by Prof. Yasser Alaa
Nature reviews drug discovery august 2010 vol 9 no 8 by Prof. Yasser Alaa
Nature reviews drug discovery august 2010 vol 9 no 8 by Prof. Yasser Alaa
Nature reviews drug discovery august 2010 vol 9 no 8 by Prof. Yasser Alaa
Nature reviews drug discovery august 2010 vol 9 no 8 by Prof. Yasser Alaa
Nature reviews drug discovery august 2010 vol 9 no 8 by Prof. Yasser Alaa
Nature reviews drug discovery august 2010 vol 9 no 8 by Prof. Yasser Alaa
Nature reviews drug discovery august 2010 vol 9 no 8 by Prof. Yasser Alaa
Nature reviews drug discovery august 2010 vol 9 no 8 by Prof. Yasser Alaa
Nature reviews drug discovery august 2010 vol 9 no 8 by Prof. Yasser Alaa
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Nature reviews drug discovery august 2010 vol 9 no 8 by Prof. Yasser Alaa

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  • 1. Nature Reviews Drug Discovery August 2010 Vol 9 No 8 1/30/2015 Prof M.A.Eldawy, by pharmacist: Yasser Alaa 1 of 24 Nature Reviews Drug Discovery August 2010 Vol 9 No 8 (Agomelatine, the first melatonergic antidepressant) Prof M.A.Eldawy, by Pharmacist: Yasser Alaa 1/30/2015
  • 2. Current management of major depression, a common and debilitating disorder with a high social and personal cost, is far from satisfactory. All available antidepressants act through monoaminergic mechanisms, so there is considerable interest in novel non-monoaminergic approaches for potentially improved treatment. One such strategy involves targeting melatonergic receptors, as melatonin has a key role in synchronizing circadian rhythms, which are known to be perturbed in depressed states. This article describes the discovery and development of agomelatine, which possesses both melatonergic agonist and complementary 5-hydroxytryptamine 2C (5-HT2C) antagonist properties. Following comprehensive pharmacological evaluation and extensive clinical trials, agomelatine (Valdoxan/Thymanax; Servier) was granted marketing authorization in 2009 for the treatment of major depression in Europe, thereby becoming the first approved antidepressant to incorporate a non- monoaminergic mechanism of action. 1/30/2015 Prof M.A.Eldawy, by pharmacist: Yasser Alaa 2 of 24 Nature Reviews Drug Discovery August 2010 Vol 9 No 8 (Agomelatine, the first melatonergic antidepressant) Prof M.A.Eldawy, by Pharmacist: Yasser Alaa 1/30/2015 Petersen, T; Dording, C; Neault, NB; Kornbluh, R; Alpert, JE; Nierenberg, AA; Rosenbaum, JF; Fava, M (January 2002). "A survey of prescribing practices in the treatment of depression". Progress in Neuro-Psychopharmacology and Biological Psychiatry (Elsevier) 26 (1): 177–87. doi:10.1016/S0278-5846(01)00250-0. PMID 11853110.
  • 3. Definition: also called major depression, is characterized by a combination of symptoms that interfere with a person's ability to work, sleep, study, eat, and enjoy once– pleasurable activities. Major depression is disabling and prevents a person from functioning normally. An episode of major depression may occur only once in a person's lifetime, but more often, it recurs throughout a person's life. Mechanisms of Depression: ‘Monoaminergic Mechanism' 1/30/2015 Prof M.A.Eldawy, by pharmacist: Yasser Alaa 3 of 24 Nature Reviews Drug Discovery August 2010 Vol 9 No 8 (Agomelatine, the first melatonergic antidepressant) Prof M.A.Eldawy, by Pharmacist: Yasser Alaa 1/30/2015 Stagnitti,M. (2005) Antidepressant Use in the US Civilian Non-Insitutionalised Population, 2002. Statistical Brief #77. Rockville,MD: Medical Expenditure Panel, Agency for Healthcare Research and Quality.
  • 4. A major hypothesis for the biology of depression was developed in the 1960s, initially proposing that depletion of norepinephrine (NE), and later proposing depletion of serotonin (5-HT) and dopamine (DA), underlie the illness. This 'monoamine hypothesis' was proposed because of the clinical observation that depression often occurs in subjects taking reserpine, an antihypertensive agent, which depletes monoamines from the synaptic vesicles. Also, consistent with the hypothesis was that tricyclic antidepressants and MAO inhibitors were found to increase synaptic monoamine concentrations. The hypothesis was later modified to include alterations of monoamine receptor properties so that it would encompass an explanation for the time (usually days to weeks) required for an antidepressant to take clinical effect despite its immediate action to elevate synaptic monoamine levels. 1/30/2015 Prof M.A.Eldawy, by pharmacist: Yasser Alaa 4 of 24 Nature Reviews Drug Discovery August 2010 Vol 9 No 8 (Agomelatine, the first melatonergic antidepressant) Prof M.A.Eldawy, by Pharmacist: Yasser Alaa 1/30/2015 Turner EH, Matthews AM, Linardatos E, Tell RA, Rosenthal R (January 2008). "Selective publication of antidepressant trials and its influence on apparent efficacy". N. Engl. J. Med. 358 (3): 252–60. doi:10.1056/NEJMsa065779. PMID 18199864 Kuhn, R (November 1958). "The Treatment of Depressive States with G 22355 (Imipramine Hydrochloride)". American Journal of Psychiatry (American Psychiatric Association) 115 (5): 459–464. doi:10.1176/appi.ajp.115.5.459 (inactive 2009-10-24). Stimmel, GL; Dopheide, JA; Stahl, SM (Jan-Feb 1997). "Mirtazapine: an antidepressant with noradrenergic and specific serotonergic effects".Pharmacotherapy (American College of Clinical Pharmacy) 17 (1): 10–21. ISSN 0277-0008. PMID 9017762
  • 5. Monoaminergicantidepressant drugs 1/30/2015 Prof M.A.Eldawy, by pharmacist: Yasser Alaa 5 of 24 Nature Reviews Drug Discovery August 2010 Vol 9 No 8 (Agomelatine, the first melatonergic antidepressant) Prof M.A.Eldawy, by Pharmacist: Yasser Alaa 1/30/2015 Tatsumi M, Groshan K, Blakely RD, Richelson E. (1997). "Pharmacological profile of antidepressants and related compounds at human monoamine transporters.". Eur J Pharmacol. 340 (2-3): 249–258. doi:10.1016/S0014-2999(97)01393-9. PMID 9537821
  • 6. ‘Melatonergic Mechanism of Depression’ • Melatonin is a naturally occurring hormone secreted by the pineal gland, a pea-size structure at the center of the brain. As our eyes register the fall of darkness and the onset of night melatonin is produced. It signals to our body to prepare for sleep, our blood pressure dips, there is a decrease in body temperature and we start to feel sleepy. Melatonin is one of the central hormonal elements to regulating our circadian rhythms.Melatonin is often referred to as the hibernation hormone. • Melatonin & Depression Melatonin is an important nighttime hormone associated with sleep and regeneration. However, excessive levels or daytime melatonin can cause depressive disorders. Medical research confirms the relationship between melatonin and mood disorders. The following paragraphs explain how melatonin works and why it causes depression. • Darkness & Melatonin Melatonin is normally released by the pineal gland in the evening as sunlight is diminishing. Melatonin causes us to feel tired and withdraw. This helps us to sleep, but if we have to be awake when melatonin is in our system, we become lethargic, disoriented, irritable and moody. This explains why shift work and jet lag can be so debilitating, and why depression rates are highest in darker climates. Almost everyone with a mood disorder suffers worse in the winter because of excess melatonin in his or her system. • Daytime Melatonin Just as with jet lag, other factors can cause our bodies to produce melatonin into the day. Some causes such as trauma, stress, injury, age or lack of light will shift your body’s timing or release of melatonin. This shift can create excessive levels during the day and not enough melatonin at night. 1/30/2015 Prof M.A.Eldawy, by pharmacist: Yasser Alaa 6 Of 24 Nature Reviews Drug Discovery August 2010 Vol 9 No 8 (Agomelatine, the first melatonergic antidepressant) Prof M.A.Eldawy, by Pharmacist: Yasser Alaa 1/30/2015 Pacchierotti, C. et al. Melatonin in Psychiatric Disorders: A Review on the Melatonin Involvement in Psychiatry. Frontiers in Neuroendocrinology. Volume 22, Issue 1, January 2001, Pages 18-32. Crasson, M. et al. Serum melatonin and urinary 6-sulfatoxymelatonin in major depression. Psychoneuroendocrinology. Volume 29, Issue 1, January 2004, Pages 1-12.
  • 7. 1/30/2015 Prof M.A.Eldawy, by pharmacist: Yasser Alaa 7 of 24 Nature Reviews Drug Discovery August 2010 Vol 9 No 8 (Agomelatine, the first melatonergic antidepressant) Prof M.A.Eldawy, by Pharmacist: Yasser Alaa 1/30/2015 Redman, J. R., Guardiola-Lemaître, B., Brown, M., Delagrange, P. & Armstrong, S. M. Dose-dependent effects of, S20098, a melatonin agonist on direction of re-entrainment of rat circadian rhythms. Psychopharmacology 118, 385–390 (1995).
  • 8. The relationship between melatonin, the suprachiasmatic nucleus and circadian rhythms: melatonergic actions of agomelatine in vivo. a | Light activates the glutamate (GLU)- containing retinohypothalamic tract (RHT) that runs from the eye to the suprachiasmatic nucleus (SCN). Through a polysynaptic projection, the SCN functionally inhibits the activity of the superior cervical ganglia (SCG), which supply the pineal gland with an excitatory, noradrenaline (NA)-containing input. This circuit allows light to suppress the production and release of melatonin from the pineal gland and, correspondingly, melatonin secretion is increased in the dark period. Melatonin reciprocally activates neurons in the SCN by actions at melatonin 1 (MT1) and MT2 receptors. Serotonergic input from the raphe nucleus modulates the SCN through actions at serotonin (also known as 5- hydroxytryptamine; 5-HT) receptor 5-HT2C and other classes of 5-HT receptor. Daily behaviours likewise influence output from the SCN, the neuronal master clock for coordinating circadian rhythms. b | Melatonergic receptors recognized autoradiographically in the SCN using [125I] iodomelatonin. c | Locomotor activity rhythms of rats drift backwards when the onset of the dark period is delayed by several hours. Daily administration of agomelatine (3.0 mg per kg, intraperitoneally) resynchronizes rhythms to their usual circadian pattern (dark period commencing at 18:00 hours) 1/30/2015 Prof M.A.Eldawy, by pharmacist: Yasser Alaa 8 of 24 Redman, J. R., Guardiola-Lemaître, B., Brown, M., Delagrange, P. & Armstrong, S. M. Dose-dependent effects of, S20098, a melatonin agonist on direction of re-entrainment of rat circadian rhythms. Psychopharmacology 118, 385–390 (1995). Nature Reviews Drug Discovery August 2010 Vol 9 No 8 (Agomelatine, the first melatonergic antidepressant) Prof M.A.Eldawy, by Pharmacist: Yasser Alaa 1/30/2015
  • 9. Agomelatine, thefirst melatonergic antidepressant 1.NAMEOF THE MEDICINALPRODUCT Valdoxan 25 mg film-coated tablets 2.Composition: Each film-coated tablet contains 25 mg of agomelatine. 3.PHARMACEUTICALFORM Film-coated tablet [tablet]. Orange-yellow, oblong, film-coated tablet with blue imprint of company logo on one side. 4.Manufacturer: Servier 5.ATCCode: N06AX22 6.CASnumber 138112-76-2 1/30/2015 Prof M.A.Eldawy, by pharmacist: Yasser Alaa 9 of 24 Nature Reviews Drug Discovery August 2010 Vol 9 No 8 (Agomelatine, the first melatonergic antidepressant) Prof M.A.Eldawy, by Pharmacist: Yasser Alaa 1/30/2015 www.emea.europa.eu/ http://en.wikipedia.org/wiki/Agomelatine
  • 10. 7.MARKETINGAUTHORISATIONHOLDER Les Laboratoires Servier 22, rue Garnier F-92200 Neuilly-sur-Seine France 8.MARKETINGAUTHORISATIONNUMBER(S) EU/1/08/499/001-008 9.DATEOF THE FIRSTAUTHORISATION/ RENEWALOF THE AUTHORISATION 19/02/2009 1/30/2015 Prof M.A.Eldawy, by pharmacist: Yasser Alaa 10 of 24 Agomelatine, thefirst melatonergic antidepressant Nature Reviews Drug Discovery August 2010 Vol 9 No 8 (Agomelatine, the first melatonergic antidepressant) Prof M.A.Eldawy, by Pharmacist: Yasser Alaa 1/30/2015 www.emea.europa.eu/ http://en.wikipedia.org/wiki/Agomelatine
  • 11. 10. Chemical Structure: 11. Formula: C15H17NO2 12. Systematic (IUPAC)name: N-[2-(7-methoxynaphthalen-1-yl)ethyl]acetamide 13. Melatonin vs. Agomelatine: Melatonin (top) vs. agomelatine (bottom); The chemical structure of agomelatine is very similar to that of melatonin. Where melatonin has an NH group, agomelatine has an HC=CH group. Thus melatonin contains an indole part, whereas agomelatine has a naphthalene bioisostere instead. 11 of 24 Agomelatine, thefirst melatonergic antidepressant Nature Reviews Drug Discovery August 2010 Vol 9 No 8 (Agomelatine, the first melatonergic antidepressant) Prof M.A.Eldawy, by Pharmacist: Yasser Alaa 1/30/2015 1/30/2015 Prof M.A.Eldawy, by pharmacist: Yasser Alaa B. Tinant, J.-P. Declercq, J. H. Poupaert, S. Yous, D. Lesieur (1994). "N-[2-(7-Methoxy-1-naphthyl)ethyl]acetamide, a potent melatonin analog". Acta Cryst. C 50: 907-910. doi:10.1107/S0108270193012922
  • 12. 14. Therapeutic indications Treatment of major depressive episodes in adults. 15. Posologyand method ofadministration The recommended dose is 25 mg once daily taken orally at bedtime. After two weeks of treatment, if there is no improvement of symptoms, the dose may be increased to 50 mg once daily, i.e. two 25 mg tablets, taken together at bedtime. Liver function tests should be performed in all patients : at initiation of treatment, and then periodically after around six weeks (end of acute phase), twelve weeks and twenty four weeks (end of maintenance phase). Patients with depression should be treated for a sufficient period of at least 6 months to ensure that they are free of symptoms. Valdoxan tablets may be taken with or without food. 12 of 24 Agomelatine, thefirst melatonergic antidepressant Nature Reviews Drug Discovery August 2010 Vol 9 No 8 (Agomelatine, the first melatonergic antidepressant) Prof M.A.Eldawy, by Pharmacist: Yasser Alaa 1/30/2015 1/30/2015 Prof M.A.Eldawy, by pharmacist: Yasser Alaa www.emea.europa.eu/ http://en.wikipedia.org/wiki/Agomelatine
  • 13. 16. MechanismofAction: Agomelatine is a melatonergic agonist (MT1 and MT2 receptors) and 5-HT2C antagonist. Binding studies indicate that agomelatine has no effect on monoamine uptake and no affinity for α, β adrenergic, histaminergic, cholinergic, dopaminergic and benzodiazepine receptors. Agomelatine resynchronises circadian rhythms in animal models of circadian rhythm disruption. Agomelatine increases noradrenaline and dopamine release specifically in the frontal cortex and has no influence on the extracellular levels of serotonin. 13 of 241/30/2015 Prof M.A.Eldawy, by pharmacist: Yasser Alaa Agomelatine, thefirst melatonergic antidepressant Nature Reviews Drug Discovery August 2010 Vol 9 No 8 (Agomelatine, the first melatonergic antidepressant) Prof M.A.Eldawy, by Pharmacist: Yasser Alaa 1/30/2015 "Summary of Product Characteristics" (PDF). European Medicine Agency. 2003. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_- _Product_Information/human/000915/WC500046227.pdf. Retrieved 2010-09-22.
  • 14. 14 of 241/30/2015 Prof M.A.Eldawy, by pharmacist: Yasser Alaa Agomelatine, thefirst melatonergic antidepressant Nature Reviews Drug Discovery August 2010 Vol 9 No 8 (Agomelatine, the first melatonergic antidepressant) Prof M.A.Eldawy, by Pharmacist: Yasser Alaa 1/30/2015 Gerdin, M. J. et al. Short-term exposure to melatonin differentially affects the functional sensitivity and trafficking of the hMT1 and hMT2 receptors. J. Pharmacol. Exp. Ther. 304, 931–939 (2003).
  • 15. 15 of 24Prof M.A.Eldawy, by pharmacist: Yasser Alaa Aloyo, V. J., Berg, K. A., Spampinato, U., Clarke, W. P. & Harvey, J. A. Current status of inverse agonism at serotonin2A (5-HT2A) and 5-HT2C receptors. Pharmacol. Ther. 121, 160–173 (2009) 1/30/2015 Agomelatine, thefirst melatonergic antidepressant Nature Reviews Drug Discovery August 2010 Vol 9 No 8 (Agomelatine, the first melatonergic antidepressant) Prof M.A.Eldawy, by Pharmacist: Yasser Alaa 1/30/2015
  • 16. 16 of 24Prof M.A.Eldawy, by pharmacist: Yasser Alaa Barden, N. et al. Antidepressant action of agomelatine (S20098) in a transgenic mouse model. Prog. Neuropsychopharmacol. Biol. Psychiatry 29, 908–916 (2005). 1/30/2015 Agomelatine, thefirst melatonergic antidepressant Nature Reviews Drug Discovery August 2010 Vol 9 No 8 (Agomelatine, the first melatonergic antidepressant) Prof M.A.Eldawy, by Pharmacist: Yasser Alaa 1/30/2015
  • 17. 17. Absorption and bioavailability: Agomelatine is rapidly and well (≥ 80%) absorbed after oral administration. Absolute bioavailability is low (< 5% at the therapeutic oral dose) and the interindividual variability is substantial. The bioavailability is increased in women compared to men. The bioavailability is increased by intake of oral contraceptives and reduced by smoking. The peak plasma concentration is reached within 1 to 2 hours. In the therapeutic dose-range, agomelatine systemic exposure increases proportionally with dose. At higher doses, a saturation of the first-pass effect occurs. Food intake (standard meal or high fat meal) does not modify the bioavailability or the absorption rate. The variability is increased with high fat food. 18. Distribution: Steady state volume of distribution is about 35 l and plasma protein binding is 95% irrespective of the concentration and is not modified with age and in patients with renal impairment but the free fraction is doubled in patients with hepatic impairment. 17 of 24Prof M.A.Eldawy, by pharmacist: Yasser Alaa1/30/2015 Agomelatine, thefirst melatonergic antidepressant Nature Reviews Drug Discovery August 2010 Vol 9 No 8 (Agomelatine, the first melatonergic antidepressant) Prof M.A.Eldawy, by Pharmacist: Yasser Alaa 1/30/2015 www.emea.europa.eu/ http://en.wikipedia.org/wiki/Agomelatine
  • 18. 19.Biotransformation: Following oral administration, agomelatine is rapidly metabolised mainly via hepatic CYP1A2; CYP2C9 and CYP2C19 isoenzymes are also involved but with a low contribution. The major metabolites, hydroxylated and demethylated agomelatine, are not active and are rapidly conjugated and eliminated in the urine. 20.Elimination: Elimination is rapid, the mean plasma half-life is between 1 and 2 hours and the clearance is high (about 1,100 ml/min) and essentially metabolic. Excretion is mainly (80%) urinary and in the form of metabolites, whereas unchanged compound recovery in urine is negligible. Kinetics are not modified after repeated administration. INRenalimpairment No relevant modification of pharmacokinetic parameters in patients with severe renal impairment has been observed (n=8, single dose of 25 mg), but caution should be exercised in patients with severe or moderate renal impairment as only limited clinical data are available in these patients 18 of 24Prof M.A.Eldawy, by pharmacist: Yasser Alaa1/30/2015 Agomelatine, thefirst melatonergic antidepressant Nature Reviews Drug Discovery August 2010 Vol 9 No 8 (Agomelatine, the first melatonergic antidepressant) Prof M.A.Eldawy, by Pharmacist: Yasser Alaa 1/30/2015 www.emea.europa.eu/ http://en.wikipedia.org/wiki/Agomelatine
  • 19. 21.POSSIBLESIDEEFFECTS: Like all medicines, Valdoxan can cause side effects, although not everybody gets them. Most side effects are mild or moderate. They usually occur within the first two weeks of the treatment and are usually temporary. - Common side effects: dizziness, sleepiness (somnolence), difficulty in sleeping (insomnia), migraine, headache, feeling sick (nausea), diarrhoea, constipation, upper abdominal pain, excessive sweating (hyperhidrosis), back pain, tiredness, anxiety, increased levels of liver enzymes in your blood. - Uncommon side effects: pins and needles in the fingers and toes (paraesthesia), blurred vision and eczema. - Rare side effects: serious skin eruption (erythematous rash), hepatitis. - Other possible side effects: suicidal thoughts or behaviour, agitation (frequency not known). 19 of 24Prof M.A.Eldawy, by pharmacist: Yasser Alaa1/30/2015 Agomelatine, thefirst melatonergic antidepressant Nature Reviews Drug Discovery August 2010 Vol 9 No 8 (Agomelatine, the first melatonergic antidepressant) Prof M.A.Eldawy, by Pharmacist: Yasser Alaa 1/30/2015 Papakostas, G. I. Tolerability of modern antidepressants. J. Clin. Psychiatry 69, 8–13 (2008). Mathew, S. J., Manji, H. K. & Charney, D. S. Novel drugs and therapeutic targets for severe mood disorders. Neuropsychopharmacology 33, 2080–2092 (2008). Lemoine, P., Guilleminault, C. & Alvarez, E. Improvement in subjective sleep in major depressive disorder with a novel antidepressant, agomelatine: randomized, double blind comparison with venlafaxine. J. Clin. Psychiatry 68, 1723–1732 (2007).
  • 20. 22.Interactionwith other medicinalproductsandother forms of interaction: Potential interactions affecting agomelatine: Agomelatine is metabolised mainly by cytochrome P450 1A2 (CYP1A2) (90%) and by CYP2C9/19 (10%). Medicinal products that interact with these isoenzymes may decrease or increase the bioavailability of agomelatine. Fluvoxamine, a potent CYP1A2 and moderate CYP2C9 inhibitor markedly inhibits the metabolism of agomelatine resulting in a 60-fold (range 12-412) increase of agomelatine exposure. Consequently, co-administration of Valdoxan with potent CYP1A2 inhibitors (e.g. fluvoxamine, ciprofloxacin) is contraindicated. Combination of agomelatine with oestrogens (moderate CYP1A2 inhibitors) results in a several fold increased exposure of agomelatine. While there was no specific safety signal in the 800 patients treated in combination with oestrogens, caution should be exercised when prescribing agomelatine with other moderate CYP1A2 inhibitors (e.g. propranolol, grepafloxacine, enoxacine) until more experience has been gained 20 of 24Prof M.A.Eldawy, by pharmacist: Yasser Alaa1/30/2015 Agomelatine, thefirst melatonergic antidepressant Nature Reviews Drug Discovery August 2010 Vol 9 No 8 (Agomelatine, the first melatonergic antidepressant) Prof M.A.Eldawy, by Pharmacist: Yasser Alaa 1/30/2015 www.emea.europa.eu/ http://en.wikipedia.org/wiki/Agomelatine
  • 21. 23.Fertility, pregnancyandlactation Fertility Reproduction studies in the rat and the rabbit showed no effect of agomelatine on fertility. Pregnancy Reproduction studies in the rat and the rabbit showed no effect of agomelatine on embryofoetal development and pre- and post natal development. For agomelatine, no clinical data on exposed pregnancies are available. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development Caution should be exercised when prescribing to pregnant women. Breast-feeding It is not known whether agomelatine is excreted into human milk. Agomelatine or its metabolites are excreted in the milk of lactating rats. Potential effects of agomelatine on the breast-feeding infant have not been established. If treatment with Valdoxan is considered necessary, breastfeeding should be discontinued. 21 of 24Prof M.A.Eldawy, by pharmacist: Yasser Alaa1/30/2015 Agomelatine, thefirst melatonergic antidepressant Nature Reviews Drug Discovery August 2010 Vol 9 No 8 (Agomelatine, the first melatonergic antidepressant) Prof M.A.Eldawy, by Pharmacist: Yasser Alaa 1/30/2015 "Summary of Product Characteristics"(PDF). European Medicine Agency. 2003. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_- _Product_Information/human/000915/WC500046227.pdf. Retrieved 2010-09-22. http://en.wikipedia.org/wiki/Agomelatine
  • 22. 22 of 24Prof M.A.Eldawy, by pharmacist: Yasser Alaa1/30/2015 Agomelatine, thefirst melatonergic antidepressant Nature Reviews Drug Discovery August 2010 Vol 9 No 8 (Agomelatine, the first melatonergic antidepressant) Prof M.A.Eldawy, by Pharmacist: Yasser Alaa 1/30/2015 Linnik, I. V. et al. The novel antidepressant, agomelatine, blocks cerebral 5-HT2C receptors in vivo: a phMRI challenge study in rats. Eur. Neuropsychopharmacol. 19, S259 (2009). Agomelatine represents an innovative approach to treating depression as it is the first regulatory approved agent to incorporate a non-monoaminergic mechanism. Its antidepressant activity across a broad range of experimental procedures in animal models and its distinctive therapeutic profile in humans probably reflect a synergistic interplay of its melatonergic (agonist) and 5-HT2C (antagonist) properties. Extensive clinical trials have established both the short-term and long-term efficacy of agomelatine in major depression in mildly and severely ill patients, with an improvement of sleep quality, preservation of sexual function, absence of weight gain and good tolerability. Moreover, discontinuation is not associated with withdrawal symptoms. This overall profile compares favourably to currently available antidepressants and should encourage adherence throughout the extensive treatment period, 6 months or more, recommended for durable improvement of a major depressive episode. Further studies and clinical use will clarify the full potential of agomelatine as an antidepressant. There is also rich potential, as highlighted above, for exploration of the broader use of agomelatine in the treatment of other central nervous system disorders.
  • 23. References 23 of 24 Petersen, T; Dording, C; Neault, NB; Kornbluh, R; Alpert, JE; Nierenberg, AA; Rosenbaum, JF; Fava, M (January 2002). "A survey of prescribing practices in the treatment of depression". Progress in Neuro-Psychopharmacology and Biological Psychiatry (Elsevier) 26 (1): 177–87. doi:10.1016/S0278-5846(01)00250-0. PMID 11853110. Stagnitti,M. (2005) Antidepressant Use in the US Civilian Non-Insitutionalised Population, 2002. Statistical Brief #77. Rockville,MD: Medical Expenditure Panel, Agency for Healthcare Research and Quality. Turner EH, Matthews AM, Linardatos E, Tell RA, Rosenthal R (January 2008). "Selective publication of antidepressant trials and its influence on apparent efficacy". N. Engl. J. Med. 358 (3): 252–60. doi:10.1056/NEJMsa065779. PMID 18199864 Kuhn, R (November 1958). "The Treatment of Depressive States with G 22355 (Imipramine Hydrochloride)". American Journal of Psychiatry (American Psychiatric Association) 115 (5): 459–464. doi:10.1176/appi.ajp.115.5.459 (inactive 2009-10-24). Stimmel, GL; Dopheide, JA; Stahl, SM (Jan-Feb 1997). "Mirtazapine: an antidepressant with noradrenergic and specific serotonergic effects". Pharmacotherapy (American College of Clinical Pharmacy) 17 (1): 10–21. ISSN 0277-0008. PMID 9017762 Tatsumi M, Groshan K, Blakely RD, Richelson E. (1997). "Pharmacological profile of antidepressants and related compounds at human monoamine transporters.". Eur J Pharmacol. 340 (2-3): 249–258. doi:10.1016/S0014-2999(97)01393-9. PMID 9537821 Pacchierotti, C. et al. Melatonin in Psychiatric Disorders: A Review on the Melatonin Involvement in Psychiatry. Frontiers in Neuroendocrinology. Volume 22, Issue 1, January 2001, Pages 18-32. Crasson, M. et al. Serum melatonin and urinary 6-sulfatoxymelatonin in major depression. Psychoneuroendocrinology. Volume 29, Issue 1, January 2004, Pages 1-12. Redman, J. R., Guardiola-Lemaître, B., Brown, M., Delagrange, P. & Armstrong, S. M. Dose-dependent effects of, S20098, a melatonin agonist on direction of re-entrainment of rat circadian rhythms. Psychopharmacology 118, 385–390 (1995). www.emea.europa.eu/ http://en.wikipedia.org/wiki/Agomelatine Gerdin, M. J. et al. Short-term exposure to melatonin differentially affects the functional sensitivity and trafficking of the hMT1 and hMT2 receptors. J. Pharmacol. Exp. Ther. 304, 931–939 (2003). Aloyo, V. J., Berg, K. A., Spampinato, U., Clarke, W. P. & Harvey, J. A. Current status of inverse agonism at serotonin2A (5-HT2A) and 5-HT2C receptors. Pharmacol. Ther. 121, 160–173 (2009) Barden, N. et al. Antidepressant action of agomelatine (S20098) in a transgenic mouse model. Prog. Neuropsychopharmacol. Biol. Psychiatry 29, 908–916 (2005). Papakostas, G. I. Tolerability of modern antidepressants. J. Clin. Psychiatry 69, 8–13 (2008). Mathew, S. J., Manji, H. K. & Charney, D. S. Novel drugs and therapeutic targets for severe mood disorders. Neuropsychopharmacology 33, 2080–2092 (2008). Lemoine, P., Guilleminault, C. & Alvarez, E. Improvement in subjective sleep in major depressive disorder with a novel antidepressant, agomelatine: randomized, double blind comparison with venlafaxine. J. Clin. Psychiatry 68, 1723–1732 (2007). Prof M.A.Eldawy, by pharmacist: Yasser Alaa1/30/2015 Nature Reviews Drug Discovery August 2010 Vol 9 No 8 (Agomelatine, the first melatonergic antidepressant) Prof M.A.Eldawy, by Pharmacist: Yasser Alaa 1/30/2015
  • 24. Thank You End 24 of 24

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