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Vertigo                                                                                                        A slide kit...
What is vertigo?               Vertigo is:                  • A type of dizziness                  • A sensation of moveme...
Vertigo can be objective or subjective               Objective vertigo:                  • the patient perceives that the ...
Vertigo is one of four types of dizziness                                                                       Dizziness ...
Etiology of vertigo               Vertigo related to inner ear                  •    Benign paroxysmal positional vertigo ...
Vertigo: Pathophysiological Pathways               Endolymph movement, depending on the direction of flow               an...
Vertigo: Role of Neurotransmitters               Neurotransmitters that work centrally and               peripherally incl...
Vertigo: Presentation               Sensation of motion either of the person or the environment               In addition,...
Vertigo episodes are debilitating and are more         than just a sensation of movement               Vertigo episodes:  ...
Vertigo is a continuous burden               Between vertigo episodes there may be:                  •    Headaches       ...
Vertigo can have a negative impact on quality         of life              Women with vertigo                             ...
Vertigo can be of central or peripheral origin                                                                            ...
Vertigo of peripheral origin: Conditions &                       causes                        Condition                  ...
Vertigo of central origin: Conditions & causes                       Condition                                 Details    ...
Distinguishing peripheral and central causes of         vertigo          Symptom                                          ...
Treatment modalities in vertigo               Pharmacological interventions:                • Anticholinergics            ...
Nootropics in Vertigo               Nootropics as a class                  • Enhance cognitive processes such as learning ...
Treating the cause: pharmacotherapy can         control some vertigo causes               Meniere’s disease               ...
Treating the cause: a simple particle repositioning         manoeuvre effectively treats most BPPV cases                  ...
Treating the cause: surgery is appropriate in         only a small fraction of vertigo patients          Clinical picture ...
Pharmacotherapy can help manage symptoms         in the short term               Treatments to manage vertigo symptoms    ...
Rehabilitation exercises can encourage         vestibular adaptation and compensation               Effective recovery fro...
There are several types of vestibular         rehabilitation exercises                                         Vestibular ...
Treatment is dependent on vertigo type          Vertigo type                                    Treatment          Periphe...
Piracetam: an alternative treatment for vertigo                                                                           ...
What is Piracetam?               Piracetam:                  • is a nootropic drug, acting on cognitive function          ...
Balance requires information of similar intensity         from both vestibular systems                                    ...
Central vertigo results from a dysfunction in         central processing                 Input from left and right vestibu...
Peripheral vertigo results from a dysfunction in         vestibular system functioning                                    ...
Vestibular suppressants suppress vestibular         function in both ears                                                 ...
Piracetam offers an interesting alternative to         existing treatments                                                ...
Piracetam’s mode of action:         the membrane hypothesis                                                               ...
Restored membrane fluidity could account for         Piracetam’s efficacy in vertigo          Neuronal effects            ...
A number of studies have examined the use of         Piracetam in vertigo                                                 ...
Piracetam eliminates vestibular symptoms in more         patients with peripheral vertigo than placebo                    ...
Piracetam significantly reduces frequency and         intensity of vertigo crises                                         ...
Piracetam’s beneficial effect on vertigo persists                                        without treatment         followi...
Piracetam rapidly and markedly improves         intensity of unspecified chronic vertigo                                  ...
More patients achieved remission of vertigo         symptoms with Piracetam than placebo           Patients with vertigo o...
Fewer patients experience instability between           crises after Piracetam treatment           Patients with chronic, ...
Piracetam reduces vertigo-related symptoms         between episodes         Patients with vertigo of varying aetiologies r...
Piracetam:                     Efficacy in post-concussion vertigoGPSRC PCP 058 PROM 0608 PIR_Nootropil Slide Kit Vertigo ...
Vertigo complaints after head trauma are         common               Dizziness occurs in approximately 50% of            ...
Three studies of similar design have been conducted with         PIRACETAM IN POST-CONCUSSION VERTIGO         Aantaa E.   ...
Results of the 3 studies after 8 weeks                                                                                    ...
Mechanism of action of piracetam in         post-concussion vertigo               Enhancement of central compensation and ...
Piracetam: Contraindications & Drug Interactions         [Refer to your local full SPC before prescribing]         Major C...
Piracetam: Warnings and common undesirable         effects [Refer to your lcoal full SPC before prescribing]         Warni...
- Prescribing InformationNOOTROPIL®Piracetam Tablets/ Syrup/ InjectionsIntroduction:Pharmacotherapeutic group: Nootropics,...
- Prescribing Information         Preclinical safety data         The preclinical data include that piracetam has a low to...
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Vertigo 2008

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Vertigo 2008

  1. 1. Vertigo A slide kit Picture adapted from Borg E, Counter A. Pour la Science 1989;144:65. © Pour la scienceGPSRC PCP 058 PROM 0608 PIR_Nootropil Slide Kit Vertigo – © UCB PHARMA S.A. 2008. All rights reserved
  2. 2. What is vertigo? Vertigo is: • A type of dizziness • A sensation of movement typically characterised by feelings of rotation or spinning Baloh RW. Lancet 1998;352:1841–6. Mukherjee A et al. JAPI 2003;51:1095–101. Sloane PD et al. Ann Intern Med 2001;134:823–32. 2GPSRC PCP 058 PROM 0608 PIR_Nootropil Slide Kit Vertigo – © UCB PHARMA S.A. 2008. All rights reserved
  3. 3. Vertigo can be objective or subjective Objective vertigo: • the patient perceives that the environment is moving around him/her Subjective vertigo: • the patient feels himself/herself moving in a static environment Mukherjee A et al. JAPI 2003;51:1095–101. Salvinelli F et al. Clin Ter 2003;154:341–8. 3GPSRC PCP 058 PROM 0608 PIR_Nootropil Slide Kit Vertigo – © UCB PHARMA S.A. 2008. All rights reserved
  4. 4. Vertigo is one of four types of dizziness Dizziness Other Vertigo Presyncope Disequilibrium subtypes • An illusion of • A feeling of • A sense of • Swimming or movement, faintness or unsteadiness in the floating usually loss of lower body sensations rotation consciousness • No effect on feelings • Feelings of in head dissociation • Relieved when • Difficult to sitting down describe Drachman DA, Hart CW. Neurology 1972;22:323–4. Sloane PD et al. Ann Intern Med 2001;134:823–32. 4GPSRC PCP 058 PROM 0608 PIR_Nootropil Slide Kit Vertigo – © UCB PHARMA S.A. 2008. All rights reserved
  5. 5. Etiology of vertigo Vertigo related to inner ear • Benign paroxysmal positional vertigo (BPPV) • Meniere’s disease • Labyrinthitis • Trauma (labyrinthine concussion) • Aminoglycoside toxicity Vertigo related to the vestibular nerve • Vestibular neuritis • Nerve compression due to meningioma or schwannoma Vertigo related to brain stem • Physiological (visual-vestibular mismatch) • Demyelination (multiple sclerosis) • Migraine • Vertebrobasilar insufficiency (as in stroke or TIA) • Drug toxicities (with anticonvulsants, aspirin, alcohol) Allen CMC, Lueck CJ. Neurological disease. In: Christopher H, Edwin RC, Nicholas AB, eds. Davidson’s Principles and Practice of Medicine. 19th ed. Edinburgh: Churchill Livingstone;2002:1103-12310. 5GPSRC PCP 058 PROM 0608 PIR_Nootropil Slide Kit Vertigo – © UCB PHARMA S.A. 2008. All rights reserved
  6. 6. Vertigo: Pathophysiological Pathways Endolymph movement, depending on the direction of flow and deflection of otoliths by gravity, either stimulates or inhibits neuronal output from the attached hair cells Nerve impulses from the vestibular system are transmitted to the vestibular nuclei in the brain stem and cerebellum through the eighth cranial nerve From there, connections are made to the oculomotor system, spinal cord, and cerebral cortex, which integrate the information to produce the perception of motion Vertigo results from lesions or disturbances along this pathway Robert BD, Mark DC. Syncope, Faintness, Dizziness, And vertigo. In: Dennis LK, Eugene B, Anthony SF et al, eds. Harrison’s Principles of Internal Medicine.16th ed. New York:McGraw-Hill;2005:126-133. 6GPSRC PCP 058 PROM 0608 PIR_Nootropil Slide Kit Vertigo – © UCB PHARMA S.A. 2008. All rights reserved
  7. 7. Vertigo: Role of Neurotransmitters Neurotransmitters that work centrally and peripherally include: • Acetylcholine: Functions as an excitatory neurotransmitter in central and peripheral pathways • Glutamate: Maintains the resting discharge of the central vestibular neurons; may modulate synaptic transmission in the VOR arc • GABA: Thought to be inhibitory for commissures of the medial vestibular nucleus McLean MJ. Principles of neuropharmacology and therapeutics. In: Bradley WG, Daroff RB, Fenichel GM, Marsden CD, eds. Neurology in Clinical Practice. 3rd ed. Boston: Butterworth Heinemann;2000:867-898. 7GPSRC PCP 058 PROM 0608 PIR_Nootropil Slide Kit Vertigo – © UCB PHARMA S.A. 2008. All rights reserved
  8. 8. Vertigo: Presentation Sensation of motion either of the person or the environment In addition, the following may be present: • Nausea or vomiting • Abnormal eye movements • Sweating Duration of symptoms can vary from a few minutes to hours and can be constant or episodic May also be associated with visual disturbances, weakness, decreased level of consciousness, difficulty in speaking Troost BT. Dizziness and vertigo. In: Bradley WG, Daroff RB, Fenichel GM, Marsden CD, eds. Neurology in Clinical Practice. 3rd ed. Boston: Butterworth Heinemann;2000:239-240. 8GPSRC PCP 058 PROM 0608 PIR_Nootropil Slide Kit Vertigo – © UCB PHARMA S.A. 2008. All rights reserved
  9. 9. Vertigo episodes are debilitating and are more than just a sensation of movement Vertigo episodes: • are characterised by a sensation of movement, usually spinning or rotating • vary in intensity and duration • are usually unpredictable • are often accompanied by:  nausea  vomiting  imbalance  anxiety  sweating  nystagmus Baloh RW. Lancet 1998;352:1841–6. Mukherjee A et al. JAPI 2003;51:1095–101. Salvinelli F, Firrisi L, Casale M, et al. Clin Ter 2003;154:341–8. 9GPSRC PCP 058 PROM 0608 PIR_Nootropil Slide Kit Vertigo – © UCB PHARMA S.A. 2008. All rights reserved
  10. 10. Vertigo is a continuous burden Between vertigo episodes there may be: • Headaches • Instability • General malaise • Anxiety and depression • Fear over recurrence of episodes These symptoms may have a negative effect on quality of life Fielder H et al. Clin Otolaryngol 1996;21:124–6. Hägnebo C et al. Scand Audiol 1997;26:69–76. Lopez-Escamez JA, Lopez-Nevot A. Acta Otorrinolaringol Esp 2000;51:377–82. Mendel B et al. Clin Otolaryngol Allied Sci 1999;24:286–93. Monzani D et al. J Psychosom Res 2001;50:319–23. Salvinelli F et al. Clin Ter 2003;154:341–8. 10GPSRC PCP 058 PROM 0608 PIR_Nootropil Slide Kit Vertigo – © UCB PHARMA S.A. 2008. All rights reserved
  11. 11. Vertigo can have a negative impact on quality of life Women with vertigo Weighted population mean Men with vertigo Mean score (scale of 0-100) Mean score (scale of 0-100) QoL parameter (SF-36) Physical functioning Limitations due to emotions Limitations due p<0.05 p<0.05 to physical problems p<0.05 Social functioning Mental health Bodily pain Vitality p<0.05 General health perception Do we take vertigo seriously enough? Fielder H et al. Clin Otolaryngol 1996;21:124–6. SF-36, short form health questionnaire, higher scores indicate better health. QoL, Quality of Life. 11GPSRC PCP 058 PROM 0608 PIR_Nootropil Slide Kit Vertigo – © UCB PHARMA S.A. 2008. All rights reserved
  12. 12. Vertigo can be of central or peripheral origin Central Involving structures in the central nervous system (e.g., cerebrum, cerebellum, brainstem) Peripheral Involving structures not part of the central nervous system, most frequently the inner ear Baloh RW. Lancet 1998;352:1841–6. Mukherjee A et al. JAPI 2003;51:1095-101. Puri V, Jones E. J Ky Med Assoc 2001;99:316–21. Salvinelli F et al. Clin Ter 2003;154:341–8. Strupp M, Arbusow V, Curr Opin Neurol 2001;14:11–20. 12GPSRC PCP 058 PROM 0608 PIR_Nootropil Slide Kit Vertigo – © UCB PHARMA S.A. 2008. All rights reserved
  13. 13. Vertigo of peripheral origin: Conditions & causes Condition Details Benign paroxysmal Brief, position-provoked vertigo episodes caused by positional vertigo abnormal presence of particles in semicircular canalDecreasing frequency Meniere’s disease An excess of endolymph, causing distension of endolymphatic system Vestibular neuronitis Vestibular nerve inflammation, most likely due to virus Acute labyrinthitis Labyrinth inflammation due to viral or bacterial infection Labyrinthine infarct Compromises blood flow to the labyrinthine Labyrinthine concussion Damage to the labyrinthine after head trauma Perilymph fistula Typically caused by labyrinth membrane damage resulting in perilymph leakage into the middle ear Autoimmune inner ear Inappropriate immunological response that attacks inner ear disease cells Baloh RW. Lancet 1998;352:1841–6. Mukherjee A et al. JAPI 2003;51:1095-101. Parnes LS et al. CMAJ 2003;169:681– 93. Puri V, Jones E. J Ky Med Assoc 2001;99:316–21. Salvinelli F et al. Clin Ter 2003;154:341–8. 13 GPSRC PCP 058 PROM 0608 PIR_Nootropil Slide Kit Vertigo – © UCB PHARMA S.A. 2008. All rights reserved
  14. 14. Vertigo of central origin: Conditions & causes Condition Details Migraine Vertigo may precede migraines or occur concurrentlyDecreasing frequency Ischaemia or haemorrhage in vertebrobasilar system can Vascular disease affect brainstem or cerebellum function Demyelination disrupts nerve impulses which can result in Multiple sclerosis vertigo Vertigo resulting from focal epileptic discharges in the Vestibular epilepsy temporal or parietal association cortex Cerebellopontine tumours Benign tumours in the internal auditory meatus Baloh RW. Lancet 1998;352:1841–6. Mukherjee A et al. JAPI 2003;51:1095-101. Salvinelli F et al. Clin Ter 2003;154: 341–8. Solomon D. Otolaryngol Clin North Am 2000;33:579–601. Strupp M, Arbusow V, Curr Opin Neurol 2001;14:11–20. 14GPSRC PCP 058 PROM 0608 PIR_Nootropil Slide Kit Vertigo – © UCB PHARMA S.A. 2008. All rights reserved
  15. 15. Distinguishing peripheral and central causes of vertigo Symptom Likely aetiology Peripheral Central Vertigo episodes Mild/moderate Chronic and unremitting Symptom onset Sudden Gradual Imbalance Mild/moderate Severe Nausea, vomiting Severe Varying Auditory symptoms Common Rare Neurological symptoms Rare Common Changes in mental status/ consciousness Infrequent Sometimes Compensation/resolution Rapid Slow Baloh RW. Otolaryngol Head Neck Surg 1998;119:55–9. Puri V, Jones E. J Ky Med Assoc 2001;99:316–21. 15GPSRC PCP 058 PROM 0608 PIR_Nootropil Slide Kit Vertigo – © UCB PHARMA S.A. 2008. All rights reserved
  16. 16. Treatment modalities in vertigo Pharmacological interventions: • Anticholinergics • Antihistamines • Benzodiazepines • Calcium channel antagonists (especially verapamil and nimodipine) • GABA modulators (like gabapentin and baclofen) • Neurotransmitter reuptake inhibitors (SSRIs, SNRIs and tricyclics) • Nootropics (piracetam) Troost BT, Arguello LC. Neuro-Otology. In: Bradley WG, Daroff RB, Fenichel GM, Marsden CD, eds. Neurology in Clinical Practice. 3rd ed. Boston: Butterworth Heinemann;2000:740-742. Oosterveld WJ. Arzneimittelforschung.1980;30(11)1947-1949. 16GPSRC PCP 058 PROM 0608 PIR_Nootropil Slide Kit Vertigo – © UCB PHARMA S.A. 2008. All rights reserved
  17. 17. Nootropics in Vertigo Nootropics as a class • Enhance cognitive processes such as learning and memory • Protect and restore cognitive abilities after cerebral insults • Facilitate interhemispheric flow of information and efficient tonic cortical/subcortical mechanism • Do not have sedative or psychostimulant effects Piracetam, a cyclic derivative of GABA, and the first nootropic agent • Alleviates vertigo after head injury/vertigo of central origin • Significantly decreases the frequency and the severity of exacerbations in patients with chronic or recurrent vertigo Balaraman, Shingala J. Indian Journal of Pharmacology. 2002;34(6)439-440 Trkanjec Z, Aleksic-Shibabi A, Demarin V. Rad za medicinske znanosti. 2007;69-73. 17GPSRC PCP 058 PROM 0608 PIR_Nootropil Slide Kit Vertigo – © UCB PHARMA S.A. 2008. All rights reserved
  18. 18. Treating the cause: pharmacotherapy can control some vertigo causes Meniere’s disease • Diuretics • Transtympanic gentamicin Migraine • Beta-blockers • Calcium channel blockers • Tricyclic amines Vertebrobasilar insufficiency or transient ischaemic attacks • Antiplatelet agents Baloh RW. Lancet 1998;352:1841–6. Goebel JA. Otolaryngol Clin North Am 2000;33:483–93. 18GPSRC PCP 058 PROM 0608 PIR_Nootropil Slide Kit Vertigo – © UCB PHARMA S.A. 2008. All rights reserved
  19. 19. Treating the cause: a simple particle repositioning manoeuvre effectively treats most BPPV cases Modified 3- position canalith repositioning manoeuvre, not requiring sedation or skull vibration Diagram shows treatment of BPPV in the right ear. Parnes LS, Agrawal SK, Atlas J. CMAJ 2003;169:681– 93. BPPV, Benign paroxysmal positional vertigo. Figure reprinted by permission of the publisher. © 2003 CMA Media Inc. 19GPSRC PCP 058 PROM 0608 PIR_Nootropil Slide Kit Vertigo – © UCB PHARMA S.A. 2008. All rights reserved
  20. 20. Treating the cause: surgery is appropriate in only a small fraction of vertigo patients Clinical picture Patient presents with Vertigo-inducing tumour Recurrent episodes of acute vertigo due to (e.g., cerebellopontine tumour) established unilateral vestibular damage unresponsive to medical therapy Surgery Tumour removal Ablative Non-Ablative Meniere’s disease or Meniere’s disease: peripheral vestibulopathy: Endolymphatic sac shunt or Labyrinthectomy decompression Vestibular nerve section BPPV: Posterior canal occlusion Goebel JA. Otolaryngol Clin North Am 2000;33:483–93. Salvinelli F et al. Clin Ter 2003;154:341–8. 20GPSRC PCP 058 PROM 0608 PIR_Nootropil Slide Kit Vertigo – © UCB PHARMA S.A. 2008. All rights reserved
  21. 21. Pharmacotherapy can help manage symptoms in the short term Treatments to manage vertigo symptoms • Vestibular suppressants  Meclizine, dimenhydrinate, diazepam • Anti-emetics  Prochlorperazine, metoclopramide Side effects include sedation and extrapyramidal reactions Baloh RW. Lancet 1998;352:1841–6. Hain TC, Uddin M. CNS Drugs 2003;17:85–100. 21GPSRC PCP 058 PROM 0608 PIR_Nootropil Slide Kit Vertigo – © UCB PHARMA S.A. 2008. All rights reserved
  22. 22. Rehabilitation exercises can encourage vestibular adaptation and compensation Effective recovery from vertigo often requires neural reorganisation and adaptation Vestibular rehabilitation exercises aim to promote adaptation and compensation of the nervous system They instigate sensory conflicts to promote neural learning Rehabilitation exercises are particularly useful when: • Medical therapy is ineffective • Patients have poor central integration or motor function Baloh RW. Lancet 1998;352:1841–6. Goebel JA. Otolaryngol Clin North Am 2000;33:483–93. Konnur MK. J Postgrad Med 2000;46:222–3. Mukherjee A et al. JAPI 2003;51:1095–101. 22GPSRC PCP 058 PROM 0608 PIR_Nootropil Slide Kit Vertigo – © UCB PHARMA S.A. 2008. All rights reserved
  23. 23. There are several types of vestibular rehabilitation exercises Vestibular rehabilitation exercises Visual-vestibular Head and neck Postural stability interaction • Performed lying, sitting or • Promotes visual-vestibular • Improves static and standing interaction dynamic posture • Vertigo-provoking • Involves ocular and hand- • Manipulates visual, movements of head & eye co-ordination exercises somatosensory and neck in different planes • Uses the vestibulo-ocular vestibular cues (ex: flexion, extension, reflex • Involves trunk rotation, etc.) head rotations, and gait • Uses cervical-ocular reflex exercises Rehabilitation exercises differ in their target Konnur MK. J Postgrad Med 2000;46:222–3. 23GPSRC PCP 058 PROM 0608 PIR_Nootropil Slide Kit Vertigo – © UCB PHARMA S.A. 2008. All rights reserved
  24. 24. Treatment is dependent on vertigo type Vertigo type Treatment Peripheral causes BPPV Canalith repositioning manoeuvre Labyrinthine concussion Vestibular rehabilitation Meniere’s disease Low-salt diet, diuretic, surgery, transtympanic gentamicin Labyrinthitis Antibiotics, removal of infected tissue, vestibular rehabilitation Perilymph fistula Bed rest, avoidance of straining Vestibular neuritis Brief course of high-dose steroids, vestibular rehabilitation Central causes Migraine Beta-blockers, calcium channel blockers, tricyclic amines Vascular disease Control of vascular risk factors, e.g., antiplatelet agents Cerebellopontine tumours Surgery Baloh RW. Lancet 1998;352:1841–6. Goebel JA. Otolaryngol Clin North Am 2000;33:483–93. 24GPSRC PCP 058 PROM 0608 PIR_Nootropil Slide Kit Vertigo – © UCB PHARMA S.A. 2008. All rights reserved
  25. 25. Piracetam: an alternative treatment for vertigo Theory behind its useGPSRC PCP 058 PROM 0608 PIR_Nootropil Slide Kit Vertigo – © UCB PHARMA S.A. 2008. All rights reserved
  26. 26. What is Piracetam? Piracetam: • is a nootropic drug, acting on cognitive function without causing sedation or stimulation • is a cyclic derivative of the neurotransmitter, γ-aminobutyric acid (GABA) • has neuronal and vascular effects Winblad B. CNS Drug Rev 2005; 11(2):169-82 26GPSRC PCP 058 PROM 0608 PIR_Nootropil Slide Kit Vertigo – © UCB PHARMA S.A. 2008. All rights reserved
  27. 27. Balance requires information of similar intensity from both vestibular systems Head movement Activation of cells in Activation of cells in left vestibular right vestibular system system Central nuclei 10 10 Normally, the input from left and right vestibular system is of similar intensity (e.g. of size ‘10’) 27GPSRC PCP 058 PROM 0608 PIR_Nootropil Slide Kit Vertigo – © UCB PHARMA S.A. 2008. All rights reserved
  28. 28. Central vertigo results from a dysfunction in central processing Input from left and right vestibular system remains of similar intensity Central nuclei 10 10 Impaired information transfer between vestibular nuclei causes central vertigo (e.g. of size ‘10’) Central vertigo requires central treatment 28GPSRC PCP 058 PROM 0608 PIR_Nootropil Slide Kit Vertigo – © UCB PHARMA S.A. 2008. All rights reserved
  29. 29. Peripheral vertigo results from a dysfunction in vestibular system functioning Central nuclei 5 10 29GPSRC PCP 058 PROM 0608 PIR_Nootropil Slide Kit Vertigo – © UCB PHARMA S.A. 2008. All rights reserved
  30. 30. Vestibular suppressants suppress vestibular function in both ears Central nuclei 5 10 1 2 Vestibular suppressants modify peripheral function bilaterally 30GPSRC PCP 058 PROM 0608 PIR_Nootropil Slide Kit Vertigo – © UCB PHARMA S.A. 2008. All rights reserved
  31. 31. Piracetam offers an interesting alternative to existing treatments Central nuclei 5 10 Piracetam appears to enhance the normal processes of vestibular compensation - recovery of oculomotor and postural functions - in patients with both peripheral and central vertigo. Such a mode of action provides a logical approach to symptomatic treatment, which is distinct from that of other agents, in particular that of vestibular suppressant agent. Rosenhall U. et al, Clin. Drug Invest. 1996;11 (5): 251-260. 31GPSRC PCP 058 PROM 0608 PIR_Nootropil Slide Kit Vertigo – © UCB PHARMA S.A. 2008. All rights reserved
  32. 32. Piracetam’s mode of action: the membrane hypothesis Nootropil® (piracetam) interacts polar head groups with the polar head groups of phospholipid membranes - + - + + Induces reorganisation of lipid phospholipid molecules bilayer piracetam Formation of mobile drug- phospholipid complexes May account for restored membrane fluidity Müller WE et al. Pharmacopsychiatr 1999;32(Suppl.1):2–9. Peuvot J et al. Biochem Pharmacol 1995;50:1129–34. 32GPSRC PCP 058 PROM 0608 PIR_Nootropil Slide Kit Vertigo – © UCB PHARMA S.A. 2008. All rights reserved
  33. 33. Restored membrane fluidity could account for Piracetam’s efficacy in vertigo Neuronal effects Vascular effects • Restored neurotransmission • Enhanced erythrocyte • Enhanced neuroplasticity deformability • Improved metabolism • Decreased adhesion of erythrocytes to endothelial wall • Facilitation of interhemispheric information transfer • Prevention of vasospasm • Normalised platelet hyperaggregability Improved neuronal function Improved microcirculation Facilitates vestibular compensation and adaptation Adapted from Winblad B. CNS Drug Rev 2005; 11(2):169-82. 33GPSRC PCP 058 PROM 0608 PIR_Nootropil Slide Kit Vertigo – © UCB PHARMA S.A. 2008. All rights reserved
  34. 34. A number of studies have examined the use of Piracetam in vertigo Patients Study Author Vertigo type randomised Intervention period (completed) Aantaa Post-concussion 60 (57) Piracetam 2.4 g/d or placebo 8 wks Deza Bringas Post-concussion 50 (50) Piracetam 4.8 g/d or placebo 8 wks Hakkarainen Post-concussion 60 (51) Piracetam 4.8 g/d or placebo 8 wks Dauman Peripheral 20 (20) Piracetam 3 g/d or placebo 30 days Haguenauer Peripheral 50 (50) Piracetam 2.4 g/d or placebo 60 days Gavalas1 Central 20 (20) Piracetam 2.4 g/d or placebo 8 wks Oosterveld* Central 22 (22) Piracetam 2.4 g/d or placebo 4 wks Rosenhall Central/peripheral 143 (89) Piracetam 2.4 g/d or placebo 8 wks *Cross over study, 2 weeks of each treatment. Aantaa. J Int Med Res 1975;3:352–5. Dauman. Les Cahiers d’O.R.L. 1995;4:241–8. Deza Bringas. Revista de Neuro-Psiquiatria 1984;47:74–86. Gavalas(1). Excerpta Medica 1988;533–8. Gavalas(2). Procs XIXth NES Meeting. March 1992. Guidetti. Riv Orl Aud Fond 1991;2:148–55. Haguenauer. Les Cahiers d’O.R.L 1986;21:460–6. Hakkarainen. Eur Neurol 1978;17:50–5. Oosterveld. Arzneimittelforschung 1980;30:1947–9. Rosenhall. Clin Drug Invest 1996;11:251–60. 34GPSRC PCP 058 PROM 0608 PIR_Nootropil Slide Kit Vertigo – © UCB PHARMA S.A. 2008. All rights reserved
  35. 35. Piracetam eliminates vestibular symptoms in more patients with peripheral vertigo than placebo Piracetam 2.4 g/day (n = 25) Placebo (n = 25) At baseline After 60 days’ treatment Nystagmus Index Imbalance Star Nystagmus Index Imbalance Star deviation gait deviation gait Haguenauer JP. Les Cahiers d’O.R.L 1986;21:460–6. 35GPSRC PCP 058 PROM 0608 PIR_Nootropil Slide Kit Vertigo – © UCB PHARMA S.A. 2008. All rights reserved
  36. 36. Piracetam significantly reduces frequency and intensity of vertigo crises Piracetam 2.4 g/day (n = 25) Placebo (n = 25) Peripheral vertigo treated for 60 days Before the study: • average of 40 vertigo episodes per month • average duration of vertigo > 6 months p<0.001 p<0.001 Haguenauer JP. Les Cahiers d’O.R.L 1986;21:460–6. Additional data on file (Oosterveld 2000) 36GPSRC PCP 058 PROM 0608 PIR_Nootropil Slide Kit Vertigo – © UCB PHARMA S.A. 2008. All rights reserved
  37. 37. Piracetam’s beneficial effect on vertigo persists without treatment following treatment cessation p<0.05 Day 84 Follow-up Piracetam 2.4 g/day Placebo n = 89 p<0.01 Day 56 treatment During Day 28 p<0.01 Adapted from Rosenhall U et al. Clin Drug Invest 1996;11:251–60. Day 84 is 4 weeks after cessation of treatment. 37GPSRC PCP 058 PROM 0608 PIR_Nootropil Slide Kit Vertigo – © UCB PHARMA S.A. 2008. All rights reserved number of vertigo episodes
  38. 38. Piracetam rapidly and markedly improves intensity of unspecified chronic vertigo Piracetam 3 g/day (n = 10) Placebo (n = 10) Worse Vertigo intensity Better Percentage improvement in vertigo intensity from baseline to day 15 was significantly greater with Piracetam than placebo (p<0.002) Dauman R et al. Les Cahiers d’O.R.L. 1995;4:241–8. 38GPSRC PCP 058 PROM 0608 PIR_Nootropil Slide Kit Vertigo – © UCB PHARMA S.A. 2008. All rights reserved
  39. 39. More patients achieved remission of vertigo symptoms with Piracetam than placebo Patients with vertigo of central origin treated for 8 weeks Piracetam 2.4 g/day (n = 10) Placebo (n = 10) % patients Clinician’s assessment of symptoms Gavalas G et al. Proceedings of the XVth Scientific meeting of the Neurootological and Equilibriometric Society. Bad Kissingen, 17-20 March 1988. (Excerpta Medica), 533–538. 1988. 39GPSRC PCP 058 PROM 0608 PIR_Nootropil Slide Kit Vertigo – © UCB PHARMA S.A. 2008. All rights reserved
  40. 40. Fewer patients experience instability between crises after Piracetam treatment Patients with chronic, unspecified vertigo of central origin Piracetam 3 g/day (n = 10) Placebo (n = 10) p<0.05 % patients without instability Dauman R et al. Les Cahiers d’O.R.L. 1995;4:241–8 40GPSRC PCP 058 PROM 0608 PIR_Nootropil Slide Kit Vertigo – © UCB PHARMA S.A. 2008. All rights reserved
  41. 41. Piracetam reduces vertigo-related symptoms between episodes Patients with vertigo of varying aetiologies received Piracetam or placebo for 8 weeks Piracetam 2.4 g/day (n = 47) Placebo (n = 42) Improvement -16 p<0.001 p<0.01 Change in VAS score (mm) -12 relative to baseline -8 -4 Deterioration 0 4 Imbalance Malaise Symptom severity between vertigo episodes Rosenhall U et al. Clin Drug Invest 1996;11:251–60. 41GPSRC PCP 058 PROM 0608 PIR_Nootropil Slide Kit Vertigo – © UCB PHARMA S.A. 2008. All rights reserved
  42. 42. Piracetam: Efficacy in post-concussion vertigoGPSRC PCP 058 PROM 0608 PIR_Nootropil Slide Kit Vertigo – © UCB PHARMA S.A. 2008. All rights reserved
  43. 43. Vertigo complaints after head trauma are common Dizziness occurs in approximately 50% of individuals after head or neck injury Usually due to pathologies in the vestibular, central nervous system or cervical structures Friedman JM. Med Health RI 2004;84:296–300 43GPSRC PCP 058 PROM 0608 PIR_Nootropil Slide Kit Vertigo – © UCB PHARMA S.A. 2008. All rights reserved
  44. 44. Three studies of similar design have been conducted with PIRACETAM IN POST-CONCUSSION VERTIGO Aantaa E. The effect of piracetam upon the late symptoms of patients with head injuries– 1975 Hakkarainen H, Hakamies L. Piracetam in the treatment of Post-Concussional Syndrome– 1978 Deza Bringas L. Treatment of the subjective post-traumatic syndrome with piracetam - 1984 ALL 3 STUDIES WERE: Double-blind and placebo-controlled With a 8-week treatment period Piracetam was administered as either a total dose of 2.4 g/day or 4.8 g/day Aantaa E, Meurman OH. J Int Med Res 1975;3:352–5; Deza Bringas L. Revista de Neuro-Psiquiatria 1984;47:74–86; Hakkarainen H, Hakamies L. A double-blind study. Eur Neurol. 1978;17(1):50-5. 44GPSRC PCP 058 PROM 0608 PIR_Nootropil Slide Kit Vertigo – © UCB PHARMA S.A. 2008. All rights reserved
  45. 45. Results of the 3 studies after 8 weeks Hakkarainen H, Aantaa E Deza Bringas L Hakamies L Patients analysed (n) 57 51 49 Patients with vertigo at 57/57 (100%) 51/51 (100%) 39/49 (79.6%) baseline (n%) Patients on piracetam 24/30 (80%) 22/26 (84.6%) 17/20 (85%) with improvement in p < 0.01 p <0.05 p < 0.001 vertigo (n%) Aantaa E, Meurman OH. J Int Med Res. 1975;3:352-5; Deza Bringas L. Revista de Neuro-Psiquiatria. 1984;47:74-86; Hakkarainen H, Hakamies L. A double-blind study. Eur Neurol. 1978;17(1):50-5. 45GPSRC PCP 058 PROM 0608 PIR_Nootropil Slide Kit Vertigo – © UCB PHARMA S.A. 2008. All rights reserved
  46. 46. Mechanism of action of piracetam in post-concussion vertigo Enhancement of central compensation and adaptation to vestibular dysfunction Enhancement of blood flow in the peripheral and central microcirculation Improvement of cognitive processes Improvement of concentration and memory problems Guidetti G., Cognition & Nootropics Summit, Athens, 2006. 46GPSRC PCP 058 PROM 0608 PIR_Nootropil Slide Kit Vertigo – © UCB PHARMA S.A. 2008. All rights reserved
  47. 47. Piracetam: Contraindications & Drug Interactions [Refer to your local full SPC before prescribing] Major Contraindications Piracetam should not be prescribed to patients with cerebral hemorrhage, end-stage renal impairment. Patients with Huntington Chorea, hypersensibility to piracetam, or other pyrrolidone derivatives, or any of the excipients. Avoid piracetam in pregnant or lactating women Drug interactions Piracetam is neither metabolized by the liver nor bound to plasma albumin. The potential for drug-drug interaction is, therefore, low. No interactions with sodium valproate have been reported. There are no known interactions of piracetam with any other drugs. Winblad B. CNS Drug Rev 2005;11(2):174. 47GPSRC PCP 058 PROM 0608 PIR_Nootropil Slide Kit Vertigo – © UCB PHARMA S.A. 2008. All rights reserved
  48. 48. Piracetam: Warnings and common undesirable effects [Refer to your lcoal full SPC before prescribing] Warnings Caution in patients with disorders of hemostasis, major surgery, or severe haemorrhage Caution in patients with renal impairment For long-term treatment in elderly, regular evaluation of Creatinine clearance is required to allow dosage adaptation if needed More common undesirable effects Hyperkinesia, weight increase, nervousness, somnolence, depression, asthenia. Winblad B. CNS Drug Rev 2005;11(2):174. 48GPSRC PCP 058 PROM 0608 PIR_Nootropil Slide Kit Vertigo – © UCB PHARMA S.A. 2008. All rights reserved
  49. 49. - Prescribing InformationNOOTROPIL®Piracetam Tablets/ Syrup/ InjectionsIntroduction:Pharmacotherapeutic group: Nootropics, The active substance, piracetam, is a pyrrolidone (2-oxo-1-pyrrolidine-acetamide), a cyclic derivative of gamma-amino butyric acid (GABA).Mechanism of action:Nootropil binds to the polar heads of membrane phospholipids physically in a dose dependent manner. It induces the restoration of the membrane lamellar structure characterized by the formation of mobile drug-phospholipid complexes. This probablyaccounts for improved membrane stability, allowing the membrane and transmembrane proteins to maintain or recover their three-dimensional folded structure essential for their function.Pharmacodynamics:Nootropil: neuronal and vascular effectsNootropil exerts its membrane activity in various ways at the level of the neurones. In animals, Nootropil enhances different types of neurotransmission, primarily through postsynaptic modulation of receptor density and activity.In both animals and man, the functions involved in cognitive processes such as learning, memory, attention and consciousness were enhanced, in the normal subject as well as in deficiency states, without the development of sedative orpsychostimulant effects. Nootropil protects and restores cognitive abilities in animals and humans after various cerebral insults such as hypoxia, intoxications and electroconvulsive therapy. It protects against hypoxia-induced changes in brain functionand performance, as assessed by electroencephalographic (EEG) and psychometric evaluations.Nootropil exerts its haemorrheological effects on the platelets, red blood cells, and vessel walls by increasing erythrocyte deformability and by decreasing platelet aggregation, erythrocyte adhesion to vessel walls and capillary vasospasm.Effects on red blood cellsNootropil improves the deformability of the erythrocyte membrane, decreases blood viscosity and prevents rouleaux formation in patients with sickle cell anemia.Effects on plateletsOpen studies with healthy volunteers and with patients have shown that gradually increasing the dose of Nootropil up to 12 g was associated with a dose-dependent reduction in platelet function compared with pretreatment values (tests of aggregationinduced by ADP, collagen, epinephrine and bTG release), without significant change in platelet count. In these studies, Nootropil prolonged bleeding time. Another study in healthy volunteers did not show any statistically significant difference betweenNootropil (up to 12 g b.i.d) and placebo regarding effects on haemostasis parameters and bleeding time.Effects on blood vesselsIn animal studies, Nootropil inhibited vasospasm and counteracted the effects of various spasmogenic agents. It lacked any vasodilatory action and did induce ‘steal’ phenomenon, nor low or neither reflow, nor hypotensive effects. In healthy volunteers,Nootropil reduced the adhesion of red blood cells to the vascular endothelium and directly stimulated prostacyclin synthesis in the healthy endothelium.Effects on coagulation factorsIn healthy volunteers, compared with pre-treatment values, Nootropil up to 9.6 g reduced plasma levels of fibrinogen and von Willebrand’s factors (VIII: C; VIII R: AG; VIII R: vW) by 30–40%, and increased bleeding time. In patients with both primaryand secondary Raynaud’s phenomenon, compared with pretreatment values, Nootropil 8 g/d administered over 6 months reduced plasma levels of fibrinogen and von Willebrand’s factors (VIII: C; VIII R: AG; VIII R: vW (RCF)) by 30–40%, reducedplasma viscosity, and increased bleeding time.PharmacokineticsThe pharmacokinetic profile of Nootropil is linear and time-independent with low inter-subject variability over a wide range of doses. This is consistent with its high permeability, high solubility and minimal metabolism. Plasma half-life of Nootropil is 5hours. It is similar in adult volunteers and in patients. It is increased in elderly patients (primarily due to impaired renal clearance) and in patients with renal impairment. Steady state plasma concentrations are achieved within 3 days of dosing.AbsorptionNootropil is rapidly and extensively absorbed following oral administration. In fasted subjects, peak plasma concentrations are achieved 1 hour after dosing. The absolute bioavailability of Nootropil oral formulations is close to 100%. Food does notaffect the extent of absorption of Nootropil but it decreases Cmax by 17% and increases tmax from 1 to 1.5 hours. Peak concentrations are typically 84 µg/ml and 115 µg/ml following a single oral dose of 3.2 g and repeat dose of 3.2 g t.i.d., respectively.DistributionNootropil is not bound to plasma proteins and its volume of distribution is approximately 0.6 l/kg. It is known to cross the blood-brain barrier as it has been measured in the cerebrospinal fluid following intravenous administration. In cerebrospinal fluid,the tmax was achieved at about 5 hours post-dose and the half-life was about 8.5 hours. In animals, NOOTROPIL highest concentrations in the brain were in the cerebral cortex (frontal, parietal and occipital lobes), in the cerebellar cortex and in thebasal ganglia. Nootropil diffuses to all tissues except the adipose tissues. It crosses placental barrier and penetrates the membranes of isolated red blood cells.BiotransformationNootropil is not known to be metabolized in the human body. This lack of metabolism is supported by its lengthy plasma half-life in anuric patients and by the high rate of recovery of the parent compound in the urine.EliminationThe plasma half-life of Nootropil in adults is about 5 hours following either intravenous or oral administration. The apparent total body clearance is 80–90 ml/min. The major route of excretion is via the urine, accounting for 80–100% of the dose.Nootropil is excreted by glomerular filtration.Renal impairmentNootropil clearance correlated with creatinine clearance. It is therefore recommended that the daily dose of Nootropil is adjusted according to creatinine clearance in patients with renal impairment. In anuric end-stage renal disease patients, the half-lifeof Nootropil is increased up to 59 hours. The fractional removal of Nootropil was 50–60% during a typical 4-hour dialysis session.Hepatic impairmentThe effect of hepatic impairment on the pharmacokinetics of Nootropil has not been evaluated. Because 80 to 100% of the dose is excreted in the urine as unchanged drug, hepatic impairment solely would not be expected to have a significant effect onpiracetam elimination. 49 GPSRC PCP 058 PROM 0608 PIR_Nootropil Slide Kit Vertigo – © UCB PHARMA S.A. 2008. All rights reserved
  50. 50. - Prescribing Information Preclinical safety data The preclinical data include that piracetam has a low toxicity potential. In vitro and in vivo studies have shown no potential for genotoxicity and carcinogenicity. Therapeutic indications In adults Symptomatic treatment of psycho-organic syndrome whose features, improved by treatment, are memory loss, attention disorders and lack of drive. Treatment of cortical myoclonus, alone or in combination Treatment of vertigo and associated disorders of balance, with the exception of dizziness of vasomotor or psychic origin For prophylaxis and remission of sickle cell vaso-occlusive crises. In children Treatment of dyslexia, in combination with appropriate measures such as speech therapy. For prophylaxis and remission of sickle cell vaso-occlusive crises. Dosage Cognitive impairment and post stroke sequelae : 4.8gms per day for 12 weeks. Cerebrovascular insufficiency Initiate treatment with 12 IV infusion (as a bolus given over 20 minutes) followed by 3gm IV infusion every 6 hour for at least 2-4 weeks. Further it is followed by 4.8gm orally for at least 12 weeks. Treatment of myoclonus of cortical origin: Nootropil is effective within a range of 7.2-24 gm/day. The starting dose could be 7.2 gm/day increasing by 4.8 gm/day every 3 days. Treatment of vertigo The recommended dosage of NTP is 2.4- 4.8 gm in BID or TID Treatment of dyslexia in combination with speech therapy NTP in 3.3 gm/day in 2 divided doses or 10 ml TID for one full school year Dosage adjustment Renal impairment The daily dose must be individualized according to Creatinine clearance. Creatinine clearanceSerum creatinine mg/100mlRecommended Dosage60-40 ml/min1.25-1.71/2 usual dosage40-20 ml/min1.7-31/4 usual dosage<20ml/min>3Contraindicated Adverse drug reactions: Psychiatric disorders, central and peripheral nervous system disorders, metabolic and nutritional disorders, were found to be associated as adverse effects with Nootropil. Contraindications • Hypersensitivity to piracetam or other pyrrolidone derivatives or any of the excipients • Patients with severe cerebral hemorrhage • End-stage renal disease patients Pregnancy and lactation • Animal studies have not indicated any direct or indirect harmful effects on pregnancy, embryonal/fetal development, parturition or post-natal development. • Insufficient data are available on the use of Nootropil in pregnant women. Nootropil should not be used during pregnancy unless absolutely necessary. • Nootropil is excreted in human breast milk and should be avoided during breastfeeding. PRESENTATION Nootropil tablets: Each film coated tablet contains Piracetam 800 mg and 1200 mg. Strip of 30 tablets. Nootropil Syrup: Each 5 ml contains Piracetam 500 mg. Bottle of 100 ml. Nootropil Injection Each ml contains Piracetam 200 mg. Bottle of 60 ml. Box of 4 ampoules of 15 ml each. Should any complaint arise, please mention the batch control number indicated on the package. UCB India Ltd. 133/2, G.I.D.C., Selvas Road, VAPI 396 195 ®Regd. Trade Mark of UCB, Belgium. 50GPSRC PCP 058 PROM 0608 PIR_Nootropil Slide Kit Vertigo – © UCB PHARMA S.A. 2008. All rights reserved

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