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Evidence for Zolpidem Efficacy in Brain Damage Clauss RP, Mbchb, M

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Evidence for Zolpidem Efficacy in Brain Damage Clauss RP, Mbchb, M Case Study Evidence for Zolpidem efficacy in brain damage Clauss RP, MBChB, M. Med. (Nuc.Med.), MD. Nuclear Medicine Department, Royal Surrey County Hospital, Guildford, Surrey, GU2 7XX, United Kingdom. Nel H W, MBChB Family Practice, 9 Media Road, Pollack Park, Springs, South Africa Keywords: Zolpidem, brain injury, dormancy, diaschisis Corresponding: RP Clauss Nuclear Medicine Department Royal Surrey County Hospital Guildford, Surrey GU2 7XX, United Kingdom. Tel: 0944 1483 571122 (ext 2130) Fax: 0944 1483 406702 Email: [email protected] Abstract Previous reports have shown that zolpidem could reverse semi-coma and improve cerebral perfusion after brain injury. Studies in animals have implicated omega 1 GABAergic action as reason for this improvement. Evidence for the efficacy of zolpidem in a wide range of brain pathology is reviewed here and the mechanism of zolpidem in brain injury is considered from the perspective of diaschisis and neurological dormancy after brain injury. (SA Fam Pract 2005;47(3): 49-50) Introduction years earlier.3 The astounding findings Figure 1: 99mTc HMPAO Brain SPECT Over the past years we have observed in this patient, such as the return to his slices showing the left fronto-parietal cortex clinical and scintigraphic improvement semi-comatose state after the lapse of of a long distance walker five years after his motor vehicle accident, (a) before and in brain injured patients after drug action and the subsequent re- (b) after zolpidem. administration of 10 mg zolpidem. awakening from semi-coma after Zolpidem is a non-benzodiazepine drug renewed drug application, and also the belonging to the imidazopiridine class, findings of improved perfusion in chemically distinct from sedatives such previously supposed dead brain tissue, as barbiturates, antihistamines, led to further exploration of this benzodiazepines and cyclopyrrolones. phenomenon in animal studies and later It has selectivity for stimulating the effect in brain-injured patients who received of gamma aminobutyric acid (GABA) the drug for treatment of insomnia.4 and is used for the therapy of insomnia. It has a short half life of 2.4 hours with Current findings no active metabolite and does not So far, most of our studies show accumulate with repeated improved perfusion after zolpidem at administrations. The drug is oxidised the brain injury site on 99mTc HMPAO and hydroxylated by the liver to (hexa-methyl-propylene amine oxime) inactive metabolites that are eliminated Brain SPECT (Single Photon Emission 1 Figure 2: 99mTc HMPAO Brain SPECT primarily through renal excretion. GABA Computed Tomography) imaging, and images showing reversal of crossed systems involve various receptors and sometimes at other brain sites such as cerebellar diashisis in a stroke patient. receptor subtypes. The GABA (A) physiologically suppressed cerebellum Image (a) shows decreased tracer uptake receptor chloride channel (cerebellar diaschisis). 99mTc HMPAO in the right cerebral hemisphere (stroke) macromolecular complex is implicated Brain SPECT maps blood flow changes and left cerebellum (crossed cerebellar diaschisis) before zolpidem. Image (b) in sedative, anticonvulsant, anxiolytic in the brain and can determine if areas shows improved left cerebellar uptake and myorelaxant drug properties. Its of the brain are functioning properly or (reversal of diaschisis) after zolpidem but major modulating site is located on the not. This is in contrast this to MRI and no change in the right cerebral hemisphere alpha sub-unit, referred to as the CT scans that typically show only uptake. benzodiazepine (omega) receptor. There structural brain abnormalities such as are at least three omega receptor tumours or necrotic lesions. Changes subtypes. Benzodiazepines bind non- on 99mTc HMPAO Brain SPECT after selectively to these while zolpidem binds zolpidem are often accompanied by preferentially to omega 1 receptors.2 improving clinical states in brain Our interest in Zolpidem was spurred damaged patients, such as awakening by the accidental discovery of its effect from semi-coma, relief from brain injury on a patient who had been in semi - symptoms and improvement in sleep coma for more than three years. The abnormality. patient woke up from his semi-coma Figure 1 shows a section of damaged after receiving zolpidem and could brain on 99m Tc HMPAO SPECT imaging recognize and greet his mother for the in the left fronto-parietal hemi-cortex of first time since losing consciousness a long distance walker before and after SA Fam Pract 2005;47(3) 49 Case Study Figure 3: Bell’s palsy in a patient (a) before Discussion the disease progresses. Zolpidem and (b) after zolpidem The above evidence indicates a role for reverses symptoms due to brain GABA and GABA-dependent systems dormancy but does not change those in brain injury and ultimately coma. When due to necrotic or scarred brain tissue. zolpidem is applied some time after Hence the clinical effect that can be brain injury, there is an improvement in expected from the drug depends on the the clinical features caused by the brain size and location of the brain dormancy injury. Concurrent changes in brain area that can be reversed, and not the perfusion and metabolism are usually size of the actual brain lesion itself. A detected on 99m Tc HMPAO Brain SPECT. lesion on CT with a disproportionate The action is highly specific and it clinical incapacitation may respond well involves in particular omega 1 GABA to Zolpidem while a lesion with a small systems. For instance, when the semi- dormancy component or one where the zolpidem. This victim of a motor vehicle comatose patient received the non- dormancy is located in an insignificant accident five years prior to the scan, selective benzodiazepine diazepam brain location, may show no clinical experienced right sided weakness and instead of zolpidem for imaging studies, response. could not walk effectively without the he was not awakened. It appears that drug. Figure 2 shows improved the majority of brain injuries or brain Conclusion symmetry of a crossed cerebellar pathologies are associated with a There is increasing evidence for an diaschisis in a stroke patient, using the neurodormancy or diaschisis that important role of zolpidem in the drug for insomnia. This patient had a left probably has its roots in a treatment of the sequelae of a wide range hemiplegia but, in addition could not neuroprotective reaction of the brain of brain pathology, based on its reversal use his right hand due to insufficient during brain damage. Dormancy results of dormant neural tissue after brain coordination, although it was not in a clinical presentation that is actually damage. A number of brain injured paralyzed. After zolpidem, the left worse than would be expected from the patients may benefit from this treatment, hemiplegia remained but the patient was lesion alone (i.e. the brain lesion without especially those with features of able to use his right hand normally again. the associated dormancy). neurodormancy as proven by 99mTc Figure 3 shows a patient with Bell’s Palsy Dormancy or hibernation of HMPAO Brain SPECT, or a clinical picture as complication after removal of an myocardium after an ischeamic insult is that is disproportionate or incongruent acoustic neuroma more than a decade a well-known phenomenon in the heart. to the one that is expected from prior to zolpidem treatment. After Hibernating myocardium is non- radiological CT findings. zolpidem, the Bell’s Palsy improved and functional but fully viable. When blood nerve conduction studies showed a supply is re-instated after bypass References 1. Salva P, Costa J. Clinical pharmakinetics and decreased latency from 4.9 ms to 4.45 surgery, hibernating myocardium pharmadynamics of zolpidem. Therapeutic 14, 15 implications. Clin Pharmacokinet 1995; 29, 142- 153. ms. In a family of patients suffering from becomes functional again. Similar 2. Sanger DJ, Griebel G, Perrault G, Claustre Y, spinocerebellar ataxia type II, four out to myocardial tissue, brain dormancy Schoemaker H. Discriminative stimulus effects of drugs acting at GABA (A) receptors: differential profiles and of five patients showed improvement in appears to occur with most forms of receptor selectivity. Pharmacol Biochem Behav 1999; 64(2), 269- 273. their clinical features after zolpidem ischeamic brain injury or other forms of 3. Clauss RP, Güldenpfennig WM, Nel WH, Sathekge application. 5 brain damage. Its reversal explains the MM, Venkannagari RR. Extraordinary arousal from semi-comatose state on zolpidem: A case report. S There are further reports of the wide efficacy of zolpidem in unrelated Afr Med J 2000; 90, 68. 4. Clauss RP, van der Merwe CE, Nel HW. Arousal from efficacy of zolpidem in brain pathology brain injuries, from genetic disorders a semi-comatose state on zolpidem. S Afr Med J 2001; 91(10). 788- 789. by other authors. In 1997 Thomas et al such as spinocerebellar ataxia type II, 5. Clauss RP, Sathekge MM, Nel HW. Transient reported the recovery from catatonia in to stroke and traumatic brain injury. Brain improvement of Spinocerebellar Ataxia with Zolpidem. 6 N Engl J Med 2004; 351(5): 511-512. patients after zolpidem. The drug was dormancy is most likely concurrent with 6. Thomas P, Rascle C, Mastain B, Maron M, Guillaume V. Test for catatonia with zolpidem. Lancet 1997; 349: 702. also reported to have a beneficial effect a structural change or folding of the 7. Daniele A, Albanese A, Gainotti G, Gregori B, in certain Parkinson’s disease patients complex GABA receptor molecule. This Bartolomeo P. Zolpidem in Parkinson’s disease. Lancet 7, 1997; 349:1222-1223. and in Progressive Supranuclear Palsy. state can be at least partially reversed 8. Mayr BJ, Bonelli RM, Niederwieser G, Költringer P, 8 Reisecker F. Zolpidem in progressive supranuclear In a recent case report, a patient with by selective GABAergic stimulation of palsy. Eur J Neurol 2002; 9(2)3: 184-185. 9. Cohen L, Chaaban B, Haberl M-O.
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