A review of the evidence of zolpidem efficacy in neurological disability after brain damage due to stroke, trauma and hypoxia: A justification of further clinical trials.

During 15 years, 23 clinical reports and 6 studies have demonstrated associations between sub-sedative doses of zolpidem and recoveries from brain damage due to strokes, trauma and hypoxia. Clinical findings include unexpected awakenings from vegetative states and regressions of stroke symptoms after dosing that disappear during elimination and reappear on repeat dosing. Initially single-photon emission computed tomography scans showed improved perfusion within, around and distant from infarctions. Then positron emission tomography scans and electroencephalography detected renewed metabolic and neuronal activity. Placebo or a similar, gamma-aminobutyric acid (GABA)-ergic, sedative zopiclone has no such effect. The effect appears only several months after the injury, reflecting recent evidence in mice of substantial differences between the states of GABA receptors in acute and chronic repair phases of recovery. Zolpidem's good safety record and rapid absorption further indicate a need for more clinical trials. List of acronyms: BOLD, Blood-Oxygen-Level Dependent contrast imaging in MRI; CRS, Coma Recovery Scale; CRS-R, Coma Recovery Scale Revised; CSI, Cerebral State Index; CSM, Cerebral State Monitor; DOC, Disorder of Consciousness; EEG, Electro Encephalography; FDG-PET, FluoroDeoxyGlucose-Positron Emission Tomography; FTD, Frontotemporal dementia; GABA, Gamma-Aminobutyric Acid; MCS, Minimally Conscious State; M-EEG, Magneto-Encephalography; MRI, Magnetic Resonance Image; MSN, Median Spiny Neurones; PET, Positron Emission Tomography; PVS, Persistent Vegetative Sate; RLAC, Rancho Los Amigos Cognitive scores; SPECT, Single-photon emission computed tomography; TFES, Tinetti Falls Efficacy Scale; 99mTc HMPAO, Technetium hexamethylpropyleneamine oxime.

Blood-brain barrier integrity in a zolpidem-responder patient.

A 27-year-old neurologically disabled but fully conscious male zolpidem-responder patient was investigated for blood brain barrier (BBB) dysfunction 5 years after a traumatic brain injury. A baseline single-photon emission computed tomography (SPECT) technetium-99m-labelled hexamethylpropylene amine oxime (99mTcHMPAO) brain scan was performed and the patient was administered 10 mg zolpidem daily. The patient was rescanned 2 weeks later when 99mTcHMPAO was injected 1 hour after zolpidem application. SPECT technetium-99m-labelled diethylene-triamine-pentacetic acid (99mTcDTPA) BBB scans were also performed before and after zolpidem treatment. There was decreased uptake of 99mTcHMPAO in the left frontoparietal brain region, left temporal region and left thalamus on baseline scanning; this improved within 1 hour after zolpidem treatment at the follow-up scan. The 99mTcDTPA scan remained within normal limits before and after zolpidem treatment. The patient's neurological disabilities, especially coordination, speech and gait, improved markedly. The Barthel Index remained normal, but the Tinetti falls efficacy scale improved from 21/100 to 15/100. The results implied that the underlying cause for the patient's long-term neurological disability and brain suppression was not due to a long-term dysfunctional BBB.

Radioiodine retention on percutaneous endoscopic gastrostomy tubes.

An 80-year-old male with recurrent thyroid cancer and a percutaneous endoscopic gastrostomy (PEG) tube in situ was referred for radioiodine therapy and was administered 5510 MBq I-131 sodium iodide intravenously. Sequential whole-body images taken over the subsequent 7 days for dosimetric evaluation revealed an area of persistent high uptake in the abdomen. Delayed imaging with single photon emission CT/CT at 15 days post administration revealed this uptake to be at the junction of the PEG tube with the anatomically normal stomach wall. We hypothesise that the PEG tube became contaminated by radioiodine secreted in the gastric mucosa during therapy and this radioactivity subsequently decayed with an increased effective half-life relative to the stomach, leading to the apparent hot spot.

Neurotransmitters in disorders of consciousness and brain damage.

Restorations from disorders of consciousness such as the minimally conscious state and the vegetative state have been achieved spontaneously or by pharmacological agents such as zolpidem, baclofen, dopaminergic agents and tricyclic antidepressants in some patients. Other restoration methods have included electric and magnetic nerve stimulation, oxygen, Kreb's cycle constituent substitution and axonal re-growth. Although apparently unrelated, these methods all influence neurotransmitter availability or production within the brain. This review proposes depleted neurotransmitter function as a cause for long term brain suppression and disorders of consciousness. It unifies fundamentally different treatment approaches and explores the restoration of neurotransmitter function as a common theme to improve brain function after brain damage.

Neurotransmitters in coma, vegetative and minimally conscious states, pharmacological interventions.

Articles on pharmacological interventions in disorders of consciousness after brain damage are increasingly appearing in the medical literature. This hypothesis links disorders of consciousness to the depletion of oxygen reliant neurotransmitters based in two biochemical axes, the amino acid axis (glutamate/GABA) and the monoamine axis (dopamine/noradrenalin and serotonin). After a brain injury, an immediate response inside the brain constitutes a surge of amino acids such as glutamate, GABA and others. Glutamate is excitatory and GABA inhibitory. The inhibitory response dominates and the brain becomes suppressed, leading to a loss in consciousness which reduces oxygen requirements. In time, GABA depletes after increased usage and leakage from the brain into the blood. If it cannot be restored sufficiently in some parts of the brain, a secondary response in these regions occurs which makes GABA receptors oversensitive to GABA, so that decreased GABA levels can maintain their suppressive effect. This occurs in prolonged disorders of consciousness as in the Vegetative State, which can be broken by agents such as zolpidem in some patients. In addition to amino acids, monoamine systems such as dopamine are essential to cognition and motor function. Their depletion or the suppression of brain regions in which they function, are proposed as contributors to disorders of consciousness. Reports of successful arousals after amino acid and monoamine based therapies supports the hypothesis that depletion of these brain chemicals may play a fundamental role in disorders of consciousness.

Measurement of cerebral perfusion after zolpidem administration in the baboon model.

A recent report showed that zolpidem (CAS 82626-48-0) can lead to the arousal of a semi-comatosed patient. Zolpidem is clinically used for the treatment of insomnia. It belongs to the imidazopyridine chemical class and is a non benzodiazepine drug. It illicits its pharmacological action via the GABA receptor system through stimulation of particularly the omega 1 receptors. In this study, the effect of zolpidem on brain perfusion was examined by 99mTc hexamethyl-propylene amine oxime (HMPAO) split dose brain SPECT on four normal baboons and in one baboon with abnormal neurological behaviour. The global and regional brain perfusion was not significantly affected in the normal brains. In some regions of the abnormal baboon brain, however, there was a disproportionate increase in perfusion after zolpidem.

Extraordinary arousal from semi-comatose state on zolpidem. A case report.

A young semi-comatose male patient was investigated using 99mTc hexamethyl-propylene amine oxime (99mTc HMPAO) brain single photon emission computed tomography (SPECT) before and after administration of the gamma-aminobutyric acid (GABA) agonist zolpidem. It was observed that 15 minutes after application of the drug the patient awoke from his semi-comatose condition and remained awake for the next 3-4 hours. When drug action subsided he returned to his semi-comatose state. Brain SPECT before drug application showed large hypo-active areas in certain parts of the brain. Brain SPECT after drug application showed a generalised cortical activation relative to the cerebellum and a marked and amplified activation of the areas that were hypo-active before drug application.

Comparison of iodotyrosines and methionine uptake in a rat glioma model.

UNLABELLED: This study compares brain tumor imaging with 3-[123I]iodo-alpha-methyl-L-tyrosine (IMT) and 3-[123I/125I]iodo-O-methyl-alpha-methyl-L-tyrosine (OMIMT) to that with [methyl-3H]-L-methionine (Met) in a rat glioma model by double-tracer autoradiography. METHODS: Cells of the glioma clone F-98 were implanted stereotactically into the right basal ganglia of 22 Fischer 344 rats. After 8 days of tumor growth, the animals simultaneously were injected with a mixture of either 123I-IMT and 3H-Met (n=5), 123I-OMIMT and 3H-Met (n=8) or 123I-IMT and 125I-OMIMT (n=9). The animals were killed 15 min after the tracer injection and cryosections of the tumor-bearing brain area were exposed to phosphor-imaging plates both immediately and after the decay of 123I. Tumor-to-brain ratios (T/B) and intratumoral distribution of the different tracers and of the cresyl violet staining of the tissue were compared. RESULTS: There was a significant correlation of the T/B ratios between all tracers (IMT versus Met: r=0.97, n=5, p < 0.01; OMIMT versus Met: r=0.94, n=8, p < 0.001; OMIMT versus IMT: r=0.95, n=9, p < 0.001). Intratumoral tracer distribution was similar for all tracers and the extent of tumor labeling was identical to that of the histological tumor extent. Mean values of the T/B ratios, however, were lower for IMT (2.81+/-0.78, n=14, mean+/-s.d., p < 0.01 compared with Met) and for OMIMT (2.03+/-0.57, n=17, p < 0.01 compared with Met) than for Met (3.86+/-1.12, n=13). CONCLUSION: This study confirms that tumor imaging with IMT is similar to that of Met but T/B ratios of IMT are lower. OMIMT intratumoral tracer distribution and tumor size are similar to Met and IMT, but the T/B contrast is rather low and makes this amino acid less suitable for clinical application.

Effect of carnitine and essential fatty acid supplementation on the uptake of 11C-carnitine in muscle of a myopathic carnitine-deficient patient using positron emission scintigraphy.

The aim of this study was to demonstrate the pattern of 11C-carnitine uptake after various treatment regimens in a myopathic carnitine-deficient patient and two normal volunteers, using a whole body counter specially adapted for positron emission. One carnitine-deficient patient and two normal volunteers were scanned after an intravenous injection of 11C-carnitine, both while on carnitine therapy and after discontinuation thereof. The third scan was done on the patient following carnitine and fatty acid therapy for 7 days. Both the carnitine-deficient patient and the normal volunteers showed improved 11C-carnitine uptake by thigh muscles after carnitine supplementation, and the carnitine-deficient patient even more so after carnitine and fatty acid supplementation. It is therefore concluded that the scintigraphic findings support the clinical impression that carnitine deficient patients improve after carnitine and essential fatty acid supplementation.

Scintigraphic evaluation of craniopagus twins.

Craniopagus twinning is a rare congenital abnormality, occurring at a frequency of 4-6 per 10 million births. A case is reported in which separation was successful for both twins. The importance of pre-operative radionuclide assessment of crucial organ function (liver, kidneys, heart, brain) and crossed circulation is stressed. The scintigraphic results were in keeping with radiographic, operative, and clinical findings. The routine use of radionuclide studies in the investigation of conjoined twins is recommended in order to delineate individual organ function, degree of fusion and measurement of cross-circulation.

Thyroidal radioisotope uptake in euthyroid cats: a comparison between 131I and 99mTcO4.

Two thyroidal evaluation systems in euthyroid cats (n = 12) were compared. A single, confirmed hyperthyroid cat was included for interest. Firstly, thyroidal uptake of an intravenous bolus of approximately 111 MBq (3 mCi) 99MTcO4 was estimated by using a scintillation camera and calculating the ratio of thyroid to salivary activities at 20 min and 4 h. Thyroid to salivary activity ratios were 1:1 at 20 min and 2:1 at 4 h. Two discrete areas of salivary uptake were identified, namely a parotid/mandibular complex and a more rostral buccal/sublingual complex. These results were compared to radioiodine uptake of an oral dose of approximately 0.925 MBq (25 microCi) 131I using a standard thyroid uptake system, measured at 1, 2, 4, 6, 8, 10, 12, 24 and 48 h after administration. Mean radioiodine thyroidal uptake started at 33% at 1 h, stabilised at 21% between 4 and 24 h, and dropped to 18% at 48 h. There was a significant correlation between the early thyroid:salivary ratio of the parotid/mandibular complex and the radioiodine uptake at 12 h.

Criteria and quantification of fibrous dysplasia on MDP scanning.

Eleven patients with histologically proven fibrous dysplasia (biopsy) were imaged with 3-phase bone scanning, using 99mTc-MDP. Ten had monostotic and one had polyostotic fibrous dysplasia. The perfusion (phase I) and uptake (phase III) of monostotic lesions was compared to the normal contralateral side and the rest of the skeleton was inspected for other abnormalities. Lesions presented with slightly increased perfusion (1.65 normal +/- 0.907) and markedly increased uptake of tracer (6.0 normal +/- 2.58). Other features that were noted are high spinal and scapula and poor renal tracer uptake.