[Toward the complete understanding of the pathogenic mechanism of clioquinol-induced subacute myelo-optic neuropathy (SMON)].

Clioquinol was extensively used as an amebicide to treat indigestion and diarrhea in the mid-1900s. However, it was withdrawn from the market in Japan because its use was epidemiologically linked to an increase in the incidence of subacute myelo-optic neuropathy (SMON). SMON is characterized by the subacute onset of sensory and motor disturbances in the lower extremities with occasional visual impairments, which are preceded by abdominal symptoms. Although pathological studies demonstrated axonopathy of the spinal cord and optic nerves, the underlying mechanisms of clioquinol toxicity have not been elucidated in detail. We previously performed a global analysis of human neuroblastoma cells using DNA chips and demonstrated that clioquinol induced 1) DNA double-strand breaks and subsequent activation of ATM/p53 signaling; 2) the expression of VGF, the precursor of neuropeptides involved in pain reactions, by inducing c-Fos; 3) the expression of interleukin-8, which is reported to be involved in intestinal inflammation, optic neuropathy, and neuropathic pain, by down-regulating GATA-2 and GATA-3. We also demonstrated that clioquinol induced zinc influx and oxidation of the copper chaperone ATOX1, leading to the impairment of the functional maturation of a copper-dependent enzyme dopamine-ß-hydroxylase and the inhibition of noradrenaline biosynthesis. Thus, clioquinol-induced neurotoxicity in SMON seems to be mediated by multiple pathways.

[Fifity years after the identification of the cause of SMON].

SMON (subacute myelo-optico-neuropathy) is toxic neurological disease which had a profound impact on the population in Japan in 1960's. The clinical characteristics of SMON includes an ascending sensory disturbance, spasticity, and visual impairment typically following abdominal symptoms. Infection was first suspected as an underlying cause of this epidemic. The disorder was ultimately attributed to the overuse of clioquinol, based on the analysis of green urine from affected patients and confirmed by the epidemiological surveys and experimental animal studies. The factors that contributed to the prevalence of SMON which remains the worst example of drug-associated toxicity in Japan to date include the conversion of clioquinol from a purely topical agent to an orally-administered drug, dogma associated with drug safety, relatively limited regulation of drug use, an increase in the number of prescriptions due to the availability of universal insurance, as well as the complexity of the associated abdominal symptoms. Periodical examination of the patients diagnosed with SMON continues to this day. As such, it is important to have a better understanding of clioquinol-induced neurotoxicity together with the mechanisms underlying drug susceptibility; we should not permit the memory of this severe and prominent drug-associated toxicity fade from view.

Sleep problems in subacute myelo-optico neuropathy (SMON).

Subacute myelo-optico neuropathy (SMON) patients typically suffer from sequelae that cause sleep disturbances. We sought to examine the prevalence of sleep problems among SMON patients. We conducted a questionnaire-based survey concerning sleep problems among 106 SMON patients, and 110 age- and gender-matched control participants. The prevalence of subjective insomnia (6 ≤ Athens Insomnia Scale score) was 89.6% among SMON patients, which was significantly higher than among control participants 54.4%. Sleep quality measured with the Pittsburgh Sleep Quality Index (PSQI) revealed that the prevalence of poor sleepers (6 ≤ PSQI score) was higher among SMON patients than control participants (75.6% vs 39.6%, respectively). Subscale analyses of rapid eye movement sleep behavior disorder screening questionnaire revealed that scores on two items ("dreams match nocturnal behavior" and "limb movements") were significantly higher among SMON patients than control participants. In addition, daytime sleepiness scores were significantly higher among SMON patients than control participants (4 ≤ Epworth Sleepiness Scale scores: 54.0% vs 29.0%, respectively). The current study revealed that most SMON patients suffer from insomnia with dissatisfactory sleep quality, likely due to their long-term physical sequelae. Moreover, SMON patients showed higher rates of daytime sleepiness and sleep medication intake, which could be related to reduced activity during the day, as well as insomnia.

Clioquinol: To harm or heal.

Clioquinol, one of the first mass-produced drugs, was considered safe and efficacious for many years. It was used as an antifungal and an antiprotozoal drug until it was linked to an outbreak of subacute myelo-optic neuropathy (SMON), a debilitating disease almost exclusively confined to Japan. Today, new information regarding clioquinol targets and its mechanism of action, as well as genetic variation (SNPs) in efflux transporters in the Japanese population, provide a unique interpretation of the existing phenomena. Further understanding of clioquinol's role in the inhibition of cAMP efflux and promoting apoptosis might offer promise for the treatment of cancer and/or neurodegenerative diseases. Here, we highlight recent developments in the field and discuss possible connections, hypotheses and perspectives in clioquinol-related research.

Oral clioquinol is effective in the treatment of a fly model of Candida systemic infection.

BACKGROUND: Clioquinol was used in the 1950s-1970s as antimicrobial but its oral formulations were withdrawn from the market due to suspected neurotoxicity. Currently, there is possibility of repositioning of oral clioquinol formulations. OBJECTIVES: To evaluate the antifungal activity and toxicological parameters of clioquinol and the other two 8-hydroxyquinoline derivatives using alternative animal models and to study the interaction dynamic of clioquinol with Candida albicans. METHODS: We used Toll-deficient Drosophila melanogaster to test the protective effect of 8-hydroxyquinolines against C. albicans infection. Toxicological parameters were investigated in chicken embryo. A mathematical model-based analysis of the time-kill data of clioquinol was performed to obtain pharmacodynamic characteristics. RESULTS: Clioquinol fully protected D. melanogaster from the infection. The 8-hydroxyquinolines did not cause changes in opening of the beak and movement of the chicken embryo; however, clioquinol and compound 2 increased arterial pulsation. Compound 3 was lethal at 1 mg mL-1 . Effective concentration found in modelling indicated that clioquinol was highly effective against C. albicans (0.306 µg mL-1 ) in easily achievable serum levels; clioquinol rapidly achieved kill rate reaching the maximum effect after 13 hours. CONCLUSIONS: These results support the potential of clioquinol to be used as a systemic antifungal agent.

Physical Disabilities Related to the Depressive Mental States of Japanese Patients with Subacute Myelo-optico-neuropathy.

Objective The aim of this study was to clarify the clinical conditions related to the depressive mental states in Japanese patients with subacute myelo-optico-neuropathy (SMON), caused by clioquinol intoxication more than 40 years previously. Methods The changes in the mental states with aging were investigated in 25 Japanese SMON patients (mean age: 77.2 years old, range: 53-90) using a Japanese version of the Zung Self-rating Depression Scale (J-SDS) questionnaires with supportive interviews by the clinical psychotherapist and medical checkup records. These mental and medical examinations were repeated more than twice within 2 to 11 years' interval. The J-SDS questionnaires were also examined in 25 age-matched non-SMON elderly people. Results The total J-SDS scores of most of the SMON patients decreased with age without significant changes in the mean Barthel index scores during this study period. The mean J-SDS scores at the first and latest studies were significantly higher than in the age-matched healthy elderly people. The total J-SDS scores of the latest study were significantly correlated with the degree of physical disability, such as the inverse total Barthel index scores, severity of SMON or gait disturbance, but not with the age. Conclusion The total J-SDS scores of most of the SMON patients tended to decrease with age. Repeating mental supportive interviews and medical examinations by experts helped to improve the depressive mental state and revealed close relationship between the mental state and the physical disabilities of the SMON patients.

Effects of clioquinol on the scuticociliatosis-causing protozoan Miamiensis avidus in olive flounder Paralichthys olivaceus.

Scuticociliatosis is a devastating and intractable protozoal disease in olive flounder, leading to a significant loss throughout the year. This study aimed to investigate a systemically effective antiscuticociliatosis agent for olive flounder for better absorption into the infected internal organs. The in vitro and in vivo antiscuticociliatosis effects of clioquinol (CQ) were examined after screening 30 biocidal agents against the highly pathogenic scuticociliate Miamiensis avidus. CQ was the most potent in vitro drug of those tested against cultured M. avidus. CQ was the least toxic in healthy olive flounder among the drugs that exhibit high potencies. In olive flounder, a single intramuscular injection of 40 mg/kg CQ significantly reduced mortality caused by artificial infection with M. avidus, and 10-20 mg/kg CQ increased fish survival times. CQ was also effective in naturally infected scuticociliatosis. Ciliate cell numbers were lower when CQ was injected in most organs, including the brain. CQ was well absorbed by the internal organs after intramuscular injection. This study suggests that CQ can be considered as a potential antiscuticociliatosis agent for systemic administration in olive flounder.

Tongue strength in patients with subacute myelo-optico-neuropathy.

Subacute myelo-optico-neuropathy (SMON) is a neurodegenerative disease that may be caused by overdose or prolonged oral administration of clioquinol. Recently, dysphagia has attracted attention as a complication of SMON. To investigate lingual control in SMON, we examined patients with SMON using assessments of maximum tongue pressure, compared with dysphagia-related diseases, such as sporadic inclusion body myositis (sIBM) and amyotrophic lateral sclerosis (ALS), and healthy volunteer. The mean maximum tongue pressure (Pmax) in patients with SMON was 14.7 ±â€¯5.8 kPa, while it was 33.6 ±â€¯4.4 kPa in the controls. In contrast, the mean Pmax for patients with ALS with or without bulbar involvement was 7.8 ±â€¯2.7 kPa and 34.4 ±â€¯5.7 kPa, respectively, while it was 29.4 ±â€¯8.2 kPa in patients with sIBM. Pmax values correlated with lower limb weakness in SMON patients. Decreases in Pmax may be involved in the development of dysphagia in patients with SMON.

The Aggravation of Depression with Aging in Japanese Patients with Subacute Myelo-optico-neuropathy (SMON).

Objective We attempted to clarify the factors related to the aggravation of depression in patients with subacute myelo-optico-neuropathy (SMON) caused by clioquinol intoxication more than 35 years previously. Methods We investigated changes in the depressive mental states that occurred with aging in 19 Japanese SMON patients (mean age, 78.3 years; range, 66-89 years) according to their scores on the Japanese version of the Zung Self-rating Depression Scale (SDS), which were obtained 3-10 years previously and their current scores. The depressive state was further evaluated using simultaneous semi-structured interviews. Results The depressive mental states of 6 patients, whose current total SDS scores had increased by ≥10% in comparison to the previous score, were considered to have been aggravated with aging. The mean current total SDS score of these six patients was significantly higher than the mean score of the 13 patients whose conditions were not aggravated. Among the 20 SDS questionnaires, the patients whose conditions were aggravated showed significantly higher scores in diurnal variation, sleep disturbance and weight loss. The semi-structured interviews revealed that physical disabilities due to the sequelae of SMON, a lack of acceptance of SMON, and a decline in social activities were important factors in the aggravation of their depressive mental states with aging. Conclusion The maintenance of social activities with public support was important for coping among Japanese SMON patients with a depressive mental state, especially those who could not walk independently or who could not go outside freely without assistance.

The prevalence of dementia in subacute myelo-optico-neuropathy (SMON) patients who underwent medical checkups.

AIM: Subacute myelo-optico-neuropathy (SMON) is a known adverse effect of clioquinol use; however, clioquinol dissolves beta-amyloid aggregation in Alzheimer's disease (AD). Therefore, we investigated the prevalence of dementia in SMON patients and whether past clioquinol use affected the current incidence of AD. METHODS: We included 647 SMON patients (195 men, 452 women; mean age 77.9 years) who had undergone medical checkups including the mini-mental state examination (MMSE) in 2012. Of them, 105 patients scored ≤23 on the MMSE assessment. The presence/absence of dementia and disease backgrounds were obtained by a questionnaire. Then, using the medical checkup database, the correlation between the degree of severity when signs of SMON were at their worst and the concurrent presence or absence of AD at present was analyzed. RESULTS: In patients ≥65 years of age, the estimated prevalence of dementia was approximately 10.9% (95% confidence interval: 7.9%-13.8%). The concurrent presence of AD at present was not correlated with the past degree of SMON severity when the SMON signs were at their worst. CONCLUSIONS: The 10.9% prevalence of dementia in SMON patients was lower than a previously reported 15% prevalence found in the general population. According to these results, we cannot draw a definitive conclusion regarding the preventive effect of clioquinol on AD. Additionally, the lack of association between the onset of AD and past severity of SMON precludes definitive conclusions on the relationship between concurrent presence of AD and past clioquinol use.

Safety, tolerability, and efficacy of PBT2 in Huntington's disease: a phase 2, randomised, double-blind, placebo-controlled trial.

BACKGROUND: PBT2 is a metal protein-attenuating compound that might reduce metal-induced aggregation of mutant huntingtin and has prolonged survival in a mouse model of Huntington's disease. We aimed to assess the safety, tolerability, and efficacy of PBT2 in patients with Huntington's disease. METHODS: In this 26-week, randomised, double-blind, placebo-controlled trial, adults (≥25 years old) with early-stage to mid-stage Huntington's disease were randomly assigned (1:1:1) by a centralised interactive response system to once daily PBT2 250 mg, PBT2 100 mg, or placebo. Randomisation was stratified by site with a block size of three. Participants, carers, the steering committee, site investigators, study staff, and the study sponsor were masked to treatment assignment. Primary endpoints were safety and tolerability. The safety population consisted of all participants who were randomly assigned and had at least one dose of study drug. The principal secondary endpoint was cognition, measured by the change from baseline to week 26 in the main composite Z score of five cognitive tests (Category Fluency Test, Trail Making Test Part B, Map Search, Symbol Digit Modalities Test, and Stroop Word Reading Test) and scores on eight individual cognitive tests (the five aforementioned plus the Trail Making Test Part A, Montreal Cognitive Assessment, and the Speeded Tapping Test). The intention-to-treat population comprised participants who were randomly assigned and had at least one efficacy assessment after administration of study drug. This trial is registered with ClinicalTrials.gov, NCT01590888. FINDINGS: Between April 18, 2012, and Dec 14, 2012, 109 participants were randomly assigned to PBT2 250 mg (n=36), PBT2 100 mg (n=38), or placebo (n=35) at 19 research centres in Australia and the USA. 32 (89%) individuals on PBT2 250 mg, 38 (100%) on PBT2 100 mg, and 34 (97%) on placebo completed the study. Six serious adverse events (acute coronary syndrome, major depression, pneumonia, suicide attempt, viral infection, and worsening of Huntington's disease) occurred in five participants in the PBT2 250 mg group, three (fall with subdural haematoma, suicide attempt, and hospital admission for stabilisation of Huntington's disease) occurred in two participants in the PBT2 100 mg group, and one (increasing aggression) occurred in a participant in the placebo group. The site investigators deemed all, except the worsening of Huntington's disease, as unrelated to study drug. 32 (89%) participants on PBT2 250 mg, 30 (79%) on PBT2 100 mg, and 28 (80%) on placebo had at least one adverse event. Compared with placebo, neither PBT2 100 mg (least-squares mean 0·02, 95% CI -0·10 to 0·14; p=0·772) nor PBT2 250 mg (0·07, -0·05 to 0·20; p=0·240) significantly improved the main composite cognition Z score between baseline and 26 weeks. Compared with placebo, the Trail Making Test Part B score was improved between baseline and 26 weeks in the PBT2 250 mg group (17·65 s, 0·65-34·65; p=0·042) but not in the 100 mg group (0·79 s improvement, -15·75 to 17·32; p=0·925); neither dose significantly improved cognition on the other tests. INTERPRETATION: PBT2 was generally safe and well tolerated in patients with Huntington's disease. The potential benefit on executive function will need to be confirmed in a larger study. FUNDING: Prana Biotechnology Limited.

Clioquinol increases the expression of VGF, a neuropeptide precursor, through induction of c-Fos expression.

Clioquinol was used extensively in the mid-1900s as an amebicide to treat indigestion and diarrhea. It was eventually withdrawn from the market because it was linked to subacute myelo-optic neuropathy (SMON) in Japan. However, the pathogenesis of SMON has not yet been elucidated in detail. As reported previously, we performed a global analysis on human neuroblastoma cells using DNA chips. The global analysis and quantitative PCR demonstrated that the mRNA level of VGF (nonacronymic), the precursor of neuropeptides involved in pain reactions, was significantly increased when SH-SY5Y and IMR-32 neuroblastoma cells were treated with clioquinol. Promoter analyses in SH-SY5Y cells revealed that a region responsive to clioquinol exists between -1381 and -1349 of the human VGF gene, which contains an activator protein (AP)-1 site-like sequence. The introduction of mutations at this site significantly reduced clioquinol-induced transcriptional activation. Clioquinol induced the expression of the AP-1 family transcription factors, c-Jun and c-Fos. Electrophoresis mobility shift assays demonstrated that c-Jun and c-Fos could bind to the AP-1 site at -1374/-1368 in SH-SY5Y cells treated with clioquinol. RNA interference against c-Fos significantly suppressed clioquinol-induced VGF mRNA expression. These results suggest that the clioquinol-induced expression of c-Fos mediates the induction of VGF expression.

Metal protein attenuating compounds for the treatment of Alzheimer's dementia.

BACKGROUND: Alzheimer's dementia (AD) may be caused by the formation of extracellular senile plaques comprised of beta-amyloid (Aß). In vitro and mouse model studies have demonstrated that metal protein attenuating compounds (MPACs) promote the solubilisation and clearance of Aß. OBJECTIVES: To evaluate the efficacy of metal protein attenuating compounds (MPACs) for the treatment of cognitive impairment due to Alzheimer's dementia. SEARCH METHODS: We searched ALOIS, the Cochrane Dementia and Cognitive Improvement Group Specialized Register, on 29 July 2010 using the terms: Clioquinol OR PBT1 OR PBT2 OR "metal protein" OR MPACS OR MPAC. SELECTION CRITERIA: Randomised double-blind trials in which treatment with an MPAC was administered to participants with Alzheimer's dementia in a parallel group comparison with placebo were included. DATA COLLECTION AND ANALYSIS: Three review authors (RM, LJ, ELS) independently assessed the quality of trials according to the Cochrane Handbook for Systematic Reviews of Interventions.The primary outcome measure of interest was cognitive function (as measured by psychometric tests). The secondary outcome measures of interest were in the following areas: quality of life, functional performance, effect on carer, biomarkers, safety and adverse effects, and death. MAIN RESULTS: Two MPAC trials were identified. One trial compared clioquinol (PBT1) with placebo in 36 patients and 32 had sufficient data for per protocol analysis. There was no statistically significant difference in cognition (as measured on the Alzheimer's Disease Assessment Scale - Cognition (ADAS-Cog)) between the active treatment and placebo groups at 36 weeks. The difference in mean change from baseline ADAS-Cog score in the clioquinol arm compared with the placebo arm at weeks 24 and 36 was a difference of 7.37 (95% confidence interval (CI) 1.51 to 13.24) and 6.36 (95% CI -0.50 to 13.23), respectively.There was no significant impact on non-cognitive symptoms or clinical global impression. One participant in the active treatment group developed neurological symptoms (impaired visual acuity and colour vision) which resolved on cessation of treatment and were possibly attributable to the drug.In the second trial a successor compound, PBT2, was compared with placebo in 78 participants with mild Alzheimer's dementia; all were included in the intention-to-treat analysis. There was no significant difference in the Neuropsychological Test Battery (NTB) composite or memory between placebo and PBT2 in the least squares mean change from baseline at week 12. However, two executive function component tests of the NTB showed significant improvement over placebo in the PBT2 250 mg group from baseline to week 12: category fluency test (2.8 words, 95% CI 0.1 to 5.4; P = 0.041) and trail making part B (-48.0 s, 95% CI -83.0 to -13.0; P = 0.009). In the executive factor Z score, the difference in least squares mean change from baseline at week 12 for PBT2 250 mg compared with placebo was 0·27 (0·01 to 0·53; p=0·042).There was no significant effect on cognition on Mini-Mental State Examination (MMSE) or ADAS-Cog scales. PBT2 had a favourable safety profile. AUTHORS' CONCLUSIONS: There is an absence of evidence as to whether clioquinol (PBT1) has any positive clinical benefit for patients with AD, or whether the drug is safe. We have some concerns about the quality of the study methodology; there was an imbalance in treatment and control groups after randomisation (participants in the active treatment group had a higher mean pre-morbid IQ) and the secondary analyses of results stratified by baseline dementia severity. The planned phase III trial of PBT1 has been abandoned and this compound has been withdrawn from development. The second trial of PBT2 was more rigorously conducted and showed that after 12 weeks this compound appeared to be safe and well tolerated in people with mild Alzheimer's dementia. Larger trials are now required to demonstrate cognitive efficacy.

A phase I study of the metal ionophore clioquinol in patients with advanced hematologic malignancies.

UNLABELLED: Clioquinol is a small-molecule metal ionophore that inhibits the proteasome through a metal-dependent mechanism. Here, we report a phase I study of clioquinol in patients with refractory hematologic malignancies. Neuropathy and abdominal pain were dose-limiting toxicities. Minimal pharmacodynamic effects were observed, and there were no clinical responses. BACKGROUND: Clioquinol is a small-molecule metal ionophore that inhibits the enzymatic activity of the proteasome and displays preclinical efficacy in hematologic malignancies in vitro and in vivo. Therefore, we conducted a phase I clinical trial of clioquinol in patients with refractory hematologic malignancies to assess its safety and determine its biological activity in this patient population. METHODS: Patients with refractory hematologic malignancies were treated with increasing doses of oral clioquinol twice daily for 15 doses. Plasma and intracellular levels of clioquinol were measured. Enzymatic activity of the proteasome was measured before and after drug administration. RESULTS: Sixteen cycles of clioquinol were administered to 11 patients with 5 patients reenrolled at the next dose level as per the permitted intrapatient dose escalation. Dose-limiting neurotoxicity and abdominal pain were observed at a dose of 1600 mg twice daily. Intracellular drug levels were low. Minimal inhibition of the proteasome was observed. No clinical responses were observed. CONCLUSION: In patients with refractory hematologic malignancies, the maximal tolerated dose of clioquinol was determined. Minimal inhibition of the proteasome was observed at tolerable doses, likely due to low intracellular levels of the drug.

Metal protein attenuating compounds for the treatment of Alzheimer's dementia.

BACKGROUND: Alzheimer's dementia (AD) may be caused by the formation of extracellular senile plaques comprised of beta-amyloid (Aß). In vitro and mouse model studies have demonstrated that metal protein attenuating compounds (MPACs) promote the solubilisation and clearance of Aß. OBJECTIVES: To evaluate the efficacy of metal protein attenuating compounds (MPACs) for the treatment of cognitive impairment due to Alzheimer's dementia. SEARCH METHODS: We searched ALOIS, the Cochrane Dementia and Cognitive Improvement Group Specialized Register, on 29 July 2010 using the terms: Clioquinol OR PBT1 OR PBT2 OR "metal protein" OR MPACS OR MPAC. SELECTION CRITERIA: Randomised double-blind trials in which treatment with an MPAC was administered to participants with Alzheimer's dementia in a parallel group comparison with placebo were included. DATA COLLECTION AND ANALYSIS: Three review authors (RM, LJ, ELS) independently assessed the quality of trials according to the Cochrane Handbook for Systematic Reviews of Interventions.The primary outcome measure of interest was cognitive function (as measured by psychometric tests). The secondary outcome measures of interest were in the following areas: quality of life, functional performance, effect on carer, biomarkers, safety and adverse effects, and death. MAIN RESULTS: Two MPAC trials were identified. One trial compared clioquinol (PBT1) with placebo in 36 patients and 32 had sufficient data for per protocol analysis. There was no statistically significant difference in cognition (as measured on the Alzheimer's Disease Assessment Scale - Cognition (ADAS-Cog)) between the active treatment and placebo groups at 36 weeks. The difference in mean change from baseline ADAS-Cog score in the clioquinol arm compared with the placebo arm at weeks 24 and 36 was a difference of 7.37 (95% confidence interval (CI) 1.51 to 13.24) and 6.36 (95% CI -0.50 to 13.23), respectively.There was no significant impact on non-cognitive symptoms or clinical global impression. One participant in the active treatment group developed neurological symptoms (impaired visual acuity and colour vision) which resolved on cessation of treatment and were possibly attributable to the drug.In the second trial a successor compound, PBT2, was compared with placebo in 78 participants with mild Alzheimer's dementia; all were included in the intention-to-treat analysis. There was no significant difference in the Neuropsychological Test Battery (NTB) composite, memory or executive scores between placebo and PBT2 in the least squares mean change from baseline at week 12. However, two executive function component tests of the NTB showed significant improvement over placebo in the PBT2 250 mg group from baseline to week 12: category fluency test (2.8 words, 95% CI 0.1 to 5.4; P = 0.041) and trail making part B (-48.0 s, 95% CI -83.0 to -13.0; P = 0.009). There was no significant effect on cognition on Mini-Mental State Examination (MMSE) or ADAS-Cog scales. PBT2 had a favourable safety profile. AUTHORS' CONCLUSIONS: There is an absence of evidence as to whether clioquinol (PBT1) has any positive clinical benefit for patients with AD, or whether the drug is safe. We have some concerns about the quality of the study methodology; there was an imbalance in treatment and control groups after randomisation (participants in the active treatment group had a higher mean pre-morbid IQ) and the secondary analyses of results stratified by baseline dementia severity. The planned phase III trial of PBT1 has been abandoned and this compound has been withdrawn from development. The second trial of PBT2 was more rigorously conducted and showed that after 12 weeks this compound appeared to be safe and well tolerated in people with mild Alzheimer's dementia. Larger trials are now required to demonstrate cognitive efficacy.

[Evaluation of neurological symptoms related to hip fracture in a 29-year longitudinal study of subacute myelo-optic-neuropathy (SMON)].

AIM: Hip fracture in elderly people is a major risk factor in the deterioration of activities of daily living (ADL). The aim of this study was to investigate the incidence of hip fractures and the neurological symptoms contributing to hip fracture in patients with subacute myelo-optic-neuropathy (SMON), a drug-induced neurological disease manifesting various symptoms. METHODS: We investigated the incidence of hip fracture in 3,269 SMON patients with 24,187 medical check-ups from 1979 through 2007 by the SMON Research Committee in Japan. Neurological symptoms were evaluated in 80 patients who had undergone clinical examinations within 2 years before the fracture (hip-fracture group: age at examination = 75.7 ± 8.8 years (mean ± SD)), and the control group (160 SMON patients without a history of hip fracture; 76.5 ± 10.4) were matched for age, gender, and duration of illness. Incidence of hip fracture in SMON as well as severity of visual acuity, motor and sensory symptoms, and ADL were investigated. RESULTS: A total 230 hip fractures occurred in 208 patients (6.4%) with a men-to-women ratio of 21 : 187. In comparison with the Japanese general population, SMON patients showed a statistically high incidence of hip fracture in the 50s and 60s age groups in women (p < 0.002 in both), and in those under 40 (p < 0.02) and in their 50s (p < 0.002) in men. In those with neurological symptoms related to gait, the percentage of subjects who could walk with crutches was significantly higher in the hip-fracture group (43.8%) than in the control group (28.1%) (p < 0.05). Analysis of the vibratory sensation revealed that the hip-fracture group showed a significantly higher percentage of severe impairment (51.9%) than the control group (32.0%) (p < 0.025). There were no significant differences in variance between the two groups in other clinical symptoms or ADL. CONCLUSIONS: Impairment of vibration sense, a deep sensation, is more likely to be associated with falling and hip fracture than visual acuity or other neurological symptoms in SMON patients. Those persons with vibration sense disturbance, such as elderly or patients with neurological diseases, should be particularly cautious of falling.

Current perception threshold in subacute myelo-optico-neuropathy.

We report the first current perception threshold (CPT) examination of sensory disturbance in subacute myelo-optico-neuropathy (SMON). SMON patients experience serious neurological symptoms, including dysesthesia, sensory loss, motor weakness, and visual impairment. During CPT examination, 5 Hz, 250 Hz, and 2,000 Hz stimulations were used to stimulate C fibers, A-delta fibers, and A-beta fibers, respectively. Ten SMON patients (mean age, 73.8 +/- 8.4 years) and ten age-matched controls (72.3 +/- 6.3 years) were studied using CPT measured at the index finger and near the external malleolus. The CPTs to 250 Hz and 2,000 Hz stimulations near the external malleolus were significantly higher and the CPT to 5 Hz stimulation was significantly lower in the SMON group than in the control group. Although peripheral nerve impairment is mild in SMON, pathological examination shows a decrease of large fibers. This is thought to increase the CPTs to 250 Hz and 2,000 Hz stimulations. The center of the gate control of pain exists in the posterior horn receiving information from the dorsal root ganglion. The dorsal root ganglion at the lumber cord is strongly impaired in SMON; therefore, the gate control may not work effectively, and decreases CPT to 5 Hz stimulation.

Depression in patients with subacute myelo-optico-neuropathy (SMON).

OBJECTIVE: We investigated the psychiatric disorders in subacute myelo-optico-neuropathy (SMON) patients by structured interview. The prevalence of major depressive disorder in SMON patients was estimated by structured interview and using Beck's depression inventory (BDI) questionnaires. MATERIALS AND METHODS: Psychiatric conditions were evaluated in 26 SMON patients (9 males, 17 females, mean age 70.7 years) living in Kyoto prefecture through a structured interview given by psychiatrists. BDI questionnaires and clinical symptoms of SMON were investigated in 106 patients, ranging from 51 to 91 years in age (mean, 73.5) with SMON patients living in Kinki area. BDI questionnaires were obtained from 92 age-matched aged healthy people, ranging from 57 to 91 years in age (mean, 75.8), living in Kyoto city. RESULTS: Among the psychiatric disorders in SMON patients, the prevalence of major depressive disorder and suicidal ideation significantly increased during the period of clioquinol intake and four patients (15.4%) out of 26 SMON patients still suffer from major depressive disorder. The prevalence of major depressive disorder in SMON patients was estimated at 15.1% (16/106) and this percentage was about seven times as frequent as in the age-matched aged healthy people (2.2%; 2/92). In female SMON patients, the degree of the depressive states was significantly correlated with the severe degree of dysesthesia of the lower extremities, and it was inversely correlated with the duration of SMON disease and the total scores of the Barthel index. CONCLUSION: This is the first report that shows the prevalence of major depressive disorder in SMON patients at present, which was seven times more frequent than age-matched aged healthy persons.