Effects of tafamidis treatment on transthyretin (TTR) stabilization, efficacy, and safety in Japanese patients with familial amyloid polyneuropathy (TTR-FAP) with Val30Met and non-Val30Met: A phase III, open-label study.

INTRODUCTION: The efficacy and safety of tafamidis in transthyretin (TTR) familial amyloid polyneuropathy (TTR-FAP) were evaluated in this open-label study. METHODS: Japanese TTR-FAP patients (n=10; mean age 60.1 years) received tafamidis meglumine (20mg daily; median treatment duration 713.5 days). The primary endpoint was TTR stabilization at Week 8. Secondary endpoints included Neuropathy Impairment Score-Lower Limb (NIS-LL), Norfolk QOL-DN total quality of life (TQOL), and modified body mass index (mBMI). RESULTS: TTR stabilization was achieved in all patients at Weeks 8 and 26, 9 out of 10 patients at Week 52, and 8 out of 10 patients at Week 78. The percentage (95% CI) of NIS-LL responders (increase from baseline in NIS-LL<2) was 80.0% (44.4, 97.5), 60.0% (26.2, 87.8), and 40.0% (12.2, 73.8) and mean(SD) NIS-LL change from baseline was 2.1 (5.6), 3.6 (4.4), and 3.3 (4.7), at Weeks 26, 52, and 78, respectively. Mean (SD) changes from baseline in TQOL and mBMI at Weeks 26, 52, and 78 were 11.8 (20.0), 9.1 (12.5), and 10.8 (13.7) for TQOL, and 26.6 (61.9), 64.9 (80.0), and 53.7 (81.4) for mBMI, respectively. Ambulation status was preserved in 4 out of 8 patients at Week 78. Most adverse events (AEs) were mild/moderate, with no discontinuations due to AEs. CONCLUSIONS: Tafamidis stabilized TTR, was safe and well-tolerated, and was effective over 1.5 years in slowing neurologic progression and maintaining TQOL and nutrition status in TTR-FAP.

Efficacy and safety of additional 200-mg dose of celecoxib in adult patients with postoperative pain following extraction of impacted third mandibular molar: a multicenter, randomized, double-blind, placebo-controlled, phase II study in Japan.

BACKGROUND: Although third mandibular molar extraction is a widely used and validated model of acute pain for evaluating analgesic efficacy, a large proportion of patients experience moderate or severe pain following this procedure and require analgesia. Current treatment options have been associated with safety concerns and alternative therapies are sought. OBJECTIVE: Our aim was to assess the efficacy and safety of an additional 200-mg dose of celecoxib, administered 5 to 12 hours after an initial 400-mg dose of the drug for the treatment of moderate or severe acute pain following extraction of an impacted third mandibular molar. METHODS: This was a multicenter, randomized, double-blind, placebo-controlled, Phase II study. Patients experiencing moderate or severe pain within 1 to 2 hours following extraction of an impacted third mandibular molar received an initial 400-mg dose of celecoxib. Patients requiring additional analgesia were subsequently randomized to receive either an additional 200-mg dose of celecoxib or placebo 5 to 12 hours after the initial dose. The study was designed and conducted by Pfizer Inc. for approval of celecoxib in Japan for the indication of acute pain. The primary end point was the patient's impression of efficacy (4-category global evaluation scale). Secondary efficacy end points included pain intensity on a 4-category pain intensity scale, pain intensity on a 100-mm visual analog scale (VAS), and the pain intensity difference (100-mm VAS). In an exploratory analysis, use of rescue medication was evaluated. Primary and secondary end points were analyzed using the full analysis set. Assessment of the safety profile included a physical examination, measurement of pulse rate and blood pressure, standard 12-lead ECG, and laboratory tests. RESULTS: A total of 69 patients (celecoxib, 42/64 [65.6%]; placebo, 27/58 [46.6%]) received the additional dose of study medication; all completed the study without the need for rescue medication. A significantly higher proportion of patients in the celecoxib 200 mg group (41/64 [64.1%]) compared with the placebo group (15/58 [25.9%]) rated the study medication as "good" or "excellent" ≥ 2 hours after the additional dose (P < 0.0001). Pain intensity (VAS) 2 hours after the additional dose was significantly higher in the placebo group than in the celecoxib 200 mg group (P = 0.0003). The reduction in pain intensity from baseline to 2 hours after the additional dose of study medication was also significantly greater in the celecoxib 200 mg group than in the placebo group (P < 0.0001). The incidence of treatment-related, all-cause adverse events was slightly lower in patients receiving celecoxib 200 mg (20.3%) compared with placebo (31.0%). CONCLUSIONS: Overall, an additional 200-mg dose of celecoxib was well tolerated and efficacious in reducing the pain associated with extraction of an impacted third mandibular molar in the study population. ClinicalTrials.gov identifier: NCT01062113.

Safety and tolerability of repetitive transcranial magnetic stimulation in patients with epilepsy: a review of the literature.

Repetitive transcranial magnetic stimulation (rTMS) is emerging as a new therapeutic tool in epilepsy, where it can be used to suppress seizures or treat comorbid conditions such as mood disorder. However, as rTMS carries a risk of inducing seizures among other adverse events, its safety and tolerability in the population with epilepsy warrant distinct consideration, as this group is especially seizure-prone. Accordingly, we performed a review of the literature to estimate the risk of seizures and other adverse events associated with rTMS in patients with epilepsy. We performed an English-language literature search, and reviewed all studies published from January 1990 to February 2007 in which patients with epilepsy were treated with rTMS, and complemented the literature search with personal correspondence with authors when necessary. We identified 30 publications that described patients with epilepsy who underwent rTMS, and noted total number of relevant subjects, medication usage, incidence of adverse events, and rTMS parameters including stimulus frequency, number of stimuli, train duration, intertrain interval, coil type, and stimulation sites. The data were analyzed for adverse events related to rTMS. Crude per-subject risk, as well as per-subject mean risk weighted by sample size and risk per 1000 stimuli weighted by number of stimuli in each study, were computed for seizures and for other adverse events. Adverse events or lack thereof was reported in 26 studies (n=280 subjects). Adverse events attributed to rTMS were generally mild and occurred in 17.1% of subjects. Headache was most common, occurring in 9.6%. The most serious adverse event was seizure during treatment, which occurred in four patients (1.4% crude per-subject risk). All but one case were the patients' typical seizures with respect to duration and semiology, and were associated with low-frequency rTMS. A single case of an atypical seizure appearing to arise from the region of stimulation during high-frequency rTMS is reported. No rTMS-related episodes of status epilepticus were reported. We cautiously conclude that the risk of seizure in patients with epilepsy undergoing rTMS is small, and the risk of other mild adverse events is comparable to that seen when rTMS is used to treat other diseases. Status epilepticus or life-threatening seizures have not been reported in patients undergoing rTMS treatment. rTMS thus appears to be nearly as safe in patients with epilepsy as in nonepileptic individuals, and warrants further investigation as a therapy in this population.

Visual phosphene perception modulated by subthreshold crossmodal sensory stimulation.

Crossmodal sensory interactions serve to integrate behaviorally relevant sensory stimuli. In this study, we investigated the effect of modulating crossmodal interactions between visual and somatosensory stimuli that in isolation do not reach perceptual awareness. When a subthreshold somatosensory stimulus was delivered within close spatiotemporal congruency to the expected site of perception of a phosphene, a subthreshold transcranial magnetic stimulation pulse delivered to the occipital cortex evoked a visual percept. The results suggest that under subthreshold conditions of visual and somatosensory stimulation, crossmodal interactions presented in a spatially and temporally specific manner can sum up to become behaviorally significant. These interactions may reflect an underlying anatomical connectivity and become further enhanced by attention modulation mechanisms.

Safety of rTMS to non-motor cortical areas in healthy participants and patients.

OBJECTIVE: rTMS is increasingly being used for stimulation to non-motor areas, but available safety guidelines are derived from experience with motor cortex rTMS. We reviewed the literature and our own data to assess the safety of rTMS to non-motor areas. METHODS: We reviewed for adverse effects all articles published from January 1998 to December 2003 that applied rTMS to non-motor areas, and analyzed data from our own studies from January 1997 to December 2003. RESULTS: Adverse effects were infrequent and generally mild. Headache was the most common, occurring in 23% of the subjects and more frequent with frontal rTMS. More serious adverse effects were rare and consisted of two seizures and four instances of psychotic symptoms induced by rTMS to the dorsolateral prefrontal cortex in patients with depression. CONCLUSIONS: Overall, as currently applied rTMS to non-motor areas appears to be safe with few, generally mild adverse effects. In future studies, we recommend systematic reporting of adverse effects and careful documentation of machine type, coils used, and actual intensity as a function of maximum stimulator output. Phosphene threshold might be used to index stimulation intensity when rTMS is applied to the visual cortex, and research should be directed to identifying other indexes of intensity for TMS to other non-motor areas. SIGNIFICANCE: rTMS under the present guidelines is safe, with minimal adverse effects, when applied to non-motor areas.

Recovery function of and effects of hyperventilation on somatosensory evoked high-frequency oscillation in Parkinson's disease and myoclonus epilepsy.

To evaluate recovery function of and effects of hyperventilation (HV) on high-frequency oscillations (HFOs) of median nerve somatosensory evoked potential (SEP), we recorded SEPs in 8 Parkinson's disease (PD) patients with enlarged HFOs, 4 myoclonus epilepsy (ME) patients and 10 healthy volunteers (N). SEP was recorded from the hand sensory area contralateral to the median nerve stimulated at the wrist. Responses were amplified with filters set at 0.5 and 3000 Hz. HFOs were obtained by digitally filtering raw SEPs from 500 to 1000 Hz. We measured amplitudes of the N20 onset-peak (N20o-p), N20 peak-P25 peak (N20p-P25p), P25 peak-N33 peak (P25p-N33p), the early (1st-2nd) and late (3rd) HFOs. For the recovery function study, paired-pulse stimuli at various interstimulus intervals (20, 50, 100, 150, 200 and 300 ms) were given. To investigate effects of HV, amplitudes of several components of SEPs recorded after HV were compared with those before HV. In PD and ME, the N20o-p recovery curve showed significantly less suppression as compared with those of N. The P25p-N33p recovery curve of ME showed longer suppression than those of N and PD. There were no significant differences in the early or late HFOs recovery curves among three groups. At the dysinhibited state after HV, the late HFO was reduced in association with a significant enlargement of the N20p-P25p amplitude in normal subjects. This suggests that the late HFOs should reflect bursts of inhibitory interneurons. In the ME patients, the early HFOs significantly decreased by HV. The pattern in ME patients may be explained by a kind of compensation for already enhanced SEPs (giant SEP) in the dysinhibited situation. We conclude that (1) Giant HFOs are normally regulated by inhibitory neuronal systems involving in paired stimulation SEP. (2) The late HFOs must reflect bursts of GABAergic inhibitory interneurons.

Somatosensory evoked potential recovery in kii amyotrophic lateral sclerosis/parkinsonism-dementia complex (kii AlS/PDC).

OBJECTIVE: To evaluate the recovery function of the sensory cortex in patients with Kii amyotrophic lateral sclerosis/parkinsonism-dementia complex (Kii ALS/PDC) using somatosensory evoked potentials (SEPs) elicited by paired stimuli of the median nerve at the wrist. METHODS: Five patients with Kii ALS/PDC were compared with 5 patients with classical ALS, 5 with Parkinson's disease (PD), and 7 healthy normal volunteers. SEPs were recorded from the hand sensory area contralateral to the side of stimulation. Recovery functions of N20-P25 and P25-N33 components were evaluated by comparing the second SEPs elicited by paired pulse stimuli at various interstimulus intervals (ISIs, 20-300 ms) with the SEPs elicited by single stimuli. RESULTS: Conventional SEPs to a single stimulus had a normal latency and size in all patients. The recovery function of the N20-P25 and P25-N33 components showed significantly less suppression at short ISIs without any facilitation at long ISIs in Kii ALS/PDC patients than in normal subjects, classical ALS or PD patients. CONCLUSIONS: In Kii ALS/PDC, the sensory cortex is disinhibited or hyperexcitable. These abnormalities may reflect cortical pathology in the sensory cortex and may be partly due to a secondary effect on the sensory cortex from the primary parkinsonian pathological changes.