Clinical Evaluation After Discontinuation of Galcanezumab in Japanese Patients with Episodic and Chronic Migraine: Analysis of a Randomized, Placebo-Controlled Trial and Open-label Extension Study.

INTRODUCTION: This analysis of two Japanese clinical trials evaluated efficacy and safety after galcanezumab (GMB) discontinuation in patients with episodic migraine (EM) and chronic migraine (CM). METHODS: Data were from a 6-month, randomized, double-blind, placebo [PBO]-controlled primary trial (patients with EM) and a 12-month open-label extension trial (patients with EM/CM). Patients received 6 months' (primary) or 12/18 months' (extension) treatment with GMB 120 mg (GMB120) plus 240-mg loading dose or 240 mg (GMB240) with 4 months' post-treatment follow-up. Efficacy was assessed as number of monthly migraine headache days during post-treatment. Safety was assessed via post-treatment-emergent adverse events (PTEAEs). RESULTS: The analysis population included 186 patients from the primary trial (PBO N = 93; GMB120 N = 45; GMB240 N = 48), 220 patients with EM from the extension trial (PBO/GMB120 N = 57; PBO/GMB240 N = 55; GMB120/GMB120 N = 55; GMB240/GMB240 N = 53), and 55 patients with CM (GMB120 N = 28; GMB240 N = 27). In patients with EM receiving 6 months' GMB120, mean standard deviation (SD) monthly migraine headache days increased from 5.69 (4.64) at treatment end to 6.24 (4.37) at end of follow-up but did not return to pre-treatment levels (8.80 [2.96]). In the extension trial, mean monthly migraine headache days in patients with EM receiving GMB120 were 4.13 (3.85) after 12 months and 4.45 (3.78) at end of follow-up, and 3.59 (3.48) after 18 months and 3.91 (3.57) at end of follow-up. Monthly migraine headache days in patients with CM (12 months' GMB120) were 10.71 (4.61) at treatment end and 11.17 (5.64) at end of follow-up (pre-treatment 20.15 [4.65]). Similar results were seen for patients receiving GMB240. The most observed PTEAE after GMB discontinuation was nasopharyngitis. CONCLUSION: Galcanezumab exhibited post-treatment efficacy for up to 4 months in Japanese patients with EM and with CM. No unexpected safety signals were observed. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT02959177 and NCT02959190.

[Impact of migraine on family members: an investigation by Impact of Migraine on Partners and Adolescent Children (IMPAC)].

Using the Japanese version of the Impact of Migraine on Partners and Adolescent Children (IMPAC) and Family Question prepared based on IMPAC, we investigated the impact of migraine on family members from the perspectives of both patients and their family members. Our results showed that migraine had an impact on the family members living with the patients in Japan as well, and the perception of migraine differed partially between patients and their family members. We also found that the Japanese version of the IMPAC showed a correlation with existing instruments to evaluate impact of migraine, indicating its validity. The application of this study's findings in clinical practice could help alleviate the disease burden of migraine on patients and their family members.

Mild hypothermia prevents post-traumatic hyperactivity of excitatory synapses in rat hippocampal CA1 pyramidal neurons.

The present experiment examined the effect of mild hypothermia (35 degrees C) on the post-traumatic hyperactivity of rat hippocampal CA1 neurons in horizontal brain slices. One week after fluid percussion injury (FPI), the optical response evoked by stimulation of the Schaffer collaterals increased in amplitude and propagation area in hippocampal CA1 slices. FPI did not alter the fast optical response that reflected the action potential of the Schaffer collaterals but enhanced the slow component that reflected the excitatory postsynaptic response. FPI increased the slope of the input-output relation (I/O function), suggesting that FPI increases the efficacy of excitatory synaptic transmission in the hippocampal CA1 pyramidal neurons. To examine the effect of low temperature on post-traumatic hyperactivity of hippocampal CA1 neurons, mild hypothermia (35 degrees C) was administered to rats 15 min after FPI and maintained for 1-3 h. One week after FPI, the activity of hippocampal CA1 neurons in rats with mild hypothermia appeared to be reduced as compared with those receiving FPI alone. The post-traumatic enhancement of the I/O function of the slow optical response was prevented by mild hypothermia. These results suggest that mild hypothermia applied 15 min after FPI attenuates the post-traumatic hyperactivity of excitatory synapses in rat hippocampal CA1 neurons.

Facilitation of glutamatergic synaptic transmission in hippocampal CA1 area of rats with traumatic brain injury.

We investigated the effects of traumatic brain injury (TBI) on the glutamatergic synaptic transmission in the hippocampal CA1 area. A moderate impact (3.8-4.8atm) was applied onto the left parietal cerebral cortex by a fluid percussion injury (FPI) device. Conventional intracellular recordings were made from hippocampal CA1 pyramidal neurons in vitro. Electrophysiological properties of these neurons were compared between three groups (control, FPI-ipsilateral, and FPI-contralateral). The excitability of postsynaptic membrane of CA1 pyramidal neurons was not altered by the moderate FPI; however, the evoked glutamatergic excitatory synaptic transmission in the pyramidal neurons of post-FPI-CA1 was enhanced. Paired-pulse facilitation (PPF) was significantly suppressed in both the FPI-ipsilateral and FPI-contralateral groups and the frequencies of mEPSPs in neurons from the bilateral FPI groups were greater than the frequency in the control group. These results suggest that the glutamatergic synaptic transmission in the hipppocampal CA1 area is facilitated through presynaptic mechanisms after TBI.

[Clinical features and surgical results of chronic subdural hematoma in the extremely aged patients].

Since low-invasive surgery provides marked symptomatic improvement of patients with chronic subdural hematoma, surgery will be recommended also for the aged. To examine the clinical features and treatment result in the aged patients, we compared the clinical features and surgical results in two groups of patients with 80 or more and less than 80 years. The subjects consisted of 266 adult patients with a total of 333 chronic subdural hematomas who had undergone closed-system drainage between January 1995 and March 2005. The items analyzed were 1) patients background including gender, laterality of hematoma, presence or absence of history of head trauma, history of drinking, and mechanism of injury, 2) clinical symptoms, such as level of consciousness on initial examination, initial symptoms, and the degree of paralysis, 3) those related to surgery, such as time from injury to surgery, length of hospital stay, operation time, and amount of drainage, 4) outcome, such as presence or absence of symptomatic improvement, and recurrence rate. The results of this study showed that chronic subdural hematomas in the extremely aged patients were characterized by 1) infrequent history of head trauma, 2) infrequent headache and frequent dementia, incontinence and deterioration of activity at onset, 3) severe degree of motor paralysis at admission, 4) larger amount of drainage volume, 5) low incidence of outcome improvement. Above these characteristics should be considered at the decision making of surgical treatments for extremely aged patients with chronic subdural hematoma.