The insulin sensitizing effect of topiramate involves KATP channel activation in the central nervous system

BACKGROUND AND PURPOSE

Topiramate improves insulin sensitivity, in addition to its antiepileptic action. However, the underlying mechanism is unknown. Therefore, the present study was aimed at investigating the mechanism of the insulin-sensitizing effect of topiramate both in vivo and in vitro.

EXPERIMENTAL APPROACH

Male C57Bl/6J mice were fed a run-in high-fat diet for 6 weeks, before receiving topiramate or vehicle mixed in high-fat diet for an additional 6 weeks. Insulin sensitivity was assessed by hyperinsulinaemic-euglycaemic clamp. The extent to which the insulin sensitizing effects of topiramate were mediated through the CNS were determined by concomitant i.c.v. infusion of vehicle or tolbutamide, an inhibitor of ATP-sensitive potassium channels in neurons. The direct effects of topiramate on insulin signalling and glucose uptake were assessed in vivo and in cultured muscle cells.

KEY RESULTS

In hyperinsulinaemic-euglycaemic clamp conditions, therapeutic plasma concentrations of topiramate (∼4 μg·mL⁻¹) improved insulin sensitivity (glucose infusion rate + 58%). Using 2-deoxy-D-[³H]glucose, we established that topiramate improved the insulin-mediated glucose uptake by heart (+92%), muscle (+116%) and adipose tissue (+586%). Upon i.c.v. tolbutamide, the insulin-sensitizing effect of topiramate was completely abrogated. Topiramate did not directly affect glucose uptake or insulin signalling neither in vivo nor in cultured muscle cells.

CONCLUSION AND IMPLICATIONS

In conclusion, topiramate stimulates insulin-mediated glucose uptake in vivo through the CNS. These observations illustrate the possibility of pharmacological modulation of peripheral insulin resistance through a target in the CNS.     

Thorough QT study of the effect of oral moxifloxacin on QTc interval in the fed and fasted state in healthy Japanese and Caucasian subjects

Aims

The aims of this study were three-fold and were to (i) investigate the effect of food (fasted and fed state) on the degree of QT prolongation caused by moxifloxacin under the rigorous conditions of a TQT study, (ii) differentiate the effects on QT_c that arise from changes in PK from those arising as a result of electrophysiological changes attributable to raised levels of C-peptide [11] offsetting in part the I_Kr blocking properties of moxifloxacin and (iii) characterize the QT_cF profile of oral moxifloxacin (400 mg) in healthy Japanese volunteers compared with Caucasian subjects.

Methods

The study population consisted of 32 healthy non-smoking, Caucasian (n = 13) and Japanese (n = 19), male and female subjects, aged between 20–45 years with a body mass index of between 18 to 25 kg m⁻². Female volunteers were required to use an effective contraceptive method or be abstinent. Subjects with ECGs which were deemed unsuitable for evaluation in a TQT study were excluded. ECGs were recorded in triplicate with subsequent blinded manual adjudication of the automated interval measurements. Electrocardiograms in the placebo arm were recorded twice in fasted and fed condition.

Results

The results demonstrated a substantial change in the typical moxifloxacin effect on the ECG. The effect on ΔΔQT_c in the fed state led to a significant delay and a modest reduction compared with the fasted state correcting both conditions with the corresponding placebo data. The largest QT_cF change from baseline in the fed state was observed at 4 h with a peak value of 11.6 ms (two-sided 90% CI 9.1, 14.1). In comparison, the largest QT_cF change observed in the fasted state was 14.4 ms (90% CI 11.9, 16.8) and occurred at 2.5 h post-dose. The PK of moxifloxacin were altered by food and this change was consistent with the observed QT_cF change. In the fed state plasma concentrations of moxifloxacin were considerably and consistently lower in comparison with the fasted state, and this applied to both ethnicities. The concentration–effect analysis revealed that there was no change in slope and confirmed that the difference in this analysis was caused by a change in the PK profile of moxifloxacin. Comparisons of the moxifloxacin effect in the fed state compared with fasted placebo also revealed a pharmacodynamic effect whereby a meal appears to antagonize the effects of moxifloxacin on the lengths of the QT_c interval.

Conclusions

Our findings demonstrate that the food effect by itself leads to a shortening of the QT_c interval offsetting in part the effects of a 400 mg single dose of oral moxifloxacin. The typical moxifloxacin PK profile is also altered by food prior to dosing reducing the C_max and delays the peak effects on QT_c up to several hours thereby reducing the overall magnitude of the effect and delaying the peak QT_c prolongation. The contribution of the two effects was clearly discernible. Given that moxifloxacin is sometimes given with food in TQT studies, consideration should be given to adequate baseline corrections and appropriate sampling time points. In this study the PK–PD relationship was similar for Japanese and Caucasian subjects in the fed and fasted conditions, thereby providing further evidence that the sensitivity to the QT_c prolonging effects of fluoroquinolones was likely to be independent of ethnicity. The small differences observed between the two subpopulations were not statistically significant. However, future studies should give consideration to formal ethnic comparisons as a secondary outcome parameter as very little is known about the relationship between ethnicity and drug effects on cardiac repolarization.     

The spiral after effect (SAE) as a measure of motion sickness susceptibility and the effect on the SAE of an antimotion sickness drug and a central nervous system depressant

A study was carried out to determine whether the spiral after effect (SAE) could be considered a reliable measure of motion sickness susceptibility as measured by Reason's motion sickness questionnaire (MSQ). In an initial correlative study it was found that MSQ scores were significantly correlated with neuroticism (N) scores on the Eysenck Personality Inventory. However, the correlation between MSQ and a measure of the SAE duration was not significant. In the subsequent controlled drug study it was shown that both dimenhydrinate, an antinauseant, and temazepam, a minor tranquillizer, decreased the duration of the SAE: although significance was only obtained with the latter drug. The results of both experiments are discussed in terms of Reason's theory of motion sickness and it is suggested, on the basis of Reason's results and those obtained in the present study, that the SAE has both a cortical and a vestibular component in its mechanism of action.