Pharmacokinetics and pharmacogenetics of capecitabine and its metabolites following replicate administration of two 500 mg tablet formulations.

PURPOSE: To describe concentration versus time profiles of capecitabine and its metabolites 5'-DFUR, 5'-DFCR and 5-FU, depending on tablet formulation and on frequent and/or relevant genetic polymorphisms of cytidine deaminase, dihydropyrimidine dehydrogenase, thymidylate synthase and methylenetetrahydrofolate reductase (MTHFR). METHODS: In 46 cancer patients on chronic capecitabine treatment, who voluntarily participated in the study, individual therapeutic doses were replaced on four consecutive mornings by the study medication. The appropriate number of 500 mg test (T) or reference (R) capecitabine tablets was given in randomly allocated sequences TRTR or RTRT (replicate design). Average bioavailability was assessed by ANOVA. RESULTS: Thirty female and 16 male patients suffering from gastrointestinal or breast cancer (mean age 53.4 years; mean dose 1739 mg) were included. The T/R ratios for AUC0-t(last) and C max were 96.7 % (98 % CI 90.7-103.2 %) and 87.2 % (98 % CI 74.9-101.5 %), respectively. Within-subject variability for AUC0-t(last) and C max (coefficient of variation for R) was 16.5 and 30.2 %, respectively. Similar results were seen for all metabolites. No serious adverse events occurred. For the MTHFR C677T (rs1801133) genotype, an increasing number of 677C alleles showed borderline correlation with an increasing elimination half-life of capecitabine (p = 0.043). CONCLUSIONS: The extent of absorption was similar for T and R, but the rate of absorption was slightly lower for T. While such differences are not considered as clinically relevant, formal bioequivalence criteria were missed. A possible, probably indirect role of the MTHFR genotype in pharmacokinetics of capecitabine and/or 5-FU should be investigated in further studies.

Critical illness VR rehabilitation device (X-VR-D): evaluation of the potential use for early clinical rehabilitation.

We present a new critical illness VR rehabilitation device (X-VR-D) that enables diversified self-training and is applicable early in the rehabilitation of severely injured or ill patients. The X-VR-D consists of a VR program delivering a virtual scene on a flat screen and simultaneously processing commands to a moving chair mounted on a motion system. Sitting in the moving chair and exposed to a virtual reality environment the device evokes anticipatory and reactive muscle contractions in trunk and extremities for postural control. In this study we tested the device in 10 healthy subjects to evaluate whether the enforced perturbations indeed evoke sufficient and reproducible EMG muscle activations. We found that particular fast roll and pitch movements evoke adequate trunk and leg muscle activity. Higher angular velocities and higher angles of inclination elicited broader EMG bursts and larger amplitudes. The muscle activation pattern was highly consistent between different subjects and although we found some habituation of EMG responses in consecutive training sessions, the general pattern was maintained and was predictable for specific movements. The habituation was characterized by more efficient muscle contractions and better muscle relaxation during the rest positions of the device. Furthermore we found that the addition of a virtual environment to the training session evoked more preparatory and anticipatory muscle activation than sessions without a virtual environment. We conclude that the X-VR-D is safe and effective to elicit consistent and reproducible muscle activity in trunk and leg muscles in healthy subjects and thus can be used as a training method.

Suppression of cutaneous reflexes by a conditioning pulse during human walking.

There are two ways in which responses to successive unexpected stimuli are attenuated, namely through habituation and conditioning. For the latter, it suffices that the unexpected stimulus is preceded by another just perceivable stimulus. In spinal cord reflexes this is termed conditioning, while in brainstem reflexes this is usually referred to as prepulse inhibition. Cutaneous reflexes in Tibialis Anterior (TA) are particularly strong during gait and they are thought to involve a transcortical loop. Can these reflexes be suppressed by giving a brief pulse prior to a reflex-evoking pulse given to the same nerve? To examine this question, electromyographic signals were recorded in healthy humans during walking. Sural nerve stimulation (train of five pulses (1 ms duration)) at 200 Hz were applied at two times perception threshold during different phases of the step cycle. The preceding pulse (single pulse of 1 ms at same intensity) was applied to the same nerve 150 ms before the reflex-evoking pulse train. Conditioning stimulation with a single pulse lowered significantly the following reflex response in the ipsilateral TA but much less in other muscles such as biceps femoris. The preceding pulse did not disturb the phase-dependent modulation or the typical reflex reversal. The finding that TA is selectively involved indicates that the suppressing mechanism may involve the motor cortex, which is known to be involved in the control of TA. The conditioning pulse did not cause a reduction in background activity. Therefore, the suppression of the reflex responses points to a premotoneuronal source such as presynaptic inhibition.

Cutaneous reflexes evoked during human walking are reduced when self-induced.

Reflex responses are often less pronounced when they are self-induced, but this question has barely been investigated quantitatively. The issue is particularly relevant for locomotion since it has been shown that reflexes elicited during normal gait are important for the regulation of locomotion. The cortex is thought to be involved in the control of reflexes during gait, but it is unclear whether it plays a role in the modulation of these reflexes during the step cycle. During gait, weak electrical stimulation of the sural nerve elicits reflexes in various leg muscles. Are these reflexes different when subjects themselves trigger the stimuli instead of being randomly released by the computer? Cutaneous reflexes were elicited by sural nerve stimulation in 16 phases of the gait cycle in healthy subjects. The stimuli were triggered either by computer or by the subjects themselves. In 6 out of 7 subjects it was observed that the facilitatory responses in leg muscles were smaller and the suppressive responses were more suppressive following self-generated stimuli. In some muscles such as tibialis anterior (TA) both effects were seen (reduced facilitation at end stance and exaggerated suppression at end swing). In all subjects the modulation of anticipatory influences was muscle specific. In the main group of six subjects, the mean reduction in reflex responses was strongest in the TA (max. 30.7%; mean over 16 phases was 12.5%) and weakest in peroneus longus (PL, max. 10.1%; mean over 16 phases was 2.6%). The observation that facilitation is reduced and suppression enhanced in several muscles is taken as evidence that anticipation of self-induced reflex responses reduces the excitatory drive to motoneurones, for example through presynaptic inhibition of facilitatory reflex pathways.

Cutaneous reflexes from the foot during gait in hereditary spastic paraparesis.

OBJECTIVE: It is known that P2 cutaneous reflexes from the foot show phase-dependent modulation during gait. The role of the motor cortex and the cortico-spinal tract in these reflexes and their modulation is unknown. Patients with hereditary spastic paraparesis (HSP) have a lesion in the cortico-spinal tract and may show deficits in P2 reflexes and/or their modulation. METHODS: Reflex responses of tibialis anterior and biceps femoris after sural nerve stimulation in 10 HSP-patients were compared with those in 10 healthy subjects. The reflexes were studied at two different moments in the step cycle during walking on a treadmill. RESULTS: Both patients and controls showed a phase-dependent modulation of P2 responses. For the individual muscles, no significant difference in reflex activity was observed between HSP-patients and the controls. However, when all muscles were taken together, the reflex activity for the controls was significantly higher than for the patients. CONCLUSIONS: The results of this study suggest that the cortico-spinal tract is involved in the regulation of the amplitude of the P2 responses and their phase-dependent modulation.