Bioequivalence of ximelagatran,an oral direct thrombin inhibitor,as whole or crushed tablets or dissolved formulation

SUMMARY

Objective: To investigate whether crushed or dissolved tablets of the oral direct thrombin inhibitor ximelagatran are bioequivalent to whole tablet administration. Ximelagatran is currently under development for the prevention and treatment of thromboembolic disorders.

Research design and methods: This was an open-label, randomised, three-period, three-treatment crossover study in which 40 healthy volunteers (aged 20–33 years) received a single 36-mg dose of ximelagatran administered in three different ways: I swallowed whole, II crushed, mixed with applesauce and ingested and III dissolved in water and administered via nasogastric tube.

Results: The plasma concentrations of ximelagatran, its intermediates and the active form melagatran were determined. Ximelagatran was rapidly absorbed and the bioavailability of melagatran was similar after the three different administrations, fulfilling the criteria for bioequivalence. The mean area under the plasma concentration-versus-time curve (AUC) of melagatran was 1.6μmol-h/l_ (ratio 1.01 for treatment II/I and 0.97 for treatment III/I), the mean peak concentration (Cmax) was 0.3μmol/L (ratio 1.04 for treatment II/I and 1.02 for treatment III/I) and the mean half-life (t1/2) was 2.8?h for all treatments. The time to Cmax (tmax) was 2.2?h for the whole tablet and approximately 0.5?h earlier when the tablet was crushed or dissolved (1.7–1.8?h), due to a more rapid absorption. The study drug was well tolerated as judged from the low incidence and type of adverse events reported.

Conclusion: The present study showed that the pharmacokinetics (AUC and Cmax) of melagatran were not significantly altered whether ximelagatran was given orally as a crushed tablet mixed with applesauce or dissolved in water and given via nasogastric tube.     

Effects of lingual nerve afferents on swallowing in sheep

We investigated in sheep the effects of stimulation of the thick afferent fibers running through the lingual nerve (LN) upon the activity of some of the muscles and medullary interneurons or motoneurons which are active during swallowing. Using electromyography (EMG), and extra- and intracellular neuronal recording, we demonstrated that LN stimulation inhibited triggering and/or distal progression of deglutition reflexly induced by stimulation of the superior laryngeal nerve (SLN). This inhibition appeared as a delay, or the interruption or total suppression, of the EMG and neuronal swallowing activities, depending on the interval between SLN and LN stimulation. It was apparent at the level of the muscles and motoneurons of the nucleus ambiguus, as well as at the level of the interneurons of the dorsal medulla within or around the nucleus of solitary tract, which are assumed to be the core of the organizing system for swallowing, the so-called central pattern generator (CPG). Taking into account the stimulation parameters used in our experiments, it was likely that only LN-mechanosensitive fibers were excited. These fibers were involved in the jaw-opening reflex, and possibly in mastication regulation. Therefore, inhibition of swallowing could result from interactions between the hindbrain mastication and swallowing CPGs. However, it was also possible that mechanosensitive afferents acted upon the swallowing CPG directly or indirectly through supramedullary, especially cortical, loops.     

Role of sensation in swallowing function

OBJECTIVES: Sensation in the oral cavity and laryngopharynx has long been believed to be crucial for normal swallowing. One illustration of this belief has been intense interest in reconstruction after cancer resection using sensate tissue transfer as a means of improving swallowing function. A contrarian view is that mucosal sensation, by itself, is, in fact, relatively unimportant to swallowing function. STUDY DESIGN: A prospective study was designed to test the hypothesis that normal swallow function can occur with anesthesia of the upper aerodigestive tract mucosa. METHODS: Baseline (sensate) swallowing function of 13 healthy adults was assessed via video endoscopic swallow studies (VESS). Each subject was then topically anesthetized with lidocaine applied to the oral cavity, oropharynx, hypopharynx, and larynx. Swallowing was then reassessed via VESS and compared to the baseline examination to look for differences in function. RESULTS: There was little difference in swallowing ability between sensate and anesthetized states, even though all the subjects felt that their swallowing had been profoundly disrupted after lidocaine was applied. The main difference was a small increase in the time from food administration to swallowing. A few experienced trace aspiration, which was instantly eliminated on subsequent swallows with simple coaching. CONCLUSION: Normal swallowing can occur spontaneously or with simple coaching even with complete anesthesia of the upper aerodigestive tract mucosa. Current beliefs about the value of sensate free flaps and the importance of sensation in swallowing in general may need refinement.     

Attaining and Maintaining Isometric and Isokinetic Goals of the Shaker Exercise

Previous studies have shown that the Shaker Exercise is effective in restoring oral intake in patients with deglutitive failure due to upper esophageal sphincter (UES) dysfunction. Our aim was to determine (1) exerciser compliance among healthy older adults, (2) number of days required to attain the isometric (IM) and isokinetic (IK) exercise goals, (3) rate and reason for dropout of exercisers, and (4) complaints associated with performance of the exercise. Twenty-six nondysphagic older adults were enrolled from an independent-living community (66–93 yr) to perform the Shaker Exercise. Each participant completed a questionnaire on exercise performance and its associated difficulties three times a day for six weeks. Four randomly chosen nondysphagic participants underwent pre- and postexercise videofluoroscopic swallow studies for biomechanical measurements. Maximum anterior hyoid and laryngeal excursions, as well as maximum anteroposterior UES opening increased (p < 0.05) following exercise. Duration to attain Shaker Exercise performance goals varied among participants. IK was more easily attained than IM. Only 50% and 70% of those enrolled initially were able to complete the exercise duration and attain its IK and IM goals, respectively. However, those who stayed in the program attained the IK and IM goals (100% and 74%, respectively). Most dropouts occurred in the first two weeks of exercise. Performance of the exercise was associated with mild muscle discomfort that resolved spontaneously after a couple of weeks. We concluded that although the Shaker Exercise can be performed independently, a structured and gradually progressive program is needed to attain the exercise goals completely.Supported in part by a grant from Retirement Research Foundation.     

Use of Respiratory Inductance Plethysmography for the Detection of Swallowing in the Elderly

It is essential to have a user-friendly, noninvasive bedside procedure at our disposal in order to study swallowing and swallowing disorders in the elderly in view of the frailty of this age group. In the present work, respiratory inductance plethysmography (RIP) is proposed as an appropriate clinical tool for such studies. An automated process for the detection of swallowing is used involving the derivative of the respiratory volume signal. The accuracy of the automated detection is given by the area under the Receiver Operating Characteristic (ROC) curve and is found to be greater than 0.9. At the optimal threshold, RIP constitutes a reliable and objective bedside clinical tool for studying swallowing in the elderly, as well as being user-friendly and noninvasive. In addition, RIP can be used to monitor swallowing in order to analyze swallowing disorders and put in place medical supervision of swallowing for individuals who might aspirate.     

Effects of withdrawal of phasic lung inflation during normocapnia and hypercapnia on the swallowing reflex in humans

Purpose This study was done to test the hypothesis that hypercapnia has a direct, inhibitory effect on swallowing.Methods We investigated changes in the frequency and timing of repeated swallows induced by continuous infusion of water into the pharynx before, during, and after transient airway occlusion at normocapnia and hypercapnia in 12 healthy volunteers. Hypercapnia was induced by adding a dead space. Ventilation was monitored using a pneumotachograph, and swallowing was identified by submental electromyogram.Results We found that hypercapnia decreased the frequency of swallows (8.2 ± 3.7 vs 11.4 ± 5.3 swallows·min^–1 [mean ± SD]: hypercapnia vs normocapnia; P 0.05), together with a loss of the preponderant coupling of swallows with expiratory phase observed at normocapnia. We also found that the withdrawal of phasic lung inflation produced by airway occlusion at end-expiration suddenly increased the swallowing frequency, both at normocapnia (from 11.4 ± 5.3 to 16.7 ± 3.7 swallows·min^–1; P 0.01) and at hypercapnia (from 8.2 ± 3.7 to 22.0 ± 6.7 swallows·min^–1; P 0.01). Although the degree of increased swallowing frequency during airway occlusion was more prominent at hypercapnia than at normocapnia (P 0.05), the distribution of the timing of swallows in relation to the phase of the respiratory cycle during airway occlusion at hypercapnia was similar to that during airway occlusion at normocapnia.Conclusion The results of our study strongly suggest that the attenuation of the swallowing reflex during hypercapnia is not due to the direct, inhibitory effect of CO₂ on the swallowing center, but, rather, is due to the increased inhibitory influence of a lung-volume-related reflex.     

Swallowing threshold and masticatory performance in dentate adults

A variety of both natural and artificial foods are commonly used for the evaluation of masticatory function. We compared swallowing thresholds of three natural foods (peanuts, cheese and carrots) to those of a standardized artificial test food (Optocal Plus) and examined the relationship between masticatory performance and the swallowing threshold. Eighty-seven healthy dentate subjects participated (25 men and 62 women, aged 42.0+/-12.1 years). We evaluated the dental state, registered the number of chewing strokes used before swallowing, analyzed the chewed particles and determined median particle sizes (X50) for Optocal Plus after 15 chewing strokes and at the moment of swallowing. The results show that the number of strokes used before swallowing each natural food linearly increased with volume (P<0.001), and that carrots required more strokes than peanuts and cheese (P<0.001). The number of chewing strokes used before swallowing Optocal Plus was comparable to the number used for carrots. Masticatory performance was significantly influenced by dental state, but not by age or gender. Significant correlations were observed for: (1) the number of chewing strokes used before swallowing natural foods and Optocal Plus; (2) the median particle sizes after 15 strokes and before swallowing; (3) the number of chewing strokes before swallowing and the corresponding median particle size. However, median particle sizes as obtained after 15 strokes did not correlate with the number of strokes used before swallowing (r=0.02). Thus, bad chewers did not necessarily chew longer before swallowing than good chewers. As a consequence bad chewers would, on average, swallow larger food particles.     

Effect of superior laryngeal nerve transection on pharyngeal muscle contraction timing and sequence of activity during eating and stimulation of the nucleus solitarius in dogs

The effect of unilateral or bilateral transection of the superior laryngeal nerve on the electromyographic activity in the hyopharyngeal, thyropharyngeal, and cricopharyngeal muscles was studied in 10 dogs during eating and during unilateral electrical stimulation of the solitary nucleus. In all groups of dogs, after unilateral or bilateral transection, there were some swallowing actions in which the sequence of activity in the pharyngeal muscles was disturbed during eating and during stimulation of the solitary nucleus. In the dogs in which the transection was unilateral, this fraction was 18% in the ipsilateral muscles during eating and 7% in the contralateral muscles. After bilateral transection it was 8% in the left muscles and 16% in the right muscles. The fractions were not significantly different when swallowing was evoked by stimulation of the solitary nucleus. Swallowing actions having a normal sequence of activity in these dogs were compared with those in a group of eight dogs in which the superior laryngeal nerves were intact. Contraction timing was not significantly different during eating, but during stimulation of the solitary nucleus the timing was significantly shorter than in the dogs with intact nerves. It was concluded that superior laryngeal nerve transection modulates the central pattern generator for pharyngeal swallowing in dogs.     

Effect of catecholamines on the swallowing reflex after pressure microinjections into the lateral solitary complex of the medulla oblongata

The present study was carried out to elucidate the influence of catecholamines on swallowing, a polysynaptic reflex organized by an interneuronal network localized mainly within the lateral solitary complex (LSC) of the medulla oblongata. The effects of catecholaminergic agents were investigated in the rat, on rhythmic swallowing elicited by repetitive stimulation of the superior laryngeal nerve (SLN). Catecholaminergic agents were microinjected by pressure application, through multibarrelled glass micropipettes, into the LSC including the tractus solitarius, the swallowing region of the nucleus of the solitary tract and the adjacent reticular formation. Microinjections of noradrenaline (NA, 0.1–5 nmol, 50 nl) induced a significant decrease of the number and the amplitude of the rhythmic swallows elicited by stimulation of the ipsilateral SLN. This inhibitory effect was dose-related. Microinjections of clonidine (2.5 nmol, 50 nl), dopamine (0.25–2.5 nmol, 50 nl) and apomorphine (0.5 nmol, 50 nl), also inhibited swallowing. No significant modification of swallowing was induced by control injections of the vehicle (50 nl) within the active sites. Moreover the NA-induced inhibition of swallowing, was significantly antagonized by pretreatment with the -adrenergic blocker phentolamine applied locally in the LSC. Furthermore neither blood pressure, nor respiratory rhythm were consistently modified by the catecholaminergic microinjections, indicating that the catecholamine-induced inhibition of swallowing was not a secondary side effect originating from alteration of these functions. It can therefore be concluded that the present results demonstrate the existence within the LSC of a catecholaminergic inhibition of the swallowing reflex. This inhibitory effect likely arises from activation of specific catecholaminergic receptors and effects the swallowing structures localized within the LSC, i.e., the laryngeal swallowing afferents running in the solitary tract and/or the swallowing interneurons within the nucleus of the solitary tract.