Biomechanics of occlusion--implications for oral rehabilitation.

The dental occlusion is an important aspect of clinical dentistry; there are diverse functional demands ranging from highly precise tooth contacts to large crushing forces. Further, there are dogmatic, passionate and often diverging views on the relationship between the dental occlusion and various diseases and disorders including temporomandibular disorders, non-carious cervical lesions and tooth movement. This study provides an overview of the biomechanics of the masticatory system in the context of the dental occlusion's role in function. It explores the adaptation and precision of dental occlusion, its role in bite force, jaw movement, masticatory performance and its influence on the oro-facial musculoskeletal system. Biomechanics helps us better understand the structure and function of biological systems and consequently an understanding of the forces on, and displacements of, the dental occlusion. Biomechanics provides insight into the relationships between the dentition, jaws, temporomandibular joints, and muscles. Direct measurements of tooth contacts and forces are difficult, and biomechanical models have been developed to better understand the relationship between the occlusion and function. Importantly, biomechanical research will provide knowledge to help correct clinical misperceptions and inform better patient care. The masticatory system demonstrates a remarkable ability to adapt to a changing biomechanical environment and changes to the dental occlusion or other components of the musculoskeletal system tend to be well tolerated.

Self-management programmes in temporomandibular disorders: results from an international Delphi process.

Self-management (SM) programmes are commonly used for initial treatment of patients with temporomandibular disorders (TMD). The programmes described in the literature, however, vary widely with no consistency in terminology used, components of care or their definitions. The aims of this study were therefore to construct an operationalised definition of self-management appropriate for the treatment of patients with TMD, identify the components of that self-management currently being used and create sufficiently clear and non-overlapping standardised definitions for each of those components. A four-round Delphi process with eleven international experts in the field of TMD was conducted to achieve these aims. In the first round, the participants agreed upon six principal concepts of self-management. In the remaining three rounds, consensus was achieved upon the definition and the six components of self-management. The main components identified and agreed upon by the participants to constitute the core of a SM programme for TMD were as follows: education; jaw exercises; massage; thermal therapy; dietary advice and nutrition; and parafunctional behaviour identification, monitoring and avoidance. This Delphi process has established the principal concepts of self-management, and a standardised definition has been agreed with the following components for use in clinical practice: education; self-exercise; self-massage; thermal therapy; dietary advice and nutrition; and parafunctional behaviour identification, monitoring and avoidance. The consensus-derived concepts, definitions and components of SM offer a starting point for further research to advance the evidence base for, and clinical utility of, TMD SM.

Anatomical changes within the medullary dorsal horn in chronic temporomandibular disorder pain.

Accumulated evidence from experimental animal models suggests that neuroplastic changes at the dorsal horn are critical for the maintenance of various chronic musculoskeletal pain conditions. However, to date, no study has specifically investigated whether neuroplastic changes also occur at this level in humans. Using brain imaging techniques, we sought to determine whether anatomical changes were present in the medullary dorsal horn (spinal trigeminal nucleus caudalis) in subjects with the chronic musculoskeletal pain. In twenty-two subjects with painful temporomandibular disorders (TMDs) and forty pain-free controls voxel based morphometry of T1-weighted anatomical images and diffusion tensor images were used to assess regional grey matter volume and microstructural changes within the brainstem and, in addition, the integrity of ascending pain pathways. Voxel based morphometry revealed significant regional grey matter volume decreases in the medullary dorsal horn, in conjunction with alterations in diffusivity properties, namely an increase in mean diffusivity, in TMD subjects. Volumetric and mean diffusivity changes also occurred in TMD subjects in regions of the descending pain modulation system, including the midbrain periaqueductal grey matter and nucleus raphe magnus. Finally, tractography revealed altered diffusivity properties, namely decreased fractional anisotropy, in the root entry zone of the trigeminal nerve, the spinal trigeminal tract and the ventral trigeminothalamic tracts of TMD subjects. These data reveal that chronic musculoskeletal pain in humans is associated with discrete alterations in the anatomy of the medullary dorsal horn, as well as its afferent and efferent projections. These neural changes may be critical for the maintenance of pathological pain.

Isotonic resistance jaw exercise alters jaw muscle coordination during jaw movements.

The aim was to investigate the effects of isotonic resistance exercise on the electro-myographic (EMG) activity of the jaw muscles during standardised jaw movements. In 12 asymptomatic adults surface EMG activity was recorded from the anterior temporalis and masseter muscles bilaterally and the right anterior digastric muscle during right lateral jaw movements that tracked a target. Participants were randomly assigned to a Control group or an Exercise group. Jaw movement and EMG activity were collected (i) at baseline, before the exercise task (pre-exercise); (ii) immediately after the exercise task (isotonic resistance at 60% MVC against right lateral jaw movements); (iii) after 4 weeks of a home-based exercise programme; and, (iv) at 8-weeks follow-up. There were no significant within-subject or between-group differences in the velocity and amplitude of the right lateral jaw movements either within or between data collection sessions (P > 0.05). However, over the 8 weeks of the study, three of the tested EMG variables (EMG Duration, Time to Peak EMG from EMG Onset, and Time to Peak EMG activity relative to Movement Onset) showed significant (P < 0.05) differences in the five tested muscles. Many of the significant changes occurred in the Control group, while the Exercise group tended to maintain the majority of the tested variables at pre-exercise baseline values. The data suggest a level of variability between recording sessions in the recruitment patterns of some of the muscles of mastication for the production of the same right lateral jaw movement and that isotonic resistance exercise may reduce this variability.

Expanding the taxonomy of the diagnostic criteria for temporomandibular disorders.

There is a need to expand the current temporomandibular disorders' (TMDs) classification to include less common but clinically important disorders. The immediate aim was to develop a consensus-based classification system and associated diagnostic criteria that have clinical and research utility for less common TMDs. The long-term aim was to establish a foundation, vis-à-vis this classification system, that will stimulate data collection, validity testing and further criteria refinement. A working group [members of the International RDC/TMD Consortium Network of the International Association for Dental Research (IADR), members of the Orofacial Pain Special Interest Group (SIG) of the International Association for the Study of Pain (IASP), and members from other professional societies] reviewed disorders for inclusion based on clinical significance, the availability of plausible diagnostic criteria and the ability to operationalise and study the criteria. The disorders were derived from the literature when possible and based on expert opinion as necessary. The expanded TMDs taxonomy was presented for feedback at international meetings. Of 56 disorders considered, 37 were included in the expanded taxonomy and were placed into the following four categories: temporomandibular joint disorders, masticatory muscle disorders, headache disorders and disorders affecting associated structures. Those excluded were extremely uncommon, lacking operationalised diagnostic criteria, not clearly related to TMDs, or not sufficiently distinct from disorders already included within the taxonomy. The expanded TMDs taxonomy offers an integrated approach to clinical diagnosis and provides a framework for further research to operationalise and test the proposed taxonomy and diagnostic criteria.

The effect of food bolus location on jaw movement smoothness and masticatory efficiency.

Masticatory efficiency in individuals with extensive tooth loss has been widely discussed. However, little is known about jaw movement smoothness during chewing and the effect of differences in food bolus location on movement smoothness and masticatory efficiency. The aim of this study was to determine whether experimental differences in food bolus location (anterior versus posterior) had an effect on masticatory efficiency and jaw movement smoothness. Jaw movement smoothness was evaluated by measuring jerk-cost (calculated from acceleration) with an accelerometer that was attached to the skin of the mentum of 10 asymptomatic subjects, and acceleration was recorded during chewing on two-colour chewing gum, which was used to assessed masticatory efficiency. Chewing was performed under two conditions: posterior chewing (chewing on molars and premolars only) and anterior chewing (chewing on canine and first premolar teeth only). Jerk-cost and masticatory efficiency (calculated as the ratio of unmixed azure colour to the total area of gum, the unmixed fraction) were compared between anterior and posterior chewing with the Wilcoxon signed rank test (two-tailed). Subjects chewed significantly less efficiently during anterior chewing than during posterior chewing (P = 0·0051). There was no significant difference in jerk-cost between anterior and posterior conditions in the opening phase (P = 0·25), or closing phase (P = 0·42). This is the first characterisation of the effect of food bolus location on jaw movement smoothness at the same time as recording masticatory efficiency. The data suggest that anterior chewing decreases masticatory efficiency, but does not influence jerk-cost.

The effect of vibration on pain during local anaesthesia injections.

BACKGROUND: The "gate control" theory suggests pain can be reduced by simultaneous activation of nerve fibres that conduct non-noxious stimuli. This study investigated the effects of vibration stimuli on pain experienced during local anaesthetic injections. METHODS: In a preliminary study, subjects were asked to rate anticipated and actual pain from regional anaesthetic injections in the oral cavity. A second study compared, within subjects, pain from injections with and without a simultaneous vibration stimulus. Both infiltration and block anaesthetic injection techniques were assessed. In each subject, two similar injections were given and with one, a vibration stimulus was randomly allocated. Injection pain was assessed by visual analogue scale and McGill pain descriptors. RESULTS: Both infiltration and block injections were painful (mean anticipated intensity: 31.25, actual: 17.82 mm on 100 mm scale). Pain intensity with and without vibration was 12.9 mm (range 0-67) and 22.2 mm (range 0-83) respectively (p = 0.00005, paired T-test), and this effect was seen with both infiltration (p = 0.032) and block anaesthetic (p = 0.0001) injection subgroups. Furthermore, compared to no vibration-stimulus injections, injections with vibration resulted in less pain descriptors chosen (p = 0.004), and the descriptors had a lower pain rating (p = 0.001). CONCLUSIONS: The results suggest that vibration can be used to decrease pain during dental local anaesthetic administration.

How does pain affect jaw muscle activity? The Integrated Pain Adaptation Model.

Pain and limitation of movement are two cardinal symptoms of temporomandibular disorders but it is unclear how one influences the other. The relationship between pain and movement is clinically significant but controversial with two major theories having been proposed: the Vicious Cycle Theory and the Pain Adaptation Model. The Vicious Cycle Theory proposes a vicious cycle between pain and muscle activity. This theory has little scientific basis but underpins many management strategies. The Pain Adaptation Model is more evidence-based and proposes that pain causes changes in muscle activity to limit movement and protect the sensory-motor system from further injury. The Pain Adaptation Model has many positive features but does not appear to explain the relation between pain and muscle activity in all situations. We propose that the relationship is influenced by the functional complexity of the sensory-motor system and the multidimensional nature of pain. This new Integrated Pain Adaptation Model states that pain results in a new recruitment strategy of motor units that is influenced by the multidimensional (i.e., biological and psychosocial) components of the pain experience. This new recruitment strategy aims to minimize pain and maintain homeostasis. This model emphasizes the individual reaction to pain and suggests a tailored approach towards management.

Disruption of default mode network dynamics in acute and chronic pain states.

It has been proposed that pain competes with other attention-demanding stimuli for cognitive resources, and many chronic pain patients display significant attention and mental flexibility deficits. These alterations may result from disruptions in the functioning of the default mode network (DMN) which plays a critical role in attention, memory, prospection and self-processing, and recent investigations have found alterations in DMN function in multiple chronic pain conditions. Whilst it has been proposed that these DMN alterations are a characteristic of pain that is chronic in nature, we recently reported altered oscillatory activity in the DMN during an acute, 5  minute noxious stimulus in healthy control subjects. We therefore hypothesize that altered DMN activity patterns will not be restricted to those in chronic pain but instead will also occur in healthy individuals during tonic noxious stimuli. We used functional magnetic resonance imaging to measure resting state infra-slow oscillatory activity and functional connectivity in patients with chronic orofacial pain at rest and in healthy controls during a 20-minute tonic pain stimulus. We found decreases in oscillatory activity in key regions of the DMN in patients with chronic pain, as well as in healthy controls during tonic pain in addition to changes in functional connectivity between the posterior cingulate cortex and areas of the DMN in both groups. The results show that similar alterations in DMN function occur in healthy individuals during acute noxious stimuli as well as in individuals with chronic pain. These DMN changes may reflect the presence of pain per se and may underlie alterations in attentional processes that occur in the presence of pain.

Altered regional brain T2 relaxation times in individuals with chronic orofacial neuropathic pain.

The neural mechanisms underlying the development and maintenance of chronic pain following nerve injury remain unclear. There is growing evidence that chronic neuropathic pain is associated with altered thalamic firing patterns, thalamocortical dysrhythmia and altered infra-slow oscillations in ascending pain pathways. Preclinical and post-mortem human studies have revealed that neuropathic pain is associated with prolonged astrocyte activation in the dorsal horn and we have suggested that this may result in altered gliotransmission, which results in altered resting neural rhythm in the ascending pain pathway. Evidence of astrocyte activation above the level of the dorsal horn in living humans is lacking and direct measurement of astrocyte activation in living humans is not possible, however, there is evidence that regional alterations in T2 relaxation times are indicative of astrogliosis. The aim of this study was to use T2 relaxometry to explore regional brain anatomy of the ascending pain pathway in individuals with chronic orofacial neuropathic pain. We found that in individuals with trigeminal neuropathic pain, decreases in T2 relaxation times occurred in the region of the spinal trigeminal nucleus and primary somatosensory cortex, as well as in higher order processing regions such as the dorsolateral prefrontal, cingulate and hippocampal/parahippocampal cortices. We speculate that these regional changes in T2 relaxation times reflect prolonged astrocyte activation, which results in altered brain rhythm and ultimately the constant perception of pain. Blocking prolonged astrocyte activation may be effective in preventing and even reversing the development of chronic pain following neural injury.

Ipsilateral interferences and working-side condylar movements.

UNLABELLED: There is limited knowledge of the effects of the occlusion on temporomandibular joint function. AIM: The aim was to investigate the influence of a working-side occlusal alteration (OA, i.e. interference) on trajectories of working-side condylar points during standardized lateral jaw movements (laterotrusion) tracked by a jaw-tracking system. METHODS: Ten trials of right laterotrusion were repeated under: control 1 (before OA), OA (immediately after placement of a working-side interference) and control 2 (immediately after removal of OA) conditions. RESULTS: During right jaw movement, the paths of the working-side condylar points under OA were significantly more inferior and anterior to those under control at the same amount of mid-incisor-point displacement from the intercuspal position. The OA significantly reduced the rotation of the mandible about the antero-posterior and supero-inferior axes and significantly increased the opening angle. Controls 1 and 2 were not significantly different. CONCLUSIONS: A working-side interference has an immediate, significant effect on working-side condylar movement.

The effects of catastrophizing on central motor activity.

BACKGROUND: Pain catastrophizing significantly affects an individual's experience of pain. High pain catastrophizing is associated with increased fear avoidance behaviours, pain intensity and disability. The aim of this investigation was to determine the effect of pain catastrophizing on ongoing brain activity and movement-evoked brain activity during acute orofacial muscle pain. METHODS: Thirty-four healthy, pain-free subjects were recruited. In 17 subjects, the effect of catastrophizing on regional brain activity was determined. In 19 subjects, functional magnetic resonance imaging was used to determine the effects of pain catastrophizing on brain activation patterns during jaw movements in the presence of ongoing pain. RESULTS: We found that in the presence of pain, catastrophizing was significantly correlated with activity in multi-sensory integrative brain regions, including the dorsolateral and medial prefrontal cortices. Importantly, this relationship did not exist when subjects were not experiencing pain. In addition, during repetitive open-close jaw movements in the presence of pain, activity in the primary motor cortex, cerebellar cortex and the trigeminal motor nucleus was positively correlated with pain catastrophizing scores. In contrast, in the dorsolateral prefrontal cortex, as pain catastrophizing scores increased, the magnitude of signal intensity change during jaw movements decreased. Again, no such relationships occurred when the individual was not in pain. CONCLUSIONS: These data show that during pain, catastrophic thinking has a significant impact on activity in motor and sensory integrative regions. Reducing negative coping strategies may be an effective means in reducing fear avoidance behaviours and the intensity of ongoing pain.

Hereditary warfarin resistance. Investigation of a rare phenomenon.

A 57-year-old black woman required a daily dosage of 50 mg of warfarin sodium to maintain her prothrombin time in a therapeutic range. The central volume of distribution and clearance of warfarin were normal for this patient. These findings, combined with the patient's requirement for plasma warfarin levels four times greater than those usually required to achieve adequate anticoagulation, indicated that the relative resistance was due to altered pharmacodynamics of warfarin. The only child of the propositus, a daughter, showed a similar relative resistance, confirming that this family is the third to be reported with hereditary resistance to warfarin.

Transcutaneous chemical collection of caffeine in normal subjects: relationship to area under the plasma concentration-time curve and sweat production.

A novel transcutaneous chemical collection device (TCD) has been developed to study the phenomenon of outward transcutaneous chemical migration. The TCD is a Bandaid-like device containing an immobilized aqueous media and binding reservoir material to prevent back-transfer into the skin. This device, when placed against the skin, allows collection and quantitation of chemicals that diffuse directly through the skin from within the body. The relationship of the amount of drug collected in the TCD to the amount in the body available for collection (as represented by the area under the plasma-concentration time curve, AUC) and the effects of sweating, a potential confounding factor, on collection of drug in a TCD were studied, using caffeine as a model compound. TCD were placed on the skin of normal male volunteers. Twenty-four hours later subjects took caffeine by mouth. Blood samples were collected and TCD were removed at various times after drug intake and analyzed by HPLC for caffeine. Studies of the sweating effect were carried out in a similar manner, except that one arm of each subject was maintained at 40 degrees C to induce local sweating, the other arm acted as a non-sweating control. The amount of caffeine collected was linearly related to the AUC. Sweating seemed to have a large (40%) contribution to transdermal collection in the early period (5.5 h) of the study, but this difference was much less (14%) at longer collection times (10 h).

Determinants of the renal clearance of digoxin.

The renal clearances of digoxin, creatinine, and urea nitrogen were determined simultaneously in each of 41 patients receiving digoxin, in most of whom there was prerenal azotemia. Mean plus or minus SD values were: blood urea nitrogen (BUN), 26.1 plus or minus 12.8 mg per 100 ml; creatine, 1.1 + 0.41 mg per 100 ml; creatinine clearance, 78 plus or minus 42 ml/min/1.73 m2; digoxin clearance, 66.6 plus or minus 42.1 ml/min/1.73 m2; urea nitrogen clearance, 27.8 plus or minus 19.2 ml/min/1.73 m2. Correlation analysis revealed that urea clearance is superior to creatinine clearance, and BUN is superior to serum creatinine concentration in the degree of relationship to renal digoxin clearance. Moreover, using partial correlation techniques, it is apparent that in these patinets digoxin clearance was significantly related to urine flow rate. These findings are compatible with the hypothesis that digoxin undergoes some degree of tubular reabsorption as well as filtration and secretion.

Prediction of the outcome of a phase 3 clinical trial of an antischizophrenic agent (quetiapine fumarate) by simulation with a population pharmacokinetic and pharmacodynamic model.

A completed phase 3 trial result was simulated 100 times on the basis of a simulation model of quetiapine fumarate (Seroquel), an antischizophrenic agent. The simulation was executed by analysts who were completely blinded from results of the actual trial until after the simulations were submitted to the holder of the trial results. Data from two clinical investigations of quetiapine in patients with schizophrenia were analyzed by use of nonlinear mixed effects modeling to derive a population pharmacokinetic- and pharmacodynamic-based simulation model. The time course of quetiapine concentrations was described by use of a one-compartment open linear pharmacokinetic model with first-order absorption and elimination. The combination of an inhibitory maximum effect pharmacodynamic model for the active treatment effect and a linear function of time for the placebo effect characterized the observed time course of change in the Brief Psychiatric Rating Scale. Simulation results were compared with those in the actual trial to evaluate how well the simulations predicted the outcome. The actual trial results for all doses except the placebo group fell within the predicted Brief Psychiatric Rating Scale scores +/- 1 SE. Unlike the phase 2 trial, from which the pharmacokinetic/pharmacodynamic model was developed, the placebo group in the actual phase 3 trial showed deterioration of Brief Psychiatric Rating Scale scores with time. We conclude that variable placebo responses observed in short-term studies of schizophrenia provide an inadequate basis for the modeling and simulation of placebo subjects in clinical trials. Knowledge of the range of placebo response observed in other studies may have provided an improved basis for the placebo effect model. The model for active drug produced adequate predictions of the actual trial outcomes.

Transcutaneous theophylline collection in preterm infants.

Transcutaneous collection of theophylline and its metabolite, caffeine, was undertaken in 33 preterm infants (2 to 89 days old) who were receiving routine theophylline therapy. Collection was done by means of a novel adhesive transcutaneous collection system. The transcutaneous collection system accumulated substances that migrated from the blood to the skin surface by trapping them in an activated charcoal-gel matrix. On one to three occasions, four transdermal collection systems were applied to the back or abdomen of each infant for 4 to 12 hours. During that time, blood samples were obtained for routine monitoring of plasma theophylline levels. Amounts of theophylline (95 +/- 198 ng) and caffeine (83 +/- 77 ng) in the transcutaneous collection system were significantly correlated with the respective average plasma drug concentration and postconceptional age (p less than 0.01). Skin reactions were limited to mild erythema. We concluded that theophylline and caffeine can be collected on the surface of the skin of preterm infants with a novel transcutaneous collection system. Amounts collected by means of the transcutaneous collection system correlated with plasma concentrations consistent with a diffusion process, but they were poor predictors of individual concentrations.

A pharmacodynamic Markov mixed-effects model for the effect of temazepam on sleep.

BACKGROUND: A hypnogram shows how sleep travels through its various stages in the course of a night. The sleep stage changes can be quantified to study sedative drug effects. METHODS: Hypnograms from 21 patients with primary insomnia were collected during a randomized, placebo-controlled crossover study of 20 mg temazepam. A separate daytime session was performed to determine the pharmacokinetics of 20 mg temazepam and its effect on saccadic eye movement and electroencephalogram. A first-order Markov model was developed to describe the probability of sleep stage changes as a function of time after drug intake and time after last sleep stage change. The influence of temazepam concentration on the probability to change sleep stage was incorporated into the model. RESULTS: Transitions between sleep stages were profoundly influenced by the time of the night and by the time since the last change of sleep stage. Temazepam reduced the time spent awake. This effect could be attributed to four mechanisms: (1) transition to "deeper" sleep was facilitated, (2) transition to "lighter" sleep was inhibited, (3) regardless of sleep stage, the transition to wake state was inhibited, and (4) return to sleep was facilitated. Daytime sensitivities to temazepam, measured with the surrogate markers saccadic peak velocity and electroencephalogram beta activity, each correlated with one of the transition probabilities influenced by temazepam. CONCLUSIONS: By the development of a Markov model for these non-ordered six categorical data, the effect of temazepam on the sleep-wake status could be interpreted in terms of known mechanisms for sleep generation and benzodiazepine pharmacology.

Adaptive control with feedback strategies for suramin dosing.

Suramin, a drug used in the treatment of parasitic diseases, is currently being evaluated in clinical trials as an antineoplastic agent. The use of therapeutic drug monitoring and adaptive control with feedback in clinical trials of suramin was initially motivated by an association between acute neurologic toxicity and plasma suramin concentrations in excess of 350 micrograms/ml. We have prospectively examined the performance of both two- and three-compartment population pharmacokinetic models in controlling plasma suramin concentrations and have found that a three-compartment model best describes this drug. No correlation was found between the clearance of suramin and creatinine clearance, as had been previously hypothesized. The low systemic clearance of suramin and the number of parameters required to describe the three-compartment model suggest the need for a bayesian approach to the estimation of individual pharmacokinetics.

Pharmacodynamics of temazepam in primary insomnia: assessment of the value of quantitative electroencephalography and saccadic eye movements in predicting improvement of sleep.

BACKGROUND AND OBJECTIVE: Quantitative electroencephalographic parameters and saccadic eye movements are frequently used as pharmacodynamic measures of benzodiazepine effect. We investigated the relationship between these measures and the hypnotic effect. METHODS: The correlation between the pharmacodynamic measures and sleep quality was determined in 21 patients with primary insomnia. The pharmacokinetic-pharmacodynamic relationships were characterized after administration of 20 mg oral temazepam. The hypnotic effect was determined on the basis of polysomnographic sleep recordings and a subjective sleep evaluation questionnaire. Correlations between pharmacodynamic measures and the improvement of sleep were investigated. RESULTS: The pharmacokinetic-pharmacodynamic relationships for the parameters derived from electroencephalography and saccadic eye movements showed considerable interindividual variability. Administration of temazepam led to a significant improvement in the objective parameters sleep period efficiency, wake time after sleep onset, and sleep efficiency and in the subjective assessment of sleep quality. No significant correlations were observed between the pharmacokinetic-pharmacodynamic-derived parameters and the improvement in objective or subjective sleep parameters. CONCLUSION: In subjects with primary insomnia the administration of 20 mg oral temazepam results in changes in both the pharmacodynamic measures and in quality of sleep. No individual correlations between the pharmacodynamic measures and quality of sleep were observed. We concluded that the investigated pharmacodynamic measures are of value in the first assessment of clinical efficacy and for the selection of the dose(s) to be investigated in subsequent trials that aim at showing clinical efficacy. However, the conclusive quantification of clinical efficacy should be performed only on the basis of the clinical end point itself.