Evaluation of hypothesis testing for comparing two populations using NONMEM analysis

In a simulation study of inference on population pharmacokinetic parameters, two methods of performing tests of hypotheses comparing two populations using NONMEM were evaluated. These two methods are the test based upon 95% confidence intervals and the likelihood ratio test. Data were simulated according to a monoexponential model and, in that context, power curves for each test were generated for (i)the ratio of mean clearance and (ii)the ratio of the population standard deviations of clearance. To generate the power curves, a range of these parameters was employed; other pharmacokinetic parameters were selected to reflect the variability typically present in a Phase II clinical trial. For tests comparing the means, the confidence interval tests had approximately the same power as the likelihood ratio tests and were consistently more faithful to the nominal level of significance. For comparison of the standard deviations, and when the volume of information available was relatively small, however, the likelihood ratio test was more able to detect differences between the two groups. These results were then compared to results on parameter estimation in order to gain insight into the question of power. As an example, the nonnormality of estimates of the ratio of standard deviations plays an important role in explaining the low power for the confidence interval tests. We conclude that, except for the situation of modeling standard deviations with only sparse information, NONMEM produces tests of significance that are effective at detecting clinically significant differences between two populations.Partial support from the Upjohn Company, NIH-BRSG SO RR 07066, and the Burroughs Wellcome Foundation.     

Anterior spinal hernia: an increasingly recognised cause of thoracic cord dysfunction.

Two cases of anterior spinal hernia are presented. The medical literature is reviewed, the syndrome characterised, and its cause and treatment discussed. The patient is typically middle aged with a history of stepwise slowly progressive mid-thoracic anterior hemicord syndrome manifesting as hemianalgesia below the affected segment, followed by contralateral lower limb spasticity that develops into an asymmetric paraparesis with sparing of dorsal column sensation. Radiological investigation demonstrates an enlarged dorsal arachnoid space in association with an apparently focally narrowed thoracic cord, kinked towards the anterior dura. At operation the cord is found to be prolapsed into an anterolateral dural diverticulum. The most likely cause of this syndrome is anterior spinal artery segmental branch ischaemia, in a cord chronically incarcerated in a congenital anterior meningocele. This readily treatable condition should be considered in all cases of thoracic cord dysfunction and surgical repair effected early to prevent stepwise progression to paraplegia.     

Xenopus Tadpole Melanophores Are Controlled by Dark and Light and Melatonin Without Influence of Time of Day

Melanophores were studied in tadpoles of the South African clawed toad, Xenopus laevis , during the first week after hatching (stages 46–49) at 25°C. The tadpoles had melanophores with dispersed melanosomes in the light and punctate melanophores in the dark in LD12:12. The melanophores remained punctate in constant dark and the melanosomes remained dispersed in constant light. Lights-out (in the light-time of LD12:12) caused the melanophores to become punctate, which occurred more quickly than the dispersion of melanosomes, which commenced when the lights were turned on (in the dark-time of LD12:12). Melanophores with dispersed melanosomes in tadpoles (in constant light) became punctate in response to a series of melatonin concentrations (0.2–5 ng/ml) in their bathing water irrespective of the time of day melatonin was administered. An image-analysis technique for assessing melanophore responses was tested.     

Receptor subtypes mediating facilitation by serotonin of excitability of spinal motoneurons

Serotonin receptor ligands, with differential affinity for subtypes of serotonin (5-HT) receptors, were administered intravenously or iontophoretically to urethane-anesthetized rats and the effects of these compounds on glutamate-evoked firing of spinal motoneurons were tested. The excitability of spinal motoneurons was markedly enhanced after intravenous administration of the selective 5-HT1A ligand 8-hydroxy-2-(di-n-propylamino) tetralin (DPAT) in rats with acute spinal transections at C1. However, local application of DPAT, directly into the ventral horn by microiontophoresis, inhibited the glutamate-evoked firing of motoneurons in direct contrast to the facilitatory effects of iontophoretically applied 5-HT. The DPAT-induced inhibition may have been nonspecific, since it was not antagonized by methysergide. Other 5-HT agonists, with relatively selective affinity for 5-HT1B, 5-HT1C and 5-HT2 receptors, increased the excitability of spinal motoneurons when applied iontophoretically or intravenously. The excitatory effect of iontophoretically applied 5-HT was antagonized by the nonselective 5-HT antagonist, methysergide and by ketanserin and ritanserin, which have relatively selective affinity for 5-HT1C and 5-HT2 receptors. These results indicate that 5-HT1A receptors do not mediate facilitation of excitability of motoneurons produced by local application of 5-HT directly into the vicinity of the motoneurons. However, the marked increase in firing of motoneurons that was caused by intravenous administration of DPAT in spinal transected rats, suggests that 5-HT1A receptors in the spinal cord may participate in 5-HT-induced enhancement of somatomotor outflow, at sites presynaptic to the motoneurons. The iontophoretic results suggest that 5-HT1B, 5-HT1C and 5-HT2 receptors may all play a role in facilitation of the excitability of spinal motoneurons by locally applied 5-HT. Differentiation between these subtypes of receptor awaits the development of more completely selective agonists and antagonists.     

Evidence for prenatal competition among the central arbors of trigeminal primary afferent neurons.

Previous studies have shown that damage to vibrissa follicles in newborn rats and mice does not alter the brainstem representations of the remaining vibrissa as demonstrated by staining for mitochondrial enzymes such as cytochrome oxidase (CO) succinic dehydrogenase. This study asked whether this lack of effect might be due to the fact that the trigeminal primary afferents in rodents are already quite well developed at birth. We assessed this possibility by using CO staining the evaluate patterns in the brainstems of pre- and postnatal rats. A vibrissa-related pattern began to emerge in trigeminal nucleus principalis and subnucleus interpolaris (Spl) by embryonic day (E-) 19 and appeared fully developed by the day of birth (P-0). We also made partial lesions of the vibrissa pad on E-15-20 and on P-0, killed pups on P-5-7, and measured the size of the CO-stained patches in Spl on both sides of the brainstem. The correspondence between CO patches and clusters of primary afferent terminal arbors was verified in some animals by combining transganglionic horseradish peroxidase tracing and CO staining. Vibrissa pad damage on E-15-18 resulted in significant (20.1-36.9%) increases in the average area of the remaining CO patches in Spl ipsilateral to the lesion. Vibrissa pad damage on E-19, E-20, and P-0 produced small (6.2-8.9%), but insignificant, increases in patch size in Spl ipsilateral to the lesion. We used anatomical and electrophysiological methods to determine whether our lesions altered the trigeminal innervation of surviving vibrissa follicles. We recorded single trigeminal ganglion cells from 12 rats that sustained vibrissa pad lesion on E-17. As in normal rats, all of the 49 vibrissa-sensitive ganglion cells isolated in the lesioned animals were responsive to deflection of one and only one vibrissa. We also dissected 11 deep vibrissal nerves from intact follicles in adult rats that sustained fetal vibrissa pad damage on E-17, and counted numbers of myelinated axons in 1 microns plastic sections. These data were compared with counts from corresponding follicles on the intact side of the face. The average number of myelinated axons innervating follicles in the damaged vibrissa pads was 196.8 +/- 27.9, and that for the corresponding contralateral nerves was 194.6 +/- 25.7. These data suggest that competitive interactions among the central arbors of trigeminal primary afferents in fetal life may influence the development of central vibrissa representations and, further, that lesion-induced central changes need not be correlated with alterations in the peripheral innervation of undamaged follicles.     

Benzazepinone calcium channel blockers. 2. Structure-activity and drug metabolism studies leading to potent antihypertensive agents. Comparison with benzothiazepinones.

As part of a program to discover potent antihypertensive analogues of diltiazem (3a), we prepared 1-benzazepin-2-ones (4). Benzazepinones competitively displace radiolabeled diltiazem, and show the same absolute stereochemical preferences at the calcium channel receptor protein. Derivatives of 4 containing a trifluoromethyl substituent in the fused aromatic ring show potent and long-acting antihypertensive activity. Studies of the metabolism of 4 lead to the metabolically stable antihypertensive calcium channel blockers 5a and 5c. Benzazepinone 5a is a longer acting and more potent antihypertensive agent than the second generation diltiazem analogue TA-3090 (3e).     

A latent class model for repeated measurements experiments.

Standard models for the analysis of repeated measurements assume a common response profile for all experimental units within a treatment group. However, in many applications this under-represents the nature of the response. There may be several distinct modes of response within a group (for example, responders versus non-responders to a given treatment), or there may be a set of distinct response profiles which are common to all the treatment groups. In these situations the effect of treatment can be characterized both by the shape of the fitted profiles and by estimating the proportion of cases who exhibit each particular response profile. This paper describes how such experiments may be analysed through the introduction of a latent variable into the standard model. Maximum likelihood estimation is straight-forward using the EM algorithm. Model choice requires some care, but good-fitting models can be identified via inspection of residuals and the use of empirical semi-variogram plots. Once the number of distinct profiles has been determined, treatment effects can be investigated using likelihood-ratio statistics. The approach is illustrated with a re-analysis of a dataset first described by Grizzle and Allen.