Cholesterol-lowering effects of NTE-122, a novel acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor, on cholesterol diet-fed rats and rabbits.

Pharmacological characterization of NTE-122 (trans-1,4-bis[[1-cyclohexyl-3-(4-dimethylamino phenyl)ureido]methyl]cyclohexane), a novel acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor, was performed with both in vitro and in vivo assay systems. NTE-122 inhibited microsomal ACAT activities of various tissues (liver of rabbit and rat, small intestine of rabbit and rat, and aorta of rabbit) and cultured cells (HepG2 and CaCo-2), with IC50 values from 1.2 to 9.6 nM. The inhibition mode of NTE-122 was competitive for HepG2 ACAT. NTE-122 had no effect on other lipid metabolizing enzymes, such as 3-hydroxy-3-methylglutaryl-CoA reductase, acyl-CoA synthetase, cholesterol esterase, lecithin:cholesterol acyltransferase, acyl-CoA:sn-glycerol-3-phosphate acyltransferase and cholesterol 7alpha-hydroxylase up to 10 microM. When NTE-122 was administered to the cholesterol diet-fed rats, serum and liver cholesterol levels were markedly reduced with an ED50 of 0.12 and 0.44 mg/kg/day, respectively. In the cholesterol diet-fed rabbits, NTE-122 significantly lowered plasma and liver cholesterol levels at more than 2 mg/kg/day. These results indicate that NTE-122 is a potent, selective and competitive inhibitor of ACAT, making it a worth while therapeutic agent for hypercholesterolemia and atherosclerosis.

Effect of passive motions on the initiation of fast knee extension in patients with paraparesis.

Using reaction time paradigm, the effect of repetitive passive motion (RPM) on the initiation of fast knee extension was analyzed in seven normal subjects and 10 patients with paraparesis. Before and after 5 min RPM of the responding lower extremity, i.e., alternate flexion and extension of the knee and the hip with frequency of 0.5 Hz, the following five variables were examined: premotor time (PMT), latency from sound stimulus to initiation of EMG activities of the rectus femoris; tension lag time (TLT), period between onset of EMG activities and rise of tension; contraction time (FTmax); maximum tension (Tmax); and rate of tension development (RTD, Fmax/FTmax). In the normal group, PMT decreased significantly after RPM, whereas the other four variables did not show any change due to RPM. In the patient group, shortening of both PMT and FTmax after RPM was significant and Fmax tended to be small. These results suggested that RPM of an extremity induces behavioral alertness when the afferent pathway from moving parts to the higher center is not interrupted and also that RPM modulates abnormal pattern of motor neuron activities at the spinal level.

Motor time of the rectus femoris during passive movements.

Motor time (MT) of 10 normal subjects were examined in three conditions: 1) during passive flexion of the knee (PFLX), 2) during passive extension (PEXT), and without passive movement (STAT). Compared to STAT, MTs of PFLX and PEXT were significantly long. MT tended to be shorter, though insignificant statistically, in PFLX than in PEXT. In conclusion, passive movements are influential in changing the physical state of the muscle including both series-elastic and contractile components.

Reaction times of normal subjects and amputees with below-knee and above-knee prostheses during stepping.

Reaction times (RTs) of nine normal subjects and 11 amputees with prosthetic limbs were examined in standing posture and during stepping movement. There were significant differences of RTs between standing and stepping, and between the phases of the stepping cycle in both the normal subjects and the BK or AK amputees with prosthetic limbs. The attentional demand during stepping movement and the applicability of probe RT procedure to assess prosthetic limb were briefly discussed.

Effect of passive movements on reaction time of the rectus femoris in normal subjects and patients with paraparesis.

Electromyographic reaction times (EMG-RTs) of the right knee extension were examined in eight normal subjects and eight patients with paraparesis under three conditions; during passive knee flexion (PFLX), passive extension (PEXT) and no passive movements (STAT). EMG-RTs of the three conditions were not significantly different between the normal and the patient group. A two-way analysis of variance (condition x group) showed that the main effect of condition was significant, but that of group and the interaction were not. Both in the normal and the patient group the shortest EMG-RTs of all was obtained in PEXT, followed by that of STAT and PFLX. Effect of passive movements on EMG-RTs in the patients whose position sense of the knee and muscle strength of the knee extension were within normal range did not vary with the abnormality of tactile sense and/or myotatic reflexes. The results indicated that activities of the pyramidal tract neurons in carrying out a movement were directly influenced by kinesthetic information of the moving limb.

Dependence of reaction time on visual fields in patients with unilateral hemispheric lesions.

Reaction times (RTs) to light stimuli which appeared at central and lateral positions were measured in 13 normal subjects and 34 patients with unilateral lesions in the left or the right hemisphere. The normal subjects showed slowing of RTs to both lateral stimuli compared to the central stimulus, the extent of which was equal between the left and right hands. The patients with left hemispheric lesions had slower RTs to the stimulus contralaterally to the lesion than ipsilaterally and centrally. The patients with right hemispheric lesions had slower RTs both to the contralateral and central stimuli than to the ipsilateral. The results are discussed in relation to functional differentiation of the left and right hemispheres for visual processing.

The interference effect of simultaneous vocalization on reaction time of hand and foot.

Reaction times (RTs) of 14 normal subjects were examined in two tasks; the extension of the right middle finger, or of the right toe or the vocalization responding to the sound stimulation (single tasks), and the simultaneous responses of the two mentioned above (simultaneous tasks). RT of each part was longer on the simultaneous response than on the separate one. Slowing of the vocal response combined with the foot was larger than that with the hand and slowing of the foot with the vocalization was larger than that with the hand. The results were interpreted as indicating that the slowing of RT in the simultaneous responses should occur at the levels of the premotor associations, including the basal ganglia and cerebellum, but not at the level of the motor cortex.

Reaction time in bimanual simultaneous motions.

Electromyographically determined reaction times (EMG-RTs) of the finger flexor and extensor of both forearms were measured for four different motions: inward (task 1), flexion of both wrists; outward (task 2), extension of both wrists; to the left (task 3), extension of the left wrist and flexion of the right; and to the right (task 4), flexion of the left and extension of the right. The EMG-RTs were shorter and synchronization errors in terms of left to right differences of EMG-RTs were smaller in tasks 1 and 2 than in tasks 3 and 4. Comparing the flexors and the extensors, the extent of prolongation of EMG-RTs in tasks 3 and 4 differed significantly on the left side, being larger in the flexor than in the extensor, but there was no difference in the extent of prolongation between the flexor and the extensor on the right. It was suggested that the timing of initiation of movements in simultaneous motions was primarily determined by the pattern of muscle coupling in both limbs, and not by the direction of movements. The steadiness of motor function and of the right hand in right-handed subjects was also discussed in regard to hand preference.