Effect of baclofen on emesis and 24-hour esophageal pH in neurologically impaired children with gastroesophageal reflux disease

OBJECTIVES: Gastroesophageal reflux disease (GERD) is difficult to control with medical therapy in neurologically impaired children. The gamma-aminobutyric acid type B receptor agonist baclofen was recently reported to reduce reflux in adult patients with GERD by reducing the incidence of transient lower esophageal sphincter relaxations. The current study was undertaken to investigate the effects of baclofen on GERD in neurologically impaired children. METHODS: Eight neurologically impaired children with GERD between 2 months and 16 years were studied. Baclofen (0.7 mg/kg/day) was administered orally or via nasogastric tube in three divided doses 30 minutes before meals for 7 days. The frequency of emesis on and off baclofen were recorded as a measure of clinical impact. Twenty-four-hour esophageal pH monitoring was conducted before and on the seventh day of the administration of baclofen. RESULTS: The frequency of emesis was significantly decreased (P = 0.03). The total number of acid refluxes was significantly decreased both during the entire 24-hour period (P = 0.01) and during the postprandial period (P = 0.049). The number of acid refluxes longer than 5 minutes was significantly decreased during the 24-hour period (P = 0.02). The percentage total time of esophageal pH <4.0 and esophageal acid clearance time were not significantly different during the 24-hour period or during the postprandial period. No adverse effects were observed, except for a slight reduction in muscle tone in one subject. CONCLUSIONS: In this 1-week trial, repetitive administration of baclofen reduced the frequency of emesis and the total number of acid refluxes in neurologically impaired children with GERD.     

Subtype selective substrates for histone deacetylases

To probe the steric requirements for deacylation, we synthesized lysine-derived small molecule substrates and examined structure-reactivity relationships with various histone deacetylases. Rat liver, human HeLa, and human recombinant class I and II histone deacetylases (HDACs) as well as human recombinant NAD(+)-dependent SIRT1 (class III enzyme) were used in these studies. A benzyloxycarbonyl substituent on the alpha-amino group yielded the highest conversion rates. Replacing the epsilon-acetyl group with larger lipophilic acyl substituents led to a pronounced decrease in conversion by class I and II enzymes; the class III enzyme displayed a greater tolerance. Incubations with recombinant FLAG-tagged human HDACs 1, 3, and 6 showed a distinct subtype selectivity among small molecule substrates. The subtype selectivity of HDAC inhibitors could be predicted with these substrates and an easily obtainable mixture of HDAC subtypes.     

Comparison of once-daily nifedipine controlled-release with twice-daily nifedipine retard in the treatment of essential hypertension

AIMS: Nifedipine is a short-acting calcium antagonist formulated into several different oral preparations, each of which may have different effects on haemodynamics and autonomic nervous function. We compared the effects of nifedipine controlled-release (CR) and nifedipine retard on 24-h blood pressure, heart rate, rate-pressure product, and power spectral measures of heart rate variability in patients with essential hypertension. METHODS: After 4 weeks of a drug-free period, 25 patients were randomized to receive either once-daily treatment with nifedipine CR (20-40 mg daily; 12 patients) or twice-daily treatment with nifedipine retard (20-40 mg daily; 13 patients) for 12 weeks. The ambulatory blood pressure, heart rate, and ECG R-R intervals were measured during a 24-h period using a portable recorder (TM-2425) at the end of the drug-free and the treatment periods. A power-spectral analysis of R-R intervals was performed to obtain the low-frequency (LF) and high-frequency (HF) components. RESULTS: Nifedipine CR and nifedipine retard reduced 24-h blood pressure significantly by 15.9 +/- 3.2 (SE)/8.7 +/- 1.4 mmHg and by 10.9 +/- 2.8/9.4 +/- 1.7 mmHg, respectively, after the 12-week treatment. Nifedipine CR did not change the 24-h heart rate significantly, while nifedipine retard increased it significantly by 3.9 +/- 2.1 beats min(-1). Nifedipine CR produced a significant reduction in rate-pressure product throughout a 24-h period, while nifedipine retard did not change the rate-pressure product significantly. In addition, nifedipine retard significantly decreased the 24-h and daytime average values of the LF and HF components, while nifedipine CR affected the nighttime LF component alone and did not change the HF component throughout a 24-h period. CONCLUSIONS: These results demonstrate that both nifedipine CR and nifedipine retard are effective as antihypertensive agents, but nifedipine CR has less influence on the autonomic nervous system and heart rate than nifedipine retard.     

Correlation of optical coherence tomography with angiography in retinal pigment epithelial detachment associated with age-related macular degeneration

PURPOSE: To correlate optical coherence tomography (OCT) with angiographic signs of choroidal neovascularization (CNV) in retinal pigment epithelial detachment (PED) associated with age-related macular degeneration (ARMD). METHODS: Prospectively, the authors performed OCT in 35 eyes of 35 patients (30 men and 5 women with a mean age of 71.6 years [range, 56-76 years]) with ARMD. All 35 eyes had CNV in the area of PED or adjacent to it, which was shown by fluorescein or indocyanine green angiography. Cross-sectional images were obtained by the OCT scanning line through the CNV and PED. RESULTS: In 10 (56%) of 18 eyes in which the CNV was at the margin of the PED, a small PED was adjacent to the central, dome-shaped PED. There was a notch between the central and small mounds of PED. In 13 (76%) of 17 eyes in which the CNV was within the PED, a notch was seen in the dome-shaped PED, resulting in a contour with 2 mounds. One of the 2 mounds contained a highly reflective mass immediately beneath the detached retinal pigment epithelium in 8 (62%) of the 13 eyes. CONCLUSION: A tomographic notch in the PED may be diagnostically important as an indication of CNV beneath the detached retinal pigment epithelium in eyes with ARMD.     

Effects of lidocaine into knee on QF strength and EMG in patients with ACL lesion

PURPOSE: In our previous study, we found that injection of lidocaine into intact knees reduced the maximal voluntary contraction (MVC) and integrated electromyogram (I-EMG) of the quadriceps femoris (QF). This study was designed to investigate changes in the MVC and I-EMG of the QF in response to lidocaine, in patients with anterior cruciate ligament (ACL) lesion, to evaluate alpha-motoneuron activity innervating the QF. METHODS: The MVC of knee extension and I-EMG of the vastus medialis (VM), vastus lateralis (VL), and rectus femoris (RF) muscles were measured in eight patients with ruptured ACL, before and after lidocaine injection into the knee. RESULTS: There were no significant differences between preinjection and postinjection values of MVC (preinjection: 167 +/- 49 N.m; postinjection: 164 +/- 55 N.m) and I-EMG (preinjection: VL: 0.11 +/- 0.06, VM: 0.13 +/- 0.10, RF: 0.09 +/- 0.04) (postinjection: VL: 0.12 +/- 0.07, VM: 0.13 +/- 0.10, RF: 0.09 +/- 0.05). CONCLUSION: Our results indicated that hindrance of afferent feedback from the knee in patients with ACL rupture did not significantly change alpha-motoneuron activity. Lidocaine injection into the knee joint of the subjects in this study only attenuated afferent feedback from mechanoreceptors in the knee joint cavity, but not in the ACL, as afferent feedback from ACL was already lost due to ACL rupture. This indicated that attenuation of afferent feedback from mechanoreceptors in the knee joint cavity other than the ACL did not significantly decrease the activity of alpha-motoneurons innervating the QF during MVC exertion. Therefore, our findings provide evidence that afferent feedback from the ACL has a major influence on the MVC exertion of the QF.     

Highly enhanced permeability of blood-brain barrier induced by repeated administration of endothelin-1 in dogs and rats

The effects of intracisternal administration of endothelin-1 on blood-brain barrier permeability were examined in dogs and rats. Single doses of endothelin-1 elevated blood-brain barrier permeability about two times compared with control groups in both species. However, repeated dosing with endothelin-1 at a 24 hr intervals caused a highly enhanced disruption of blood-brain barrier permeability in dogs, but not in rats, whereas the repeated administration with a 48 hr interval markedly increased the blood-brain barrier permeability in both species of animals (dogs: 923%, rats: more than 661%). Moreover, this abnormally enhanced permeability of blood-brain barrier in dogs was completely blocked by pretreatment with the endothelin ET-A receptor selective antagonist, S-0139, administered prior to either the first or second dosing with endothelin-1. From these results, we conclude that a repeated attack of endothelin-1 from the adventitial site of brain blood vessels produces a severe disruption of blood-brain barrier permeability through an endothelin ET-A receptor-mediated process.     

An extract of the root of Lithospermun erythrorhison accelerates wound healing in diabetic mice

Many people suffer from intractable bedsores, which sometimes develop because of chronic metabolic failure in patients. An extract of the root of Lithospermun erythrorhison (SK) has been reported to have an effect on wound healing. However, the effects of SK have not been studied in chronic wounds, such as bedsores. The healing-impaired diabetic (db/db) mouse is a good model for the investigation of clinical healing therapies. Therefore, we examined whether SK accelerates wound healing in db/db mice. Full-thickness round wounds of 6-mm diameter were created on the backs of mice. After applying SK, we covered the wound with a film dressing to keep it moist. At three weeks, wound closure was complete in SK-treated mice but not in controls. Capillary vessel number and collagen synthesis increased early in wound healing in SK-treated wounds. At this time, vascular endothelial growth factor (VEGF)-positive neutrophils had infiltrated the wound and the appearance of apoptotic fibroblasts and endothelial cells in the granulation tissue was more advanced than in the controls. Where the wound was covered with epithelium, there tended to be less infiltration of VEGF-positive cells and apoptotic cells. These results suggest that the inflammatory phase was shortened, and the proliferative and maturation phases were advanced by SK. It is known that SK also has antibacterial activity. Therefore, we conclude that SK is useful for wound healing in db/db mice, and could potentially help patients with intractable bedsores.