Analgesic effects of flecainide on postherpetic neuralgia.

Sodium channel blockers have been reported to be effective in relieving neuropathic pain. However, although intravenous lidocaine has proved to be effective, in some patients oral mexiletine fails to produce adequate pain relief. In this study, we investigated the analgesic effect of flecainide, a long-lasting antitachyarrhythmic drug, on postherpetic neuralgia. Twenty patients with postherpetic neuralgia received an intravenous infusion of flecainide and 15 (75%) of those who achieved pain relief subsequently received oral flecainide. The patients were assessed using a 100 mm visual analog scale 1 month after treatment. Significant improvement compared with the pretreatment reading was found. This study suggests that the action of flecainide in blocking the sodium channel is potent and long-lasting and that, like the intravenous formulation, the oral formulation has a stable analgesic effect on postherpetic neuralgia.

Flecainide reverses neuropathic pain and suppresses ectopic nerve discharge in rats.

We investigated effects of flecainide, a Class IC sodium channel blocker, in the rat chronic constrictive injury (CCI) and ectopic nerve discharge models. In the behavioral evaluation, 2, 6, and 12 mg/kg flecainide were intravenously given to the CCI model, and a dose-dependent analgesic effect was shown on both thermal hyperalgesia and tactile allodynia. In the electrophysiological evaluation using the ectopic nerve discharge model produced by saphenous neurectomy, i.v. administration of 2, 6, and 12 mg/kg flecainide suppressed spontaneous discharge at the peripheral nerve level in a dose-dependent fashion as with the behavioral evaluation, but flecainide did not affect nerve conduction at the dose of 12 mg/kg.

Persistent infection with Listeria monocytogenes in the kidney induces anti-inflammatory invariant fetal-type gammadelta T cells.

After intraperitoneal inoculation with Listeria monocytogenes, gammadelta T cells appear in the peritoneal cavity preceding the appearance of alphabeta T cells. Such gammadelta T cells predominantly express T-cell receptor (TCR)Vgamma1/Vdelta6, develop through an extrathymic pathway, and contribute to host defence against the bacteria. We have observed a gradual increase in gammadelta T cells in kidneys of mice after intrarenal inoculation with L. monocytogenes, which resulted in an unusually long-lasting local infection. In this study, we examined the characteristics and the roles of the gammadelta T cells induced in this model. It was found that these gammadelta T cells predominantly expressed TCRVgamma6/Vdelta1 with canonical junctional sequences identical to those expressed on fetal thymocytes. Although depletion of such gammadelta T cells in vivo did not affect the number of bacteria, it resulted in histologically exacerbated inflammation in the kidneys. These results indicate that a persistent infection with L. monocytogenes in kidneys induces a different kind of gammadelta T cell from that induced after intraperitoneal infection. The former expresses invariant fetal-type Vgamma6/Vdelta1+TCR and plays a regulatory role in resolution of inflammation.

The characterization of testicular cell (TC)-specific T-cell clones induced by intratesticular Listeria monocytogenes infection: TC-specific T cells with atypical cytokine profile transfer orchitis.

A unilateral infection of Listeria monocytogenes into the testis of mice induces not only Listeria-specific T cells but also autoreactive T cells that can transfer experimental autoimmune orchitis (EAO) into naive mice. To investigate the characteristics of the autoreactive T cells, we established six testicular cell (TC)-specific T-cell clones from the spleen of the intratesticularly infected mice. All the clones expressed CD4 and T-cell receptor (TCR) alpha beta, and four of the six clones expressed V beta 8. They showed proliferative response to TC in the presence of syngeneic spleen antigen-presenting cells, but did not cross-react to Listeria antigen (Ag). They produced interferon-gamma (IFN-gamma) when stimulated with TC, but interleukin-2 (IL-2), IL-4 and IL-10 were undetectable. IL-2 production was not detected even when they were restimulated with TC after a 10-day resting culture without Ag and IL-2, although they proliferated in the restimulation culture. Even in the presence of anti-IL-2 mAb, the TC-specific T-cell clones showed proliferative response against TC. The observations indicate that the TC-specific IFN-gamma-producing T cells proliferate in the absence of autocrine. Both intravenous and intratesticular injection of these clones transferred EAO in syngeneic naive mice. These results suggest that L. monocytogenes infection in the testis induces autoreactive orchitogenic CD4+ T cells without cross-reactivity to bacterial Ag. Furthermore, these data demonstrate that CD4+ T cells with an atypical cytokine profile can efficiently cause EAO.

[The analgesic effect of iontophoresis with magnesium sulfate].

The analgesic effect of iontophoresis with magnesium sulfate was studied in fourteen healthy adult volunteers. Magnesium sulfate 0.5 mg.5 ml-1 was locally administered by the iontophoresis with 1.0 mA electric current for 10 min. The pain recognition time was measured by the pain thermometer before and after 5, 15, 30, 60 and 120 min of iontophoresis. The pain recognition time was significantly extended and lasted for 60 min. These results support the view that the iontophoresis with magnesium sulfate has analgesic effect and produces a good pain relief clinically.

[The effect of iontophoresis with several Ca channel blockers for PHN patients].

We performed iontophoresis with Ca channel blockers for healthy adult volunteers. In this clinical study, we used iontophoresis with Ca channel blockers. Ten out patients with PHN treated at our pain clinic were treated with iontophoresis. They were randomly assigned to one of the following four treatments: (1) 5 ml of 4% lidocaine HCl, (2) 2 mg of nicardipine HCl + 5 ml of distilled water, (3) 2 mg of verapamil HCl + 5 ml of distilled water, and (4) 2 mg of diltiazem HCl + 5 ml distilled water. Iontophoresis was performed using the above four drugs on the positive pole. Using a VAS, each patient was evaluated concerning the analgesic effect. The pain before treatment (10 points) was used as the base line. Compared with the scores before treatment, VAS scores decreased significantly after iontophoresis in all four groups. In the lidocaine group, a significant decrease in VAS scores occurred immediately after iontophoresis and lasted up to 24 hours, reaching the nadir at 2 hours. In the nicardipine group, the decrease occurred immediately after iontophoresis and lasted up to one day, reaching the nadir at four hours. In the verapamil group, the decrease started 1 hour after iontophoresis and lasted up to 48 hours, reaching the nadir at 8 hours. In diltiazem group, the decrease started 1 hour after iontophoresis and lasted up to 48 hours, reaching the nadir at 4 hours. Iontophoresis with Ca channel blockers produced a prolonged analgesic effect in PHN patients. Previously we had observed the same effect in adult volunteers. Therefore, we believe that this therapy will be clinically useful.

[Reversal by the calcium ion of the pain threshold elevated by calcium channel blockers].

We investigated calcium ion effects on pain thresholds by iontophoresis in healthy adult volunteers. The pain thresholds were measured by the pain thermometer to evaluate the effect of iontophoresis. At first, one of calcium channel blockers (nicardipine, verapamil or diltiazem) was administered by iontophoresis with 1.0 mA for 10 minutes. Then, next to calcium channel blockers, calcium chloride or saline was locally administered after the elevation of pain threshold had been recognized and the pain threshold had been measured again. Calcium ion decreased the elevation of pain threshold significantly, but saline had no effect. These results suggest that not only sodium channel but also calcium channel influences pain mechanism during iontophoresis.

[Prefeeding of aldose reductase inhibitor inhibits galactose cataract].

To examine the effect of prefeeding the aldose reductase inhibitor (ARI) on the cataract induced by the subsequent feeding of galactose diet, rats were first fed rat chow with or without ARI for 2 weeks. The animals were then transferred to a 25% galactose diet for different periods of time. Lenses were enucleated and examined by light microscopy. The amount of galactitol in the lenses was examined biochemically. The cataract was less severe and there was less galactitol in the lenses in the rats first fed with ARI than in those without ARI. These results indicate that the feeding the ARI prior to galactose feeding partly inhibits galactose cataract.

Proliferative changes of lens epithelial cells in rat and mouse galactose cataracts--examination using whole-mount preparations.

The proliferative activity of the lens epithelium in the early stages of cataract crisis was investigated in rats and mice using the 3H-thymidine autoradiographic method with the whole-mount preparations of total lens epithelial cells. Three-week-old Sprague-Dawley (SD) rats were given a diet which included galactose in three different concentrations (15%, 25%, 50%) to produce sugar cataracts of three different degrees. Seven-week-old ICR mice were given a 50% galactose-diet. In the lenses of control rats and mice, 3H-thymidine labeled cells were observed mainly in the germinative zone at the lens equator; a few labeled cells were detected in the anterior subcapsular central zone. In the lenses of the SD rats on the 4th day of the diet, labeled cells increased remarkably in the central zone. However, labeled cells decreased as the cataract progressed. The peak in the number of labeled cells was observed on the 4th day of the diet regardless of the galactose concentrations, and was not proportional to the degree of the cataracts. In the galactose-fed ICR mice, the blood galactose level was high, but there was no increase in the number of labeled cells or the development of galactose cataract. The marked increase of labeled cells in the central zone in the SD rat lenses had probably occurred because of the accumulation of galactitol.

[The localization of aldose reductase mRNA in the rat lens].

The localization of aldose reductase (AR), which is thought to be involved in the pathogenesis of sugar and galactosemic cataracts, has been studied using various methods. The AR exists in the lens and its presence is considered to be important at the site of the cataractogenesis. In this study, the localization of AR messenger RNA (ARmRNA) in the lenses of 3-week old and fetal rats was studied by in situ hybridization using a complementary DNA to the rat AR gene. In the lens of 3-week-old rats, ARmRNA was present in the lens-epithelium and the equatorial superficial cortex. The distribution profile was similar to that of AR-immunoreactivities revealed by an immunocytochemical study. In the fetal lens, however ARmRNA was present in the epithelium and the equatorial region, while AR-immunoreactivity was observed mainly in the center of the lens.

[A comparison of the effects of omeprazole with those of ranitidine on intragastric pH and volume in patients for elective surgeries].

This study compared the effect of omeprazole with those of ranitidine on intragastric secretion during perioperative period. Thirty-one patients were randomly allocated to three groups. Each group received either omeprazole, ranitidine orally or one on the night before surgery. Intragastric pH and volume were measured after induction of anesthesia. Omeprazole group and ranitidine group had a higher mean pH than control group (P less than 0.01). None of the omeprazole group had an aspirate of pH lower than 2.5. One patient (10%) in the ranitidine group and five patients (50%) in the control group and five patients (50%) in the control group had aspirates of pH lower than 2.5. Mean gastric volume was not significantly different among these groups. A single dose of omeprazole 20 mg significantly decreased the number of patients at risk of aspiration pneumonitis.

[Ciliary body changes associate with aldose reductase in galactosemic rats (2)].

Morphological changes of the ciliary body epithelium in rats fed a 50% galactose diet for 18 months with or without aldose reductase inhibitor (ARI: FR74366, Fujisawa) were investigated on coronal sections by both the light microscopic observation and the measurement of the area of non-pigmented epithelium (non-PE) as the ratio of non-PE/PE. The measurement was performed with color image analyzer. Structural change (hypertrophy) was observed only in non-pigmented epithelial cells of galactosemic rats. In contrast, no hypertrophic changes were seen in galactosemic rats treated with FR74366. These results strongly suggest that aldose reductase is associated with hypertrophic change of non-pigmented epithelial cells of the ciliary body as one of the diabetic complications.

[Influence of calcium channel blockers and beta-blockers on pain relief with iontophoresis].

We studied usefulness of iontophoresis on pain relief using several Ca channel blockers, propranolol and guanethidine. Subjects were 18 healthy adult volunteers. We used 4% lidocaine with/without several drugs (2 mg of nicardipine, verapamil, diltiazem, propranolol and 10mg of guanethidine), and evaluated the pain relief effect with Nakahama's algesimeter. In all groups except for propranolol group, the pain recognition time was elongated significantly in comparison with control. In making comparison between each Ca channel blocker, we did not observe any significant differences, but, in propranolol group, elongation of pain threshold time was observed in some subjects. During these processes, systemic blood pressure and heart rate showed no remarkable changes. Our results suggest that it is possible to achieve more prolonged analgesic effect by the Ca channel blockers.

[Differences in cataractogenesis according to neodymium-YAG laser injury site].

The author examined morphological changes of the lens induced by mechanical damage with a Q-switch Nd-YAG laser (anterior capsule, anterior subcapsular deep cortex, posterior capsule). In the ruptured anterior capsule group, epithelial cell proliferation covered the ruptured capsule, and separation of posterior subcapsular sutures and swelling of the posterior subcapsular end of lens fiber cells were observed. In the ruptured subcapsular deep cortex group, swollen lens fiber cells were observed in both the anterior subcapsular and the posterior subcapsular cortex. In the ruptured posterior capsule group, the ruptured cortex was not repaired. Swollen lens fiber cells were first recognized in areas surrounding the ruptured capsule, then at the posterior side of the equator, and finally at the anterior subcapsular cortex. The continuity of the lens capsule and lens fiber cells themselves is very important part to maintain lens clarity. The destruction of this feature induced swelling of fiber cells on the opposite side of the injury area.

[Formation of congenital cataract in the offspring of galactosemic rats].

It has been established that lenses of offspring of galactosemic rats form sugar cataracts. In the present study, in order to clarify the critical period in pregnancy for the cataract formation, lenses of offspring of pregnant rats which were fed galactose diets at each of three terms of pregnancy, were examined histologically and biochemically. Severe cataract and a large amount of galactitol in the lenses were found in the offspring of rats fed a galactose diet in the last term of pregnancy. Moreover, focal cataract was found in the offspring of rats fed a galactose diet in the middle term. These results indicate that the critical period in pregnancy for cataract formation of the offspring is the last term of pregnancy and that cataract formation begins in the middle term in offspring of galactosemic rats.

[Cell kinetics of lens epithelial cells on the whole-mount preparation (3). Changes in mouse cataract lens by feeding galactose].

In this study, we used ICR (Institute of Cancer Research) strain mouse because they showed hypergalactosemia but not cataractogenesis. We examined the proliferative ability of the lens epithelial cells by means of a whole-mount preparation of epithelium and 3H-thymidine autoradiography. An increased number of labelled cells was not found in the mouse. The increased proliferative ability of epithelial cells in rat galactose cataract did not seem to be caused by hypergalactosemia.

[The influence of aging on the development of rat galactosemic cataract].

In order to investigate the effect of age on the rat galactosemic cataract, 3, 6, 12 and 24-week-old rats were fed with a 50% galactose diet. The cataractous lenses were observed by light microscopy, and the amount of galactitol measured. All rats fed with 50% galactose developed cataracts in the equatorial region. However, the morphological and biochemical development of the galactose cataract in old rats was slower than in young rats. These results suggested that older diabetic patients are less likely to develop diabetic cataract than younger patients.

[Quantitative study of rat diabetic cataract, by the relaxation times of nuclear magnetic resonance].

The prophylactic effects of a new aldose reductase inhibitor (ARI), FR74366 on streptozotocin-induced rat diabetic cataract were examined by means of proton nuclear magnetic resonance (1H-NMR) relaxation time. We compared the findings with the histological finding, and it was recognized that longitudinal and transverse relaxation times (T1, T2) were prolonged before the histological changes appeared. The ARI, FR74366, prevented histologic changes and had detected by the 1H-NMR method. The results showed that 1H-NMR could be useful in the early detection of human diabetic cataract and the evaluation of the effectiveness of anti-cataract agents, for example, AR inhibitors.

[Changes in cell kinetics of rat lens epithelial cells with aging].

Whole-mount preparations of developing rat lens epithelium were made and 3H-thymidine autoradiography was performed on them. The distribution of 3H-thymidine-labeled (DNA-synthesizing) epithelial cells was examined by the above combined methods. Labeled cells were evenly distributed in the epithelial cell layer (not the definitely germinal zone) until 1 week after birth. In 3- or 7-week-old rat lens, labeled cells were mainly distributed in the germinal zone, and the number of labeled cells localized in the anterior subcapsular epithelial cell layer decreased according to age of the rat. The 24-week-old rat showed localization of labeled cells at the germinal zone, which seemed to be similar to the human adult lens.

Prevention of retinal vessel changes associated with diabetic retinopathy in galactose-fed dogs by aldose reductase inhibitors.

Vascular changes associated with early diabetic retinopathy that include the selective degeneration of pericytes, the formation of microaneurysms and acellular capillaries, and vessel dilation have been experimentally investigated in age- and sex-matched beagle dogs fed a 30% galactose diet and treated with or without the aldose reductase inhibitors sorbinil and/or M79175. Eyes from dogs in each group were periodically enucleated during a 36-month period and their retinal capillaries were examined as trypsin-digested flat preparations. These studies reveal that the destruction of retinal pericytes to form pericyte ghosts is the earliest observable retinal vessel change occurring after 19 to 21 months of galactose feeding. By 24 months, both an irregular distribution of endothelial cell nuclei near pericyte ghosts and the presence of acellular capillaries containing neither endothelial cells nor pericytes can be observed. This was followed by the histologic appearance of microaneurysms after 27 months and the funduscopic appearance of intraretinal hemorrhages after 33 months. Varicose enlargements of capillaries were also observed in the trypsin-digested preparations from dogs fed galactose for 33 to 36 months. All of these changes are linked to the initial aldose reductase-associated destruction of pericytes. The onset and progression of these retinal changes were retarded in a dose-dependent manner with aldose reductase inhibitors.