Dilazep Dihydrochloride Research Articles

Effects of Combination Therapy with Renin-Angiotensin System Inhibitors and Eicosapentaenoic Acid on IgA Nephropathy

The beneficial effects of renin-angiotensin-aldosterone system inhibitors (RASI) and the omega-3 polyunsaturated fatty acid eicosapentaenoic acid (EPA) on IgA nephropathy (IgAN) have been reported. However, it is unknown whether these agents have any synergistic interactions. We divided 38 IgAN patients into two groups: an EPA group (n=18) treated with RASI plus EPA and a DILAZEP group (n=20) treated with RASI plus dilazep dihydrochloride. We analyzed the clinical and histological background of each patient, any relevant clinical findings obtained one year after treatment and any factors significantly related to decreases in proteinuria. The clinical findings were largely similar between the groups, except for body mass index (24.9±4.5 in the EPA group vs. 21.4±2.1 in the DILAZEP group, p=0.0041) and total cholesterol (median: 206.0 vs. 177.5 mg/dL, p=0.0493). The histological findings, evaluated according to the Oxford classification, were also similar between the groups. At one year after treatment, the EPA group demonstrated a significantly decreased mean blood pressure (from 94.7±9.0 to 86.4±7.2 mmHg, p=0.0007) and a significantly decreased median level of proteinuria (from 0.80 to 0.41 g/g creatinine, p<0.001). In the DILAZEP group, the mean blood pressure significantly decreased (from 95.2±13.2 to 88.1±7.7 mmHg, p<0.001) without any significant decrease in the median level of proteinuria (from 0.88 to 0.60 g/g creatinine). According to a multivariate logistic analysis, EPA was found to be the only independent factor related to decreases in proteinuria (odds ratio = 5.073, 95% CI: 1.18-26.7, p=0.0285). We conclude that EPA accelerates the effects of RASI and thus decreases the proteinuria observed in patients with IgAN.

The effects of dilazep dihydrochloride and vitamin E on P50 in patients with chronic obstructive pulmonary disease

The effects of dilazep dihydrochloride and vitamin E on P50 in patients with chronic obstructive pulmonary disease

Dilazep Decreases Lipopolysaccharide-Induced Nitric Oxide and TNF-α Synthesis in RAW 264 Cells

Dilazep dihydrochloride (dilazep) is used to treat ischemic dysfunction, although the mechanisms underlying the anti-inflammatory effects of the drug have not yet been elucidated. The present study evaluated the anti-inflammatory effect of dilazep. Dilazep suppressed the production of nitric oxide (NO) and the expression of TNF-α mRNA by lipopolysaccharide (LPS) in RAW 264 cells. However, 1400W, an inducible NO synthase inhibitor, suppressed the production of NO but did not suppress the expression of TNF-α mRNA following treatment with LPS. Caffeine, an adenosine antagonist, restored LPS-stimulated NO synthesis, which is suppressed by dilazep. Therefore, these observations may suggest that the suppression of NO synthesis after dilazep treatment in RAW 264 cells is caused by the inhibition of TNF-α expression via adenosine receptors.

A 10-YEAR-OLD GIRL WITH IGA NEPHROPATHY WHO 5 YEARS LATER DEVELOPED THE CHARACTERISTIC FEATURES OF HENOCH-SCHÖNLEIN PURPURA NEPHRITIS

We report a patient who developed Henoch-Schönlein purpura (HSP) 5 years after she presented with immunoglobulin A nephropathy (IgAN). A 10-year-old Japanese female was identified with proteinuria and hematuria by a school urinary screening. The first renal biopsy showed mesangial proliferative glomerulonephritis with immunofluorescent findings consistent with IgAN. She was treated with prednisolone, warfarin, and dilazep dihydrochloride, and the proteinuria and hematuria disappeared 4 months after the onset of treatment. Five years later she developed abdominal pain, gross hematuria and a classic purpuric rash of HSP after acute pharyngitis. The second renal biopsy showed diffuse mesangial proliferation with cellular crescent formation, and the patient was treated with methylprednisolone pulse therapy, prednisolone and mizoribine, resulting in a gradual decrease in urinary protein excretion. Our patient is unusual in that she developed Henoch-Schönlein purpura nephritis 5 years after clinical and biopsy evidence of IgAN, which suggests that IgAN and HSP are different clinical manifestations of the same disease, probably sharing a common pathogenesis.

メニエール症候群の聴力改善治療―塩酸ジラゼプ，イソソルビドの使用経験―

We report 2 cases of Lermoyez's disease and a case of Meniere's disease at advanced stages showing hearing improvement following treatment with a combination of Dilazep dihydrochloride and Isosorbide. It is suggested that this combined treatment is quite effective for Lermoyez's disease, suggesting that Lermoyez's disease is caused by both endolymphatic hydrops and disturbance of vascular circulation. Comparison of the hearing improvements among cases for which this treatment was effective and ineffective indicated that this treatment could be useful not only for Lermoyez's disease but also for Meniere's disease when vertigo is under control in patients whose job is not very busy or stressful.

Efficacy of Prednisolone and Mizoribine Therapy for Diffuse IgA Nephropathy

Objective: There have been only a few studies concerning oral prednisolone and mizoribine therapy for diffuse IgA nephritis (IgAN). We evaluated the efficacy of prednisolone and mizoribine therapy for diffuse IgAN. Methods: We enrolled 34 patients who had been diagnosed as having diffuse IgAN with severe proteinuria during the period from 1992 to 1999. Following diagnostic renal biopsy, the patients were treated with prednisolone, mizoribine, warfarin and dilazep dihydrochloride. The clinical features, laboratory data and pathological findings between pre- and post-therapy were investigated. Results: The mean urinary protein excretion after 6 months of treatment had decreased significantly compared to pre-therapy. The incidence of hematuria in post-therapy was lower than that of pre-therapy. The grading index decreased significantly from 4.8 ± 2.1 at the first biopsy to 2.3 ± 1.7 at the second biopsy (p < 0.001) and the staging index decreased significantly from 4.1 ± 1.9 at the first biopsy to 2.7 ± 2.4 at the second biopsy (p < 0.05). Macrophage infiltration and α-smooth muscle actin-positive cells in the glomerulus and interstitial region decreased significantly in post-therapy compared with pre-therapy. At the most recent follow-up, none of the 34 patients had renal insufficiency. Conclusions: Our study suggested that prednisolone and mizoribine therapy is effective for those patients with the risk of progression of IgAN.

長期経過を追えたレルモワイエ症候群の１例

We report a patient with Lermoyez's syndrome who was followed up for 9 years and whose hearing activity was well maintained. The main pathological factor in this case was considered to be endolymphatic hydrops, judging from such findings as positive glycerol test, repeated vertigo attacks like Meniere disease and well-maintained hearing activity under Isosorbide therapy. Since Dilazep dihydrochloride was also effective in preserving good hearing function, disturbance of vascular circulation might have played a role in the pathology of this case.

Effect of Dilazep Dihydrochloride on Serum Cardiac Troponin T Levels in Hemodialysis Patients

Background/Aim: Cardiac troponin T is a highly sensitive marker for the detection of myocardial injury. We studied whether dilazep dihydrochloride affects cardiac troponin T levels in hemodialysis patients. Methods: Our study included 60 hemodialysis patients without symptoms of acute myocardial ischemia. We measured serum cardiac troponin T levels by the Elecsys^® troponin T assay and randomized 40 hemodialysis patients with left ventricular hypertrophy (LVH) into two treatment groups: a dilazep dihydrochloride group (300 mg/day, n = 20) and a placebo group (n = 20). Treatment was continued for 12 months. Results:There were no significant differences between pre- and postdialysis cardiac troponin T levels before treatment. LVH was noted in 40 patients out of 60 hemodialysis patients (67%). Cardiac troponin T levels were significantly higher in these patients (0.23 ± 0.08 µg/l) than in hemodialysis patients without LVH (0.09 ± 0.03 µg/l). Cardiac troponin T levels were reduced from 0.24 ± 0.08 to 0.12 ± 0.06 µg/l (p < 0.01) in patients treated with dilazep dihydrochloride. There were no change in cardiac troponin T levels in patients receiving placebo (from 0.21 ± 0.08 at baseline to 0.20 ± 0.07 µg/l). Conclusion: Dilazep dihydrochloride may be effective in ameliorating myocardial damage in hemodialysis patients.

COMBINATION AST-120 AND DILAZEP DIHYDROCHLORIDE THERAPY REDUCED URINARY PROTEIN EXCRETION AND SERUM CREATININE LEVELS IN PATIENTS WITH CHRONIC RENAL FAILURE

The effect of AST-120 and dilazep dihydrochloride on serum creatinine levels and urinary protein excretion was assessed in patients with chronic renal failure. We found that both drugs in combination provide an additive renoprotective effect over each drug in some chronic renal failure pateints.

Effect of Dilazep Dihydrochloride on Urinary Albumin Excretion in Patients with Autosomal Dominant Polycystic Kidney Disease

Proteinuria and microalbuminuria occur with a highly variable severity and are associated with progression of autosomal dominant polycystic kidney disease (ADPKD). Dilazep dihydrochloride, an antiplatelet drug, is effective in patients with immunoglobulin A nephropathy or diabetic nephropathy. We studied whether dilazep dihydrochloride affects the urinary albumin excretion (UAE) in normotensive and hypertensive patients with ADPKD. Twelve normotensive ADPKD patients with microalbuminuria were randomly assigned to two groups: a dilazep (300 mg/day) treatment group (n = 6, group A) and a placebo group (n = 6, group B). In addition, 10 hypertensive ADPKD patients with microalbuminuria were randomly assigned to two groups: a dilazep (300 mg/day) treatment group (n = 5, group C) and a placebo group (n = 5, group D). Treatment with dilazep was continued for a period of 6 months, at the end of which the UAE was reduced form 130 ± 52 to 46 ± 26 µg/min (p < 0.01) in group A. There was no reduction in group C. There were no changes in UAE in placebo groups B and D. These results suggest that dilazep dihydrochloride may be effective in reducing UAE in normotensive ADPKD patients with microalbuminuria.

A Vasoactive Agent Enhances the Effect of ATP on Cochlear Blood Flow

Adenosine 5-triphosphate (ATP) has a dual effect on cochlear blood flow (CBF). It induces on initial, transient decrease, which is followed by a long-lasting increase in CBF. Dilazep dihydrochloride (DZ) is a unique vasoactive agent, which increases CBF as well as decreases systemic blood pressure (BP). This agent is thought to keep the concentration of extracellular adenosine higher than normal by preventing the absorption of adenosine into the intracellular space. Thus, it may potentiate the effect of ATP on CBF. In this study, the effects are reported of ATP on CBF in the presence of DZ as measured with a laser Doppler flowmeter in the guinea pig cochlea. In the presence of DZ, the effect of ATP on CBF was amplified and prolonged. Specifically, the mean value of CBF initially decreased to 30.0% of the baseline, determined prior to administration of any agent, and increased gradually up to 287.8% of the baseline. This pharmaceutical effect of DZ might involve a longer activation of both P2x- and P2y-purinoceptors.

Dilazep dihydrochloride prolongs the infarct size-limiting effect of ischemic preconditioning in rabbits.

Recent studies have indicated the key role of adenosine receptor activation as a trigger for ischemic preconditioning (PC). Hence, the augmentation of endogenous adenosine may potentiate the cardioprotective effects of PC. In this study. we aimed to test the hypothesis that dilazep dihydrochloride, an adenosine transport inhibitor, potentiates the PC effect. Protocol 1: Infarcts were produced in open-chest anesthetized rabbits by 30-min occlusion of a coronary artery and 2 days' reperfusion. PC was elicited by a preceding 5-min occlusion and either 5, 40, or 120 min of reperfusion. PC with the 5-min reperfusion markedly limited the infarct size after the 30-min ischemia (infarct size to area at risk (IS): 10%+/-3% vs 41%+/-3%, P < 0.05). PC was not protective when the reperfusion periods were 40 or 120 min (IS: 47%+/-5% and 44%+/-3%. P = not significant (NS) vs control, respectively). However, concomitant treatment with dilazep (0.2mg/kg) preserved the PC effect in the 40-min reperfusion group (18%+/-5%, P < 0.05 vs control) but not in the 120-min reperfusion group (43%+/-4%, P = NS vs control). Protocol 2: Infarct was produced in a similar rabbit model by either a 45- or 50-min occlusion of a coronary artery and 2 days of reperfusion. PC was elicited by a preceding 5-min occlusion and a 5-min reperfusion. PC was protective in the 45-min occlusion group (30%+/-7% vs 67%+/-3%, P < 0.05) but not in the 50-min occlusion group (74%+/-4% vs 79%+/-5%, P = NS). Treatment with dilazep (0.2mg/kg) failed to retrieve protection in this preconditioned group (77%+/-6%, P = NS vs 50-min occlusion group without PC). Thus, dilazep prolonged the infarct size-limiting effect of PC, but failed to retrieve protection in the group with a longer sustained ischemia.

椎骨脳底動脈循環不全によるめまい症例の赤血球変形能

Hemorheological impairment is thought to be one of the pathological conditions of vertebro-basilar insufficiency (VBI). To determine the contribution of impaired red blood cell deformability (RCD), one of the important factors of hemorheological impairment, to the pathogenesis of VBI, RCD was measured and compared between a group of VBI patients (21 males, 42 females) and a group of control adults without vertigo (22 males, 23 females). Diagnosis of VBI was based on the Guidelines established by the Japan Society for Equilibrium Research. RCD was measured by the red blood cell (RBC) centrifugation method according to the criteria established by the International Committee for Standardization in Haematology. RCD was significantly decreased in the VBI group (p<0.01). Blood levels of total cholesterol and triglyceride in the VBI group were significantly higher than those in the control group (p<0.05). RCD was not correlated with RBC counts, Hb, Ht, MCV, MCHC, platelet count or total cholesterol or triglyceride level. Administration of dilazep dihydrochloride (300 mg/day for 8 weeks) to VBI patients induced significant (p<0.05) improvement in RCD and relieved vertiginous symptoms. Vertigo in VBI is considered to result from a combination of conditions involving microcirculation disorder induced by decreased RCD, decreased vertebral arterial blood flow due to high blood levels of total cholesterol and triglyceride, and rapid occurrence of right-left difference in blood flow by action stimulation.

Effects of antiplatelet drug dilazep dihydrochloride on anionic sites and extracellular matrix (ECM) components in glomerular basement membrane of STZ-induced diabetic rats.

A study of anionic sites in the glomerular basement membrane (GBM) of streptozotocin (STZ)-induced diabetic rats with or without treatment by an antiplatelet drug, dilazep dihydrochloride, is described. Expression of glomerular extracellular matrix (ECM) components was examined by immunofluorescence. Renal specimens were immersed in polyethyleneimine (PEI) as a cationic probe and then examined by electron microscopy. Renal specimens were also incubated with rabbit antirat type IV collagen, laminin, and fibronectin antisera and then stained with fluorescein isothiocyanate (FITC)-labeled goat antirabbit IgG antiserum. Mean values of proteinuria in the dilazep-treated diabetic rats were significantly decreased compared with those in nontreated diabetic rats. There was no significant correlation between the levels of proteinuria and those of creatinine clearance (CCr). Number of anionic sites on the GBM in the dilazep-treated diabetic rats were greater than those in diabetic rats. There was no significant difference in the staining of such ECM components between both rat groups. The authors concluded that the dilazep dihydrochloride might prevent anionic charges on the GBM and decrease the urinary excretion of proteins in STZ-induced diabetic rats.

The effect of pancreatic elastase on diabetic nephropathy

Pancreatic elastase has been shown to inhibit the thickening of glomerular basement membranes in experimental diabetic animals. We explored the clinical significance of the prologned administration of pancreatic elastase on diabetic nephropathy, in patients whose blood glucose levels and blood pressure were controlled. Pancreatic elastase was administered for 12 months. Body weight levels, blood glucose levels, HbA lc values and blood pressure remained unchanged. Administration of 10 800 U of pancreatic elastase caused a significant decrease in albuminuria (before administration, 512.4 ± 79.8 mg/g creatinine vs. 12 months after administration, 284.1 ± 61.9 mg/g creatinine, P < 0.01, n = 28). In the contrast group ( n = 18), no significant changes in albuminuria were observed after administration of 300 mg of dilazep dihydrochloride. Serum levels of creatinine and urinary levels of NAG and β 2MG were not affected by pancreatic elastase. The present study indicates a significant inhibitory effect of pancreatic elastase on increased albuminuria in diabetic patients.

Effects of K-7259 on neuronal activity and synaptic transmission in the rat dorsolateral septal nucleus.

K-7259 is a dilazep dihydrochloride derivative that minimizes the damaged area from middle cerebral artery hemiocclusion in the rat (Yamauchi et al. 1992a, b). The effects of K-7259 on the electrophysiological properties of neurons in the rat dorsolateral septal nuclei (DLSN) were examined. K-7259 (100 microM-3 mM) depolarized the membrane with a decrease in input resistance in 36% of the DLSN cells. K-7259 (100 microM) depressed the inhibitory postsynaptic potential (IPSP) and the late hyperpolarizing potential (LHP). The magnitudes of the depressions of the IPSP and LHP with 100 microM K-7259 were 50 +/- 25% (n = 5) and 52 +/- 15% (n = 4), respectively. The amplitudes of the excitatory postsynaptic potentials (EPSPs) were augmented during the inhibition of the IPSP and LHP. However, a voltage-clamp analysis showed that K-7259 did not affect the isolated excitatory postsynaptic current (EPSC). The outward current produced by pressure application of gamma-aminobutyric acid (GABA) to the recording cell was not inhibited by K-7259. These results indicate that K-7259 presynaptically inhibits the IPSP and LHP through a GABAergic pathway.

Effect of Pancreatic Elastase on Diabetic Nephropathy

Pancreatic elastase has been shown to inhibit the thickening of glomerular basement membranes in experimental diabetic animals. We explored the clinical significance of the prolonged administration of pancreatic elastase on diabetic nephropathy, in patients whose blood glucose levels and blood pressure were controlled. Pancreatic elastase was administered for 12 months. Body weight levels, blood glucose levels, HbA,, values and blood pressure remained unchanged. Administrationof 10 800 U of pancreatic elastase caused a significant decrease in albuminuria (before administration, 512.4 f 79.8 mg/g creatinine vs. 12 months after administration, 284.1 + 61.9 mg/g creatinine, P < 0.01, n = 28). In the contrast group (n = 18), no significant changes in albuminuria were observed after administration of 300 mg of dilazep dihydrochloride. Serum levels of creatinine and urinary levels of NAG and &MG were not affected by pancreatic elastase. The present study indicates a significant inhibitory effect of pancreatic elastase on increased albuminuria in diabetic patients.

Effect of dilazep dihydrochloride against ischemia and reperfusion-induced disruption of blood-brain barrier in rats: a quantitative study.

The effect of dilazep dihydrochloride (dilazep) against ischemia and reperfusion-induced disruption of blood-brain barrier (BBB) was quantitatively investigated in Slc:Wistar strain rats using Evans blue dye as a BBB destruction indicator. The forebrain of sham-operated animal had a small amount of the dye. A treatment of 3.5-h ischemia plus 2-h reflow extravasated the dye into the brain and markedly increased the dye content as compared with that of sham group (P less than 0.01 vs. sham group). Continuous infusion (i.v.) of dilazep during cerebral ischemia dose-dependently reduced the increase of the dye content, and a significant reduction was found at 3 mg/kg/h (P less than 0.05 vs. control group). Evans blue dye extravasation after ischemia was also greatly reduced in saline-perfused brains by the treatment with dilazep. Dilazep has been reported to inhibit edema formation in cerebral ischemia model of spontaneously hypertensive rats. These results suggest that dilazep prevents the ischemic damage of BBB, which may contribute to reduction of the brain edema.

末梢性めまいに対する抗血小板療法の検討 コメリアンとアスピリン併用療法

Comelian® (dilazep dihydrochloride) and aspirin were administered for 8 weeks to patients with peripheral vertigo, and clinical effects and platelet aggregation were investigated.1. Subjective symptoms were significantly or moderately improved in 11 patients (55.0% of total series). Slight improvement was noted in 19 (95.0% of that).Objective findings were improved more than subjective symptoms.2. Maximal aggregation, maximal slope and aggregability induced by collagen was reduced after the administration of Comeliane

Effect of urokinase on preservation of renal function in patients with diabetic nephropathy

Long-term effects of urokinase on the preservation of renal function in patients with diabetic nephropathy were evaluated. Twenty-nine adult patients with non-insulin-dependent diabetes mellitus and overt proteinuria were randomly divided into two groups. One group was treated with daily oral administration of dipyridamole or dilazep dihydrochloride and weekly intravenous administration of urokinase; the other group was treated with dipyridamole alone. There was a significant decrease in the amount of proteinuria in the first group after 3 months of the treatment compared with the second group. There was also a significant preservation of renal function in the first group after three years of treatment compared with the second group. It was concluded that continuous administration of urokinase in addition to antiplatelet agents is useful in the treatment of patients with diabetic nephropathy.