A vasodilating ß1 blocker celiprolol inhibits muscular release of uric acid precursor in patients with essential hypertension.

Although nonvasodilating ß1 blockers increase the levels of uric acid in serum, it is not known whether vasodilating ß1 blockers have a similar effect. In the present study, we evaluated the effect of celiprolol on the release of hypoxanthine, a uric acid precursor, from muscles after an exercise. We used the semi-ischemic forearm test to examine the release of lactate (ΔLAC), ammonia (ΔAmm), and hypoxanthine (ΔHX) before and 4, 10, and 60 min after an exercise in 18 hypertensive patients as well as 4 normotensive subjects. Before celiprolol treatment, all the levels of ΔHX and ΔAmm, and ΔLAC were increased by semi-ischemic exercise in hypertensive patients, and the increases were remarkably larger than those in normotensive subjects. Celiprolol decreased both systolic and diastolic pressure. It also decreased the levels of ΔHX and ΔAmm without changes in ΔLAC after an exercise. These findings also were confirmed by summation of each metabolite (ΣΔMetabolites). Celiprolol caused a marginal decrease of serum uric acid, but the difference was not statistically significant. On the other hand, nonvasodilating ß1 blockers did not suppress the levels of ΔHX and ΔAmm, whereas they significantly increased ΔLAC after an exercise. Celiprolol improved energy metabolism in skeletal muscles. It suppressed HX production and consequently did not adversely affect serum uric acid levels.

Diagnostic accuracy of cardiac metaiodobenzylguanidine scintigraphy in Parkinson disease.

BACKGROUND AND PURPOSE: To estimate the diagnostic accuracy of cardiac (123)I-metaiodobenzylguanidine (MIBG) scintigram for detection of Parkinson disease. METHODS: A cross-sectional study with index test of MIBG scintigram and reference standard of U.K. Parkinson's Disease Brain Bank Criteria was performed in 403 patients. Ratio of cardiac-to-mediastinum MIBG accumulation was determined at 20 min (early H/M) and 4 h (late H/M). Area under the receiver-operator characteristic (ROC) curve, sensitivity and specificity in detecting Parkinson disease were analyzed. Accuracy was analyzed in a subgroup of patients with disease duration of 3 years or less. RESULTS: Area under the ROC curve was 0.89 using either early or late H/M as a diagnostic marker (95% CI 0.85-0.92 for early H/M and 0.86-0.93 for late H/M). Sensitivity and specificity were 81.3% (76.1-85.8%) and 85.0% (77.7-90.6%) for early H/M and 84.3% (79.3-88.4%) and 89.5% (83.01-94.1%) for late H/M. In the subgroup with duration of 3 years or less, the ROC curve area, sensitivity, and specificity were 0.86 (0.79-0.92), 76.0% (64.8-85.1%), and 83.9% (71.7-92.4%) for early H/M and 0.85 (0.78-0.92), 73.3% (61.9-82.9%), and 87.5% (75.9-94.8%) for late H/M. CONCLUSION: Although diagnostic accuracy of cardiac MIBG scintigram is high, it is limited because of insufficient sensitivity in patients with short duration.

Effect of Antihypertensive Drugs on Uric Acid Metabolism in Patients with Hypertension: Cross-Sectional Cohort Study.

Background: Hypertension is a common complication in patients with gout and/or hyperuricemia. Besides, hyperuricemia is a risk factor of gout as well as ischemic heart disease in hypertensive patients. Moreover, the risk of gout is modified by antihypertensive drugs. However, it remains unclear how antihypertensive agents affect uric acid metabolism. Purpose: In the present study, we investigated the uric acid metabolism in treated hypertensive patients to find out whether any of them would influence serum levels of uric acid. Patients and methods: 751 hypertensive patients (313 men and 438 women) under antihypertensive treatment were selected. Blood pressure (BP), serum uric acid (SUA) and serum creatinine (Scr) were measured and evaluated statistically. Results: In patients treated with diuretics, beta-blockers and/or alpha-1 blockers SUA levels were significantly higher than in patients who were not taking these drugs. Besides, the estimated glomerular filtration rate (eGFR) in patients treated with diuretics, beta-blockers and/or alpha-1 blockers was negatively correlated with SUA level. There were gender differences in the effects of beta-blockers and alpha-1 blockers. Multiple regression analysis indicated that both diuretics and beta-blockers significantly contributed to hyperuricemia in patients with medication for hypertension. Conclusion: Diuretics, beta-blockers and alpha-1 blockers reduced glomerular filtration rate and raised SUA levels. Calcium channel blockers, ACE inhibitors and angiotensin receptor blockers, including losartan, did not increase SUA levels.

Effects of Uric Acid on the NO Production of HUVECs and its Restoration by Urate Lowering Agents.

BACKGROUND: Although urate impaired the endothelial function, its underlying mechanism remains unknown. We hypothesized that urate impaired nitric oxide (NO) production in human umbilical vein endothelial cells (HUVECs) via activation of uric acid transporters (UATs). PURPOSE AND METHOD: In the present study, we studied effects of urate on NO production and eNOS protein expression in HUVEC cells in the presence and absence of urate lowering agents using molecular biological and biochemical assays. RESULTS: HUVECs expressed the 4 kinds of UATs, URATv1, ABCG2, MRP4 and MCT9. Exposure to urate at 7 mg/dl for 24 h significantly reduced production of NO. Pretreatment with benzbromarone, losartan or irbesartan normalized NO production. The same exposure resulted in dephosphorylation of endothelial NO synthase (eNOS) in HUVECs. Again pretreatment with benzbromarone, losartan or irbesartan abolished this effect. CONCLUSION: Urate reduced NO production by impaired phosphorylation of eNOS in HUVEC via activation of UATs, which could be normalized by urate lowering agents.

Solution conformation of endothelin determined by nuclear magnetic resonance and distance geometry.

The solution conformation of endothelium-derived vasoconstrictor peptide, endothelin, has been determined by two-dimensional 1H-NMR spectroscopy and distance geometry. Conformation in the N-terminal core region (residues 1-15) is well-defined and a characteristic is the helix-like conformation in the segment from Lys9 to Cys15. Contrarily, the C-terminal tail region (residues 16-21) does not assume a defined conformation and there are no specific interactions between the core and the tail regions.

Neuroleptic malignant syndrome in a parkinsonian woman during the premenstrual period.

A 45-year-old woman with Parkinson's disease developed neuroleptic malignant syndrome (NMS) despite lack of levodopa withdrawal. She experienced two episodes characterized by indomethacin-resistant hyperthermia, hyperhidrosis, and aggravation of parkinsonism. The symptoms, however, disappeared during menstruation. We suggest that the development of NMS may depend, in part, upon the hormonal state.

The dopamine D1 receptor agonist SKF 38393 suppresses detrusor hyperreflexia in the monkey with parkinsonism induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP).

A pharmacological study using monkeys, in which parkinsonism was induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), was undertaken to elucidate the mechanism underlying urinary bladder dysfunctions in Parkinson's disease. Under ketamine anesthesia, cystometrograms showed that, in MPTP-treated monkeys, a contraction of the urinary bladder was induced with smaller bladder volume than that in normal monkeys. In MPTP-treated monkeys, subcutaneously injected SKF 38393, a dopamine D1 receptor agonist, significantly increased the bladder volume and pressure thresholds for inducing the micturition reflex without affecting those in normal monkeys. In contrast, subcutaneous injections of quinpirole, a dopamine D2 receptor agonist, and apomorphine, a dopamine D1 and D2 receptor agonist, slightly, but significantly reduced the volume threshold of the bladder for the micturition reflex in both normal and MPTP-treated groups. These results indicate that, in parkinsonism, the degeneration of dopaminergic neurons in the substantia nigra leads to the detrusor hyperreflexia, probably due to a failure of activation of dopamine D1 receptors.

Behavioural effects of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) in monkeys.

Subcutaneous injections of a 5-HT1A receptor agonist, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), in monkeys induced distinct behavioural changes characterized by head weaving, hindlimb extension and upper limb fluttering. The effects were dose-dependent and were similar to the 5-HT syndrome induced in rats by 8-OH-DPAT. The 5-HT receptor antagonist, metergoline, attenuated the behavioural syndrome seen in response to 8-OH-DPAT. These results suggest that 8-OH-DPAT induces a 5-HT1A receptor-mediated behavioural syndrome in monkeys as well as in rodents.

Co-induction of heme oxygenase-1 and peroxiredoxin I in astrocytes and microglia around hemorrhagic region in the rat brain.

Heme[none1] oxygenase-1 (HO-1) and peroxiredoxin I (PrxI) are known to be oxidative stress- and heme-related proteins. The antioxidant activity of PrxI is inhibited by heme, therefore co-expression of HO-1 and PrxI is considered to be a reasonable mechanism to maintain its antioxidative function. Immunoblotting demonstrated that HO-1 and PrxI were induced around the hemorrhagic region. Immunohistochemical studies revealed that, in acute phase, HO-1 and PrxI were induced primarily in microglia. In the subacute and chronic phase, the immunoreactivity of HO-1 and PrxI in astrocytes was the most intense. These data are the first to demonstrate co-induction of HO-1 and PrxI in the brain. Our results suggest that HO-1 and PrxI are localized in a similar manner to assure the antioxidant activity of PrxI under stress conditions associated with intracerebral hemorrhage.

Influence of interleukin-1beta gene polymorphisms on age-at-onset of sporadic Parkinson's disease.

We studied genetic polymorphisms in the promoter region (position -511) and exon 5 (position +3953) of the interleukin (IL)-1beta gene in 122 Japanese patients with Parkinson's disease (PD) and 112 controls. We also examined polymorphisms in the IL-1alpha and the IL-1 receptor antagonist genes. No significant difference was found in these genetic markers between PD patients and controls. However, PD patients with homozygotes for allele 1 at position -511 of the IL-1beta gene (IL-1B-511*1), a low producer of IL-1beta, were significantly earlier in the disease onset than those with the IL-1B-511*2 homozygotes, a high producer of IL-1beta. This suggests that IL-1beta might play a role, possibly a protective effect for dopaminergic neurons, in PD. Further population and functional studies are necessary to clarify the role of IL-1beta in PD patients.

Tumor necrosis factor gene polymorphisms in patients with sporadic Parkinson's disease.

We studied promoter region polymorphisms in the tumor necrosis factor (TNF) gene at position -1031, -863, and -857, in 172 Japanese patients with sporadic Parkinson's disease (PD). The frequency of the -1031C allele, a high producer of TNF, increased significantly in early onset PD patients compared with controls. In addition, PD patients with the -1031C allele showed a significantly earlier onset than those without -1031C allele, after stratification of the data by an interleukin-1beta gene polymorphism. Our findings suggest that TNF might have a toxic effect in PD.

Riluzole stimulates nerve growth factor, brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor synthesis in cultured mouse astrocytes.

Riluzole is an antiexcitotoxic agent used for the treatment of amyotrophic lateral sclerosis, and reported to have neuroprotective effects in animal models of Parkinson's disease, Huntington's disease and brain ischemia. We investigated the effects of riluzole on synthesis of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) in cultured mouse astrocytes. The protein and mRNA levels were measured by enzyme-linked immunosorbent assay and semiquantitative reverse transcription-polymerase chain reaction, respectively. Treatment with riluzole at 100 microg/ml (426 microM) for 24 h increased the contents of NGF, BDNF, and GDNF in the culture medium 109-fold, 2.0-fold and 3.1-fold over the control, respectively. The drug-induced relative mRNA levels of NGF, BDNF, and GDNF were 7.3-fold at 2 h, 2.1-fold at 4 h, and 1.9-fold at 2 h, respectively. These results indicate that riluzole stimulates synthesis of NGF, BDNF and GDNF in cultured astrocytes. Riluzole might exert neuroprotective effects, at least in part, via stimulation of neurotrophic factors.

Multiple early gastric cancer associated with sarcoid-like reaction in the regional lymph nodes.

A 68-year-old man was admitted to our hospital because of epigastric pain. An upper gastrointestinal contrast study and endoscopy revealed a II c type tumor in the posterior wall of the pyloric antrum. and computed tomography showed lymph node enlargement along the left gastric artery. Operation was performed after a presumptive diagnosis of gastric cancer with lymph node involvement. During the laparotomy, more extensive lymphadenopathy was found than was detected preoperatively, and tumor metastasis was suspected because of its firmness. Distal partial gastrectomy with D, and more extensive lymph node dissection were performed. Subsequently, the histology of permanent sections revealed not tumor metastasis but a sarcoid-like reaction in the lymph nodes. The patient recovered uneventfully: however, he was killed in an accident 38 months after the surgery. A postmortem examination was not performed, but there had been no clinical signs of either recurrence of gastric cancer or sarcoidosis.

Effect of D-penicillamine on pharmacokinetics of levodopa in Parkinson's disease.

A 42-year-old man had suffered from Parkinson's disease for 5 years. Levodopa was effective, but the wearing-off phenomena were severe. Because of relatively low levels of serum copper and ceruloplasmin, D-penicillamine was administered. D-penicillamine increased plasma levodopa concentrations, thereby improving his parkinsonian symptoms. We propose that D-penicillamine facilitates levodopa absorption and, hence, the efficacy of the antiparkinsonian drug.

Therapeutic effects of arotinolol, a beta-adrenergic blocker, on tremor in MPTP-induced parkinsonian monkeys.

The effect of arotinolol, a peripherally acting beta-adrenergic-blocking agent, on postural or kinetic tremor was studied in monkeys with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonism. Male cynomolgus monkeys (Macaca fascicularis) were treated with three injections of MPTP hydrochloride (0.3 mg/kg, i.v.) at an interval of 3-4 days, followed by several injections of the same dose every 7 days. Four monkeys with persistent parkinsonian symptoms manifested for greater than 1 year were used. The animals developed mild to moderate degrees of postural or kinetic tremor, and their motor activity was reduced. Arotinolol (20-30 mg/kg, s.c.) significantly suppressed postural tremor in a dose-dependent manner. Propranolol (20-30 mg/kg) was also effective in suppressing the tremor. However, the application of propranolol induced emesis, whereas arotinolol had no adverse effects. These results suggest that arotinolol is a useful adjunct to dopaminergic therapy for tremor in Parkinson's disease.

Antiparkinsonian effects of BAM-1110, a novel ergoline derivative, in MPTP-treated cynomolgus monkeys.

BAM-1110 [(5R,8R,10R)-6-methyl-8-(1,2,4-triazol-l-ylmethyl) ergoline maleate] is a newly synthesized dopamine agonist that produces little anorexic side effects (nausea and vomiting). The current study examines the effects of BAM-1110 on parkinsonian symptoms in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys, an animal model of Parkinson's disease. First, a significant antiparkinsonian effect of apomorphine hydrochloride (0.3 mg/kg given subcutaneously) was confirmed in these animals. BAM-1110 (0.1, 0.3, and 1 mg/kg subcutaneously) relieved parkinsonian symptoms in a dose-dependent manner. Significant effects were observed at doses of 0.3 and 1 mg/kg and lasted for at least 3 h. BAM-1110, at a dose of 0.3 mg/kg that produced the submaximal antiparkinsonian effect, did not induce significant abnormal behaviors such as hyperactivity and stereotyped behaviors. Significant stereotyped behaviors were observed at 1 mg/kg of BAM-1110. Apomorphine induced hyperactive and stereotyped behaviors in parallel with its antiparkinsonian effect. BAM-1110 appears to be a potentially useful dopamine agonist to treat Parkinson's disease because of its relatively weak drug-induced hyperactive disturbances and anorexic side effects.

Carriomycin, a new polyether antibiotic produced by Streptomyces hygroscopicus.

Carriomycin, a new polyether antibiotic, was isolated from culture broth of Streptomyces hygroscopicus strain T-42082. It is active against Gram-positive bacteria, several fungi, yeasts and mycoplasma. It is also coccidiostatic. The free acid of carriomycin occurs as colorless prisms having the molecular formula C47H80O15 (M.W. 885.15), m.p. 120 approximately 122 degrees C and [alpha]25D -0.5 in methanol. It has no characteristic absorption maxima in the ultraviolet spectrum. The presence of one carboxyl and three methoxy groups was observed from its infrared, PMR and CMR spectra.

Pancreatic ascites--a collected review of 37 cases in Japan.

Thirty seven cases of pancreatic ascites in the Japanese literature were reviewed. The ratio of males to females was high, and the incidence of associated pancreatic pleural effusion was higher than in the English literature. Other aspects of pancreatic ascites in Japan were similar to those reported in the English literature. Twelve patients were completely cured by conservative therapy and 18 patients required surgery. With care, the progress of pancreatic ascites was usually good. The frequency of alcoholic pancreatitis has increased, so it is important to watch out for the occurrence of pancreatic ascites as a complication of chronic pancreatitis.

[The studies on distributions of cefsulodin and cefotiam to human aqueous humor and cornea].

Distributions of cefsulodin (CFS) and cefotiam (CTM), new parenteral cephalosporins, to human aqueous humor and cornea were studied in comparison with those of sulbenicillin (SBPC) and cefazolin (CEZ), and pharmacokinetic analysis was made by theory of compartment model, to obtain the following results. 1. Maximum aqueous humor levels of CFS and CTM were noticed at 2.5 hours after the start of 1 g CFS or CTM administration by 30 minute intravenous drip infusion, with the levels of 3.6 micrograms/ml and 4.2 micrograms/ml respectively. On the other hand, in case of 5 g SBPC or 2 g CEZ administration maximum aqueous humor levels were 12.5 micrograms/ml and 5.2 micrograms/ml respectively. 2. The ratios of maximum aqueous humor level to plasma level of the same time in CFS, CTM, SBPC and CEZ were 15.0, 16.8, 6.4% and 5.5%. Distribution of CFS or CTM was 2 to 3 times better than that of SBPC or CEZ. 3. From the result of pharmacokinetic analysis, ratios of aqueous humor to plasma levels in area under curves (AUC) of CFS, CTM, SBPC and CEZ were 25.6, 29.9, 16.4% and 7.9% respectively. Maximum aqueous humor levels of CFS, CTM, SBPC and CEZ were 2.9, 3.6, 11.4 micrograms/ml and 4.3 micrograms/ml and biological half life of gamma-phase were 2.57, 2.31, 2.77 hours and 2.24 hours respectively. 4. Cornea levels of CFS or CTM at one hour after the start of 1 g CFS or CTM administration by 30 minutes intravenous drip infusion were 2.9 micrograms/g and 5.2 micrograms/g, and their ratios to plasma level were 7.5% or 14.3% respectively. In case of 5 g SBPC or 2 g CEZ administration, the cornea levels were 26.7 micrograms/g and 5.0 micrograms/g, and the ratios were 9.4% and 3.4% respectively. 5. From the above, the distribution of CFS or CTM to human aqueous humor and cornea is better than that of SBPC or CEZ, and it is considered that clinical usefulness of both CFS and CTM by parenteral administration is expected in intraocular infections.

Pharmacokinetics of cefotiam in the exudate from wounds of patients with breast cancer operated upon for radical mastectomy.

Cephalosporin antibiotics have been widely used to prevent infections during and after operation. To establish an efficient use of prophylactic antibiotics for patients undergoing surgery, it is important to investigate the drug levels in exudate from wounds of the patients and to elucidate the relation between drug concentration in the blood and that in the exudate. In a previous paper, the present authors (except E.M. and Y.K.) determined cefotiam (CTM) concentrations in serum and exudate from wounds of patients with breast cancer who underwent radical mastectomy and discussed an adequate regimen of CTM prophylaxis after the operation. However, CTM concentrations in serum and exudate from the wounds of the patients were not analyzed pharmacokinetically. In the present paper we report on the disposition kinetics of CTM in serum and exudate from wounds after the administration of CTM following bolus intravenous injection into patients with breast cancer operated upon for radical mastectomy.