Hepatic Clearance of ONO-5046, a Novel Neutrophil Elastase Inhibitor,in Rats and in the Rat Perfused Liver

The hepatic clearance of ONO-5046 (N-[2-[4-(2,2-dimethylpropionyloxy)phenylsulphonyl-amino]benzoyl]aminoacetic acid), a low-molecular-weight neutrophil elastase inhibitor, has been investigated in rats and in the rat perfused liver. This ester was easily hydrolysed to its inactive metabolite EI-601 (N-[2-[(4-hydroxy-phenyl)sulphonylamino]benzoyl]aminoacetic acid) in liver homogenate and in erythrocytes suspension in-vitro. On the other hand, it was stable in biological media such as plasma and whole blood, which contain plasma proteins. Scatchard plot analysis of ONO-5046 binding to bovine serum albumin (BSA) in-vitro indicated that the association constant (K) and number of binding sites (n) were 6.91 times 10⁴ (M^?1) and 4.33, respectively. Thus, ONO-5046 (100 μM) would bind to plasma proteins to an extent >99% at physiological plasma-protein concentrations. The total plasma clearance of ONO-5046 in rats was constant (approximately 9 mL min^?1 kg^?1) under different steady-state plasma concentrations (5–50 μM) a value equivalent to the hepatic clearance. In the rat perfused liver, the hepatic extraction ratio of ONO-5046 was significantly reduced by adding BSA to the dosing solution. Thus, the relatively low hepatic clearance of ONO-5046, which has an ester linkage in its structure and is naturally susceptible to enzymatic hydrolysis, was found to be because of the extremely high protein-binding of the compound.     

Lack of association between the incidence of testicular germ cell tumors and Y-chromosome haplogroups in the Japanese population

BACKGROUND: Despite being relatively uncommon, testicular germ cell tumors (TGCT) are the most common malignant disease in young men. Epidemiological studies concerning patients with testicular cancer indicate that the most of them have poor semen quality or testicular dysgenesis. However, many studies have shown that the Y chromosome harbors many candidate genes responsible for spermatogenesis process and development and maintenance of the germ cells. The Y chromosome is thought to have a relationship with the formation and progression of TGCT. MATERIALS AND METHODS: To verify this relationship, we investigated if there is any correlation between the Y chromosome structural variations presented as different haplogroups and the occurrence of TGCT in the Japanese population. Using combined haplogroups based on typing of three Y chromosome polymorphic binary markers, we analyzed 68 TGCT derived from Japanese patients together with randomly selected 104 unrelated healthy Japanese matched male controls who were confirmed as residents of the same geographic area. RESULTS: Our findings showed a lack of association between the incidence of TGCT and the different Y- chromosome haplogroups in Japanese population. CONCLUSION: We concluded that there are no significant variations in males from different Y chromosome lineages regarding their susceptibility or resistance for developing TGCT. The previously hypothesized role of the Y chromosome in the development of TGCT is still uncertain and needs further verification.     

Transperineal extended biopsy improves the clinically significant prostate cancer detection rate: A comparative study of 6 and 12 biopsy cores

BACKGROUND: We evaluated the improvement in the rate of prostate cancer detection when using a 12-core transperineal biopsy protocol including transitional zone biopsy. METHODS: Between April 2003 and November 2004, 247 consecutive men underwent transperineal systemic 12-core biopsy of the prostate. Six cores were obtained at the peripheral zone, four at the transitional zone and two at the apex. We examined the cancer detection rate in each of the 12 cores, and also determined the improvement of cancer detection resulting from the extensive 12-core versus standard 6-core biopsy. RESULTS: Using the extensive 12-core biopsy, prostate cancer was detected in 98 cases (39.7%). Prostate-specific antigen (PSA), PSA density, the positive rate in digital rectal examination and transrectal ultrasound findings were significantly higher in the prostate cancer group than in the non-prostate cancer group, and prostate volume was larger in non-prostate cancer group. Every site showed almost the same positive rate, between 17.8 and 21.5%. There were 20 cases which were positive in the extended biopsy, but negative in the sextant. The detection improved significantly (20.4%). The improvement of cancer detection in extended biopsy was better in men with PSA levels of 10 ng/mL or less (28.9%), PSA density 0.3 or less (25.8%), negative digital rectal examination (23.3%), and negative transrectal ultrasound (21.6%). Of these twenty patients, no cases with insignificant tumor were detected in the six prostatectomy cases. In particular, three cases of the six were transitional-zone-only cancer. CONCLUSION: Transperineal extended 12-core biopsy including 4 transitional zone cores is a more useful procedure than transperineal 6-core biopsy. Routine transitional zone biopsy, that is different from transrectal biopsy, might be useful for detecting biologically significant cancer.     

New interpretation and management of dry lung syndrome: A case report

A premature female infant with life-threatening respiratory distress which was diagnosed as ‘dry lung syndrome’ is reported. The mother had 4 weeks of large volume leakage of the amniotic fluid due to premature rupture of the fetal membranes (PROM) at 23 weeks' gestation. The infant was bom after 27 weeks' gestation (birthweight, 1016 g) and was suffering severe respiratory distress. Although a chest radiogram and gastric juice microbubble test did not prove the possibility of respiratory distress syndrome (RDS), very high ventilator settings did not improve her respiratory disorders. Considering the infant's deteriorating respiratory status and the prolonged leakage of the amniotic fluid, we suspected the presence of pulmonary hypoplasia. Although an attempt at high frequency oscillation (HFO) to rescue this infant had no effect, intratracheal instillation of epinephrine (EP) showed dramatic improvement of her respiratory status. This clinical course showed that the patient did not have pulmonary hypoplasia but might have severe airway obstruction and this airway obstruction may be the major cause of ‘dry lung syndrome’. We postulate that when a newborn with suspected pulmonary hypoplasia is unresponsive to respiratory support, HFO should be administered. If HFO is ineffective in relieving the respiratory distress, one should suspect the presence of airway collapse and administer a bronchodilator such as EP. If the infant improves, a diagnosis of ‘dry lung syndrome’ may be assumed.     

GROWTH HORMONE MODULATION OF ARGININE-INDUCED GLUCAGON RELEASE: STUDIES OF ISOLATED GROWTH HORMONE DEFICIENCY AND ACROMEGALY

Plasma glucagon and insulin responses to l -arginine were compared in normal controls and patients with isolated growth hormone deficiency and acromegaly. Patients with isolated growth hormone deficiency were characterized by high plasma glucagon response and low plasma insulin response, whereas acromegalic patients showed exaggerated plasma glucagon response and almost normal insulin response. These results suggest that growth hormone is probably required for optimum function of the islets, and since hyperglucagonaemia was observed in both growth hormone deficiency and acromegaly, metabolic disturbances stemming from the respective primary diseases may affect glucagon secretion.     

An early gallstone clearance following repeat piezoelectric lithotripsy

Piezoelectric extracorporeal litotripsy was performed in 128 symptomatic patients with radiolucent gall-bladder stones to assess the significance of disintegration in fragment clearance. Up to 10 repeat lithotripsy sessions were scheduled to achieve a fragment target size of <3 mm. Fragmentation assessed by the size of the largest fragments after the last session was graded into three classes. I: sludge-like disintegration, 18%; II: <3 mm (mean ± s.d., 1.7 ± 0.5 mm), 56%; and III: < 3 mm (3.3 ± 0.6), 26%. All patients were initially subjected to lithotripsy alone. Bile acid dissolution therapy was started only when ultrasonography failed to show the evidence of decrease in the <3 mm fragments during a 1 month follow up. Finally, 69 patients (54%) were treated by lithotripsy alone, and the remaining 59 received additional dissolution therapy at a mean period of 2.5 months after the initial lithotripsy. The rate of complete clearance in class I, II and III patients was 91, 42 and 10% at 6 months and 100, 68 and 49% at 18 months, respectively. Significant differences were noted between the three fragmentation grades (I vs II, III, P <0.0001; II vs III, P <0.02). The patients with complete clearance within 6 months were seen only in those treated by lithotripsy alone, while the majority (87%) of patients with complete clearance during the later period were seen in those treated by additional dissolution therapy. We conclude that a high degree of fragmentation appears to lead stones to an earlier period clearance, and reduce the need for dissolution therapy.     

Sympathetic Nervous System Response to Dynamic Exercise in Complete AV Block Patients Treated with AV Synchronous Pacing with Fixed AV Delay or with Auto-AV Delay

IGAWA, O., ET AL.: Sympathetic Nervous System Response to Dynamic Exercise in Complete AV Block Patients Treated with AV Synchronous Pacing with Fixed AV Delay or with Auto-AV Delay. To investigate the sympathetic nervous system (SNS) responses and circulatory responses to exercise in eight patients (five male and three female) with complete atrioventricular block (CAVB) treated with atrio-ventricular (AV) synchronous pacing, a symptom-limited, multistaged treadmill stress test was performed, and plasma norepinephrine (NE) and circulatory parameters were measured at rest, at peak exercise, and in the recovery period. The eight patients were tested using the fixed AV interval (150 or 156 msec). Their exercise tolerance was generally poor. In all measured points, plasma NE levels were significantly higher in the eight study patients than those in the 12 normal subjects (eight male and four female). Systolic blood pressure (SBP) of CAVB patients elevated significantly after exercise compared to that at peak exercise. Heart rate (HR) responses of CAVB patients were characterized by their poor increase at peak exercise. These results suggest that some latent cardiac dysfunction continues in the CAVB patients however satisfactorily the AV synchronous pacing might perform. AV synchronous pacing with three different kinds of auto-atrioventricular delay (auto-AVD) was applied to three of the eight patients. In each AVD mode, a treadmill stress test was performed repeatedly according to the same protocol. Plasma NE concentrations under the condition with fixed AVD at peak exercise increased compared to those under the other two conditions with auto-AVD. These findings suggest that AV synchronous pacing with auto-AVD WQS better than that with fixed AVD during exercise. Plasma NE response to exercise seems to be a useful indicator for evaluating the condition of patients treated with DDD pacemakers and their adaptation for cardiac function.