Pharmacokinetic behaviour in polymorphonuclear leucocytes of N,N-dimethylcarbamoylmethyl α,2-dimethyl-5H-[1]benzopyrano[2,3-b]-pyridine-7-acetate (Y-23023), a new prodrug type of antiinflammatory agent,and indomethacin after oral administrations in rats

Abstract— N,N-Dimethylcarbamoylmethyl α,2-dimethyl-5H-[1]-benzopyrano[2,3-b]pyridine-7-acetate (Y-23023) is a prodrug developed as a new non-steroidal anti-inflammatory drug (NSAID). Y-23023 is rapidly hydrolysed to an active metabolite, α,2-dimethyl-5H-[1]benzopyrano[2,3-b]pyridine-7-acetic acid (M₁) following its absorption and then exhibits a strong anti-inflammatory activity. We have examined the pharmacokinetic behaviour in polymorphonuclear leucocytes (PMNs) of M₁ and of indomethacin after oral administration to rats of Y-23023 and indomethacin, respectively. Y-23023 was rapidly absorbed, producing a mean C_max (1·13 μg mL^?1) of M₁ after 1 h in plasma. Indomethacin was less rapidly absorbed, producing a mean C_max (3·38 μg mL^?1) after 3 h in plasma. The mean AUC of M₁ and indomethacin in plasma were 5·45 μg h mL^?1 and 22·49 μg h mL^?1, respectively. The mean t_max, C_max and AUC of M1 in PMNs were 1 h, 11·1 ng (41 pmol)/10⁸ cells and 58·6 ng (164 pmol) h/10⁸ cells, respectively. The same parameters for indomethacin in the PMNs were 3 h, 15·4 ng (57 pmol)/10⁸ cells and 95·2 ng (266 pmol) h/10⁸ cells, respectively. The PMNs/plasma ratio of M₁ was about 2·8 times that of indomethacin. These results indicate that the association of M₁, an active metabolite of Y-23023, from blood to the PMNs is greater than that of indomethacin.     

Two cases of sleep-disordered breathing in climacteric

Abstract Two cases of sleep disordered-breathing in climacteric were reported. Polysomnography including esophageal pressure (Pes) measurement was performed. Case 1 was diagnosed as upper airway resistance syndrome. Case 2 was diagnosed as obstructive sleep apnea syndrome, while many episodes of upper airway resistance also existed. Hormone replacement therapy improved clinical symptoms, and in case 1, Pes nadir was improved but incidence of arousals which was induced by breathing disturbances was not significantly changed. Sleep disordered-breathing should be suspected as a cause of sleep disorder even in females, especially in climacteric age. Pes measurement and evaluation of arousals is required. Hormone replacement therapy may release the upper airway resistance.     

Expression of Lewis X-related antigens in adenocarcinomas of lung

Fifty primary lung adenocarcinomas were examined immunohistochemically using monoclonal antibodies to determine changes in the expression of N-acetyl-lactosamine (blood group type-2 chain), Le^x, Le^Y and sialyl Le^x-i. These antigens were expressed in 60%, 70%, 90% and 94% of carcinomas, respectively; in 8%, 12%, 56% and 86% of normal broncho-bronchiolar epithelium; and in 32%, 0%, 100% and 0% of normal alveolar epithelium. The greater the complexity of the antigenic structure, the greater the incidence of positive staining in the adenocarcinomas. Although the more complex antigens such as sialyl Le^x-i and Le^Y have also been demonstrated in the sera of lung cancer patients, they were not always cancer-selective in our immunohistochemical study. In contrast, the less complex antigens such as N-acetyl-lactosamine (type-2 chain) and Le^x seem to be cancer-selective, as they showed low positivity in normal lung tissue.     

Stepped care medical treatment for cirrhotic ascites: Analysis of factors influencing the response to treatment

Abstract Thirty-two patients with liver cirrhosis and ascites were treated by stepped care diuretic treatment as follows: step 1, placed on a 35 mEq sodium diet; step 2, given 400 mg/day of potassium canrenoate in addition to step 1 treatment; step 3, given 40-80 mg/day of furosemide in addition to step 2 treatment. Eleven out of 32 patients (34.4%, group 1) and 12 of 21 patients (57.1%, group 2) lost their ascites at step 1 and step 2, respectively. The remaining nine patients (group 3) required step 3 treatment. Basal urinary sodium excretion and creatinine clearance were significantly lower and β₂-microglobulin was significantly higher in group 3 than those in groups 1 and 2. Elevation of basal plasma renin activity and norepinephrine was evident only in group 3. In group 1, urinary sodium excretion decreased after the treatment. In group 2, plasma α-atrial natriuretic polypeptide was lowered and plasma renin activity and norepinephrine were elevated after the treatment. These results suggest that basal renal function and plasma renin activity and norepinephrine levels are useful indices to predict the effect of ascites treatment and that responders to sodium restriction or potassium canrenoate may be in the state of vascular overflow, while non-responders to potassium canrenoate may be in the state of vascular underfilling. In summary, this stepped care treatment is safe without any side effects, although the diuretics themselves may lead to relative vascular underfilling.     

The female partner''s satisfaction with sildenafil citrate treatment of erectile dysfunction

BACKGROUND: Data on female partners' satisfaction are scarce, although there have been many articles on patient satisfaction after sildenafil citrate treatment. The aim of this study was to evaluate the satisfaction of female partners of patients receiving sildenafil citrate for their erectile dysfunction (ED) and to assess the female partners' sexual function. METHODS: Ninety-eight patients with ED were treated. Their female partners were asked to answer a questionnaire we have prepared to evaluate the efficacy of treatment, sexual satisfaction and changes in quality of life. It also included a question about female sexual function. From the results, the relationship between their female partner's satisfaction and efficacy of treatment, as well as female sexual function, were assessed. RESULTS: Thirty (31%) questionnaires were returned to us for analysis. Effectiveness of the treatment was acknowledged by 90% of the partners. An improvement in their partner's quality of life was noticed by 60% of the women. The majority (66.7%) of the female partners were satisfied with sildenafil citrate treatment and 20% were disappointed. Moreover, 20% of the female partners were concerned about adverse events. Regarding female sexual function, some form of sexual dysfunction affected 46.7% of the women. Furthermore, a significant number (P = 0.0230) of the female partners disappointed with the treatment had some kind of sexual dysfunction. CONCLUSIONS: The results indicated that female partners reported relatively high levels of treatment satisfaction. Female partners' sexual function and anxiety regarding adverse events should be evaluated when their satisfaction with sildenafil citrate treatment is poor despite an improvement of erectile function.     

A new oral margarine loading test in children

Margarine (2g/kg) was orally administered to 39 children with normal fat digestion and absorption (control group) and 17 children with abnormal fat digestion and absorption (malabsorbed group). The serum triglyceride (TG) level was serially determined by capillary blood sampling. In the control group, the TG level was significantly elevated after 2, 3 and 4 h as compared with the level before margarine ingestion (basal TG). The maximum TG elevation rate [MTER - (maximum TG-basal TG)/basal TG x 100] was > 50% in all but three children. In contrast, a significant increase in TG was not observed in the malabsorbed group after margarine ingestion, and the MTER was < 50% in all but two children. The MTER was significantly lower in children with a high microscopic score of fecal fat than that in children with a low score. This oral margarine loading test is a simple and semi-quantitative evaluation of fat digestion and absorption, and is considered to be useful for the assessment of the presence or severity of fat maldigestion and malabsorption in children.     

Enzymatic Hydrolysis of Zenarestat 1-O-Acylglucuronide

Abstract— Zenarestat, (3-(4-bromo-2-fluorobenzyl)-7-chloro-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-1-y1) acetic acid, an aldose reductase inhibitor is metabolized mainly to the glucuronide in rat and man. The glucuronide was purified from urine of volunteers after ingestion of zenarestat. The structure of the glucuronide was confirmed by LC-MS and NMR as 1-O-acyl-β-glucuronide. This compound was unstable at physiological pH, being converted to its structural isomers and the aglycone with half-life of 25 min at pH 7·4 and 37°C in aqueous solution. Enzymatic hydrolysis of the glucuronide was studied in urine, blood and tissues. β-Glucuronidase in human urine contributed little to the hydrolysis of the glucuronide, while in rat urine at pH 6, it was degraded by β-glucuronidase and the formation of zenarestat was clearly faster than its formation in buffer at pH 6. In both rat and human blood, these reactions were accelerated by albumin, although rat red blood cells may also contribute. The rate of degradation was not affected by red blood cell membrane, haemoglobin, globulin, esterases or β-glucuronidase. Arylesterase in rat liver, arylesterase and acetylcholinesterase in the kidney, and β-glucuronidase in both tissues may contribute. Thus, enzymatic degradation of zenarestat 1-O-acyl-β-glucuronide is dependent not only on pH and temperature but also on species and the type of tissue or body fluid.