Efficacy and safety of laparoscopic surgery for pheochromocytoma

OBJECTIVE: Laparoscopic surgery for primary aldosteronoma and Cushing's syndrome is well established. We report on our experiences with laparoscopic adrenalectomy for pheochromocytoma, and assess the efficacy and safety of the laparoscopic approach. METHODS: Between April 1998 and April 2003, a total of 23 patients underwent laparoscopic adrenalectomy for pheochromocytoma at Chiba University Hospital and Yokohama Rosai Hospital, Japan. We compared the surgical outcomes of these patients with those of 106 patients with adrenal tumors due to other pathologies who underwent laparoscopic adrenalectomy during the same period. RESULTS: The mean tumor size of pheochromocytoma was 4.96 cm. Mean operative time was 192.7 min, and mean estimated blood loss was 130 mL. Neither mean operative time nor mean estimated blood loss was greater for patients with pheochromocytoma. Intraoperative hypertension (systolic blood pressure > 180 mmHg) occurred in 39.1% (9/23) of patients with pheochromocytoma. During the follow-up period, there were no mortalities or recurrences of endocrinopathy. CONCLUSIONS: Laparoscopic adrenalectomy for pheochromocytoma is a safe and minimally invasive procedure.     

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.     

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.     

Chromophobe cell renal carcinoma with acquired cystic disease of the kidney in a long-term hemodialysis patient

We report a rare case of chromophobe cell renal carcinoma found in a 52-year-old female who had received hemodialysis therapy for 13 years. She was diagnosed as having a left renal tumor 7.5 cm in diameter with acquired cystic disease of the kidney (ACDK) by ultrasonographic examination during periodical systemic screening. As abdominal computed tomography scanning and enhanced color Doppler ultrasonography suspected that the hypervascular tumor was renal cell carcinoma, she underwent translumbar nephrectomy in July 2000. The histopathological diagnosis was chromophobe cell carcinoma with pT2 and grade 2 malignancy. Chromophobe cell carcinoma is uncommon among renal tumors with ACDK found in long-term hemodialysis patients.     

Long-term sequential changes of antibody to p40tax in HTLV-I carrier mothers and children

Antibody to p40^tax (anti-p40^tax) in serum specimens obtained sequentially from a human T cell lymphotropic virus type I carrier population of mothers and children were assayed. The prevalences of anti-p40^tax at the initial sampling were 88% (7/8) in children and 55% (16/29) in mothers. Two of the seven positive children lost their anti-p40^tax during the investigation period, resulting in a final prevalence of 63% (5/8) in children. However, anti-p40^tax status was constant in all the 22 mothers with multiple serum samples (15 remained positive and seven remained negative). A decline in the absorbance value of EIA for anti-p40^tax was observed in seven of the 15 anti-p40^tax positive mothers. This decline may result in the disappearance of anti-p40^tax in some of them.     

Accidental transmission of HCV and treatment with interferon

Accidental transmission of contagious pathogens, especially hepatitis C virus (HCV), by needlestick or other means as an occupational hazard for medical staff is of concern. We retrospectively analysed cases of work-related accidental injury with pathogens such as hepatitis B virus (HBV), HCV, syphilis and human immunode?ciency virus (HIV) reported to the centres for disease control at 15 hospitals (total 5776 beds) in the Gunma prefecture, Japan, from December 1990 to August 1993 (24.7 months). There were 416 such cases (16.8 cases/month), with an incidence of 0.2–3.5 accidents per month per hospital. Such accidents occurred in 297 (71.2%) nurses, 98 (23.5%) medical doctors, 13 (3%) laboratory technicians, four (1.0%) hospital maintenance workers, one (0.2%) assistant nurse, one secretary and two others. There were 323 (77.6%) injuries caused by needlestick, 42 (10.1%) from suture needles or surgical knife cuts, 17 (4.1%) from blood splatters from patients into the eyes or mouth, 10 (2.4%) from contact with injured skin and 24 (5.8%) simple skin contacts. Of the pathogens, 60.3% were HCV, 22.6% HBV, 5.8% syphilis, 0.7% HIV and 10.6% were of unknown origin. Four cases (1.6%) of HCV infection were found and treated with one or two courses of interferon therapy, and HCV was subsequently cleared. All four patients were cured with interferon therapy. None of the HBV-injured cases resulted in infection, possibly because of prophylaxis with HB immunoglobulin and HB vaccine. No HIV or syphilis infection was contracted. In summary, chronic HCV infection acquired as an occupational hazard can be cured by appropriate treatment, such as with interferon, after early detection of the infection.     

In-vitro Characterization of YM872, a Selective,Potent and Highly Water-soluble α-Amino-3-hydroxy-5-methylisoxazole-4-propionate Receptor Antagonist

The in-vitro pharmacological properties of (2,3-dioxo-7-(1H-imidazol-***1-yl)-6-nitro-1,2,3,4-tetrahydro-1-quinoxalinyl)-acetic acid monohydrate, YM872, a novel and highly water-soluble α-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA)-receptor antagonist were investigated. YM872 is highly water soluble (83 mg mL^?1 in Britton-Robinson buffer) compared with 2,3-dihydroxy-6-nitro-7-sulphamoyl-benzo(F)quinoxaline (NBQX), 6-(1H-imidazol-1-yl)-7-nitro-2,3(1H,4H)-quinoxalinedione hydrochloride (YM90K) or 6-cyano-7-nitroquinoxa-line-2,3-dione (CNQX). YM872 potently inhibits [³H]AMPA binding with a K_i (apparent equilibrium dissociation constant) value of 0.096 ± 0.0024 μM. However, YM872 had very low affinity for other ionotropic glutamate receptors, as measured by competition with [³H]kainate (high-affinity kainate binding site, concentration resulting in half the maximum inhibition (IC50) = 4.6 ± 0.14 μm), [³H]glutamate (N-methyl-D-aspartate (NMDA) receptor glutamate binding site, IC50 > 100 μM) and [³H]glycine (NMDA receptor glycine-binding site, IC50 > 100 μM). YM872 competitively antagonized kainate-induced currents in Xenopus laevis oocytes which express rat AMPA receptors, with a pA₂ value of 6.97 ± 0.01. In rat hippocampal primary cultures, YM872 blocked a 20-μM AMPA-induced increase of intracellular Ca²⁺ concentration with an IC50 value of 0.82 ± 0.031 μM, and blocked 300-μM kainate-induced neurotoxicity with an IC50 value of 1.02 μM. These results show that YM872 is a potent and highly water-soluble AMPA antagonist with great potential for treatment of neurodegenerative disorders such as stroke.     

A history of investigation on the mood stabilizing effect of carbamazepine in Japan

Abstract A history of investigation on the antimanic and prophylactic effects of carbamazepine in Japan is described. Following the initial open trials in the early 1970s in which the antimanic and prophylactic effects of carbamazepine were indicated for the first time in the world, the mood stabilizing effect was confirmed by the double blind studies which were performed with a multi-institutional cooperation in Japan in the late 1970s. During the course of the double blind trials, the problem of different therapeutic dosages of psychotropic drugs between Japan and Western countries emerged; that is, the doses of chlorpromazine and lithium carbonate, which were used as the control drugs to carbamazepine in the two double-blind group-comparison studies in Japan, were both much lower than the dosage used in most of the Western countries. The low dosage of control drugs made the evaluation of the results of the double blind studies performed in Japan difficult, and caused a delay of publication in the Western journals of the results. Whether the difference is due to biological factors or to psychosocial and cultural factors is an important problem in psychopharmacology and should be investigated further.     

Prognosis of the middle-aged and aged patients with obstructive sleep apnea syndrome

Abstract The long-term natural course of obstructive sleep apnea syndrome (OSAS) is studied in order to determine whether severity of nocturnal oxygen desaturation associated with apnea/hypopnea, body mass index (BMI), and hypertension influence survival in young (<40 years), middle-aged (40–64 years), and aged (65 years) using a questionnaire survey. One hundred and forty-eight patients with OSAS aged 17–78 years (136 men, 12 women, mean 52.0±12.3 yean), who were diagnosed by standard polysomnography (PSG) between 1983 and 1993, participated in the study. The survey revealed 15 deaths and 101 survivors; 32 subjects could not be located. The survival rate was 71.4% (95% confidence interval:55.6–87.2%). The survival rate in patients with OSAS was significantly lower than that in the age and sex-adjusted control Japanese population (87.6%). In the young group, only one death (a 19–year-old woman) occurred unexpectedly during sleep. The patient showed an apnea/hypopnea index (AHI) of 33 per h and the length of time that the nocturnal oxygen saturation (SaO₂) fell below 90% (time of SaO₂ < 90%) of 205 min. The survival rate in middle-aged patients with OSAS was significantly lower than that in the age and sex-adjusted control Japanese population (79.2 vs 91.0%), but this pattern was not seen among the aged. Time of SaO₂ <90% was significantly longer in the middle-aged patients than in the aged patients, but AHI did not differ between the two groups. Moreover, it was significantly correlated with AHI in middle-aged patients, but not in the aged patients. The survival rate was significantly lower in patients with hypertension than in the patients without such complications in the middle-aged group (57.9 vs 90.4%). Cox proportional-hazard regression model including age, hypertension, BMI, AHI, lowest SaO₂, and time of SaO₂ <90% showed that hypertension was only significantly associated with lower survival rate in total group and middle-aged patients, but not in the young or aged patients. The prognosis in patients with OSAS may differ among the generations. The prognosis in the middle-aged population may depend on the role of OSAS on the complications of hypertension or severity of oxygen desaturation, but not on AHI only.