Comparative Pharmacokinetic and Pharmacodynamic Properties of Oral and Intravenous (+)-Sotalol in Healthy Volunteers

Abstract— The pharmacokinetic and pharmacodynamic properties of (+)-sotalol (BMY-5763) were studied to analyse the relationship between plasma concentration and QT_c prolongation in healthy male volunteers given single oral doses of 50, 100, 200 and 300 mg, repeated oral doses of 200 mg twice daily for 6·5 days, and single intravenous doses of 1·0 and 1·5 mg kg^?1. The plasma concentration of (+)-sotalol peaked about 3 h after oral administration and declined with a half-life of 7·9–9·7 h. The C_max and AUC showed dose-related increases, while the urinary recovery as the unchanged form remained constant (66–68% of the dose). During repeated oral administration the plasma concentration of (+)-sotalol reached almost a steady state on the 3rd day and there was no change in renal clearance of (+)-sotalol measured on the 1st, 4th and 7th days. After intravenous administration, (+)-sotalol in plasma decreased biexponentially with a terminal half-life of 7·6–8·3 h and the urinary recovery as unchanged drug amounted to 84–88% of the dose. The increase in QT interval was significant after a single oral administration except for the lowest dose, and regression analysis revealed a significant correlation between QT_c interval and concentration of (+)-sotalol in plasma. The same correlation was evident with repeated oral doses on the 1st, 4th and 7th days. In the case of single intravenous administrations of (+)-sotalol, a combined pharmacokinetic-pharmacodynamic model was attempted by assuming an effect compartment. This analysis was shown to be effective to adjust the lag of effect behind a rapid change in plasma concentration which occurred in the early distributive phase because there was no evidence that the metabolite made any significant contribution to the effect of (+)-sotalol.     

Composite tumor of mucinous cystadenoma and somatostatinoma of the kidney

Approximately 30 cases of carcinoid tumor of the kidney have been reported in the English literature, including three cases found as components of teratomas. Renal composite tumors associated with somatostatinoma have not been described. A 53-year-old female presented with an incidentally found right renal cystic lesion. Computed tomography demonstrated a cystic lesion associated with a solid nodule in the right kidney and postcontrast dynamic MRI revealed enhancement of the solid nodule. The patient underwent radical nephrectomy for the kidney lesion and is now well without recurrence 21 months after the operation. From the histopathological findings we diagnosed the cystic lesion as a composite tumor composed of mucinous cystadenoma and carcinoid tumor. Immunohistochemistry demonstrated the majority of cells of in carcinoid portion to be positive for antisomatostatin staining. The present case is the first documented composite tumor of mucinous cystadenoma and somatostatinoma of the kidney.     

Pathological effects of neoadjuvant hormonal therapy help predict progression of prostate cancer after radical prostatectomy

BACKGROUND: It is not clear whether pathological changes following neoadjuvant hormonal therapy (NHT) prior to radical prostatectomy have any value as predictors of progression in prostate cancer. METHODS: We conducted a study of 100 patients with prostate cancer who underwent radical prostatectomy following NHT. We used the Japanese general rule as the criterion to assess the biochemical recurrence rate and pathological changes after NHT. RESULTS: In terms of preoperative risk factors, the probability of recurrence was significantly higher for patients with more than 20 ng/mL of pretreatment serum prostate-specific antigen (PSA) and/or a Gleason score of 7 or higher for biopsy specimens. We defined these pretreatment findings as high-risk factors. Among 65 patients with high-risk factors, patients with a post-NHT pathological effect of grade 3 according to the Japanese general rule showed no recurrence, whereas patients with a grade 0 had a poor prognosis. Patients with a PSA nadir 0.5 ng/mL or less tended to have a better prognosis. CONCLUSION: Despite preoperative high-risk factors, patients showing good pathological effects after NHT tend to have a favorable prognosis after radical prostatectomy. Therefore; assessment of the pathological effects of NHT using the Japanese general rule as the criterion proved to be useful for the prediction of biochemical recurrence.     

EFFECTS OF INTRACAROTID ADMINISTRATION OF β-PHENYL-γ-AMINOBUTYRIC ACID ON THE PERFUSED CAT BRAIN

An investigation was carried out on the effects of intracarotid administration of β-phenyl-γ-aminobutyric acid (β-phenyl-GABA) on the functions of a perfused cat brain. After injecting one ml, each of containing 1, 5, 10, 20, 25, or 35mg/ml of β-phenyl-GABA into the tubes perfusing the carotid arteries with standard artificial blood, the acute effects of the drug on EEG, cerebral blood flow, and oxygen consumption were observed. The results may be briefly summarized as follows.

• 1). EEG is inhibited shortly after the drug reaches the brain. The extent of inhibition rises and the duration of the inhibition is longer as the dose is increased.
• 2). β-phenyl-GABA increases the cerebral blood flow in the cat brain and the increase reaches its maximum with a dose of 5 mg. Above this dose it declines.
• 3). This drug increases the oxygen consumption of the brain slightly.
• 4). It has no effect on the systemic blood pressure.

     

Pathomorphological study of HCV antibody-positive liver cirrhosis

A morphological investigation was carried out to study the pathological features of liver cirrhosis caused by hepatitis C virus (HCV) infection. The materials consisted of liver specimens taken from 47 cases of anti-HCV antibody-positive liver cirrhosis (37 by surgery for hepatocellular carcinoma and 10 by autopsy), and from 21 cases of hepatitis B surface antigen-positive liver cirrhosis as the control. Liver specimens containing more than 10 regenerative nodules were examined. In addition, a histometric study was conducted to determine the degree of fibrosis and the size of regenerative nodule using a computer image-analysis system. The results showed that the histological characteristics of HCV antibody-positive liver cirrhosis are: (i) broadly expanded fibrous septa and small regenerative nodules; (ii) relatively strong inflammatory reaction and prominent lymphoid aggretation in the fibrous septum; and (iii) mild regenerative activity of the liver parenchyma, and infrequent liver cell dysplasia. These findings may facilitate better understanding of the pathology of HCV antibody-positive liver cirrhosis and more accurate pathological diagnosis by needle biopsy.     

Long-term administration of natural interferon-α in patients with chronic hepatitis C: Relationship to serum RNA concentration, HCV-RNA genotypes, histological changes and hepatitis C virus

To virologically assess the efficacy of interferon therapy in chronic hepatitis C, either 5 or 10 MU/day natural interferon-α (IFNα) was administered to 57 patients with chronic hepatitis C for 38 weeks. A complete and sustained response (CR-SR), as evidenced by the absence of serum hepatitis C virus (HCV)-RNA during the administration period and at 6 months after the final administration of IFNα and a normal GPT level at 6 months after final administration, occurred in 42.6% (23/54) of subjects. Liver tissue was histologically evaluated using the histological activity index (HAI) score before and after the administration period. In CR-SR cases, significant improvements (P <0.01) occurred in periportal necrosis, intralobular necrosis, portal inflammation and total score. A comparison, by HCV genotypes, revealed that CR-SR occurred in 60% (9/15) of subjects with type 2a and 30.3% (10/33) of subjects with type Ib. A comparison by virus concentration revealed that CR-SR occurred in 71.4% (15/21) of those subjects having a virus concentration of < 10⁵ copies/mL, but in only 24.2% (8/33) of those having a virus concentration of > 10⁵ copies/mL. Analysis by a multiple logistic model revealed a strong correlation between the therapeutic effect of interferon therapy and the pre-administration virus concentration (P=0.0061) and genotype (P=0.0015). These results suggest that the preadministration virus concentration and genotype are both key factors affecting the therapeutic effect of interferon therapy in chronic hepatitis C and that the therapeutic effect of interferon is satisfactorily high, irrespective of virus concentration, in subjects with type 2a HCV, but varies depending on virus concentration in subjects with type 1b.     

Treatment of Malignant Neurocardiogenic Vasovagal Syncope with a Rate Drop Algorithm in Dual Chamber Cardiac Pacing

A 29-year-old man with malignant vasovagal syncope presented with episodes of abrupt loss of consciousness associated with an aura, totaling more than 10 episodes over 3 months. Holter monitoring showed cardiac arrest with a duration of 15 seconds. Oral propranolol and disopyramide therapy failed to prevent the syncope. A dual chamber pacemaker with a rate drop response algorithm successfully prevented the syncope but not the aura. There may be multifactors involved in the mechanism of this syndrome. The patient has returned to a normal active life. This rate drop algorithm is an effective therapy for the prevention of syncope in malignant vasovagal syncope.     

Microdislodgment:

High impedance tined steroid-eluting leads, Medtronic CapSure Z family, incorporating a small surface (1.2 mm²) electrode made of porous platinum material are designed to reduce battery current drain. However, in some prior studies, an increased incidence of microdislodgment with this lead was reported thought to be due to the reduced electrode surface area. This article reports the experience that ventricular pacing failure due to microdislodgment occurred after CapSure Z lead implantation and the previous literature is reviewed. (PACE 2003; 26[Pt. I]:1541–1543)     

Effect of occlusal pressure on the histopathological changes in denture supporting tissues

summary Histopathological changes in the denture supporting tissues in relation to the occlusal pressure exerted through an experimental denture base were studied. An experimental denture, which prescribed the occlusal pressure by the amount of subsidence of the denture base (100, 50 and 13 μm), was con- structed for the palate of the molar region of rat. Histopathological changes caused by the occlusal pressure were observed, and the intensity of the pressure was also estimated. In the 100 μm subsidence group, compression of epithelium and lamina propria mucosae, inflammatory change and bone resorption were caused by the occlusal pressure. In the 50 μm subsidence group, compression of epithelium and lamina propria mucosae and bone resorption were observed, while in the 13 μm subsidence group, no evidence of inflammatory change and bone resorption were observed. The epithelium and lamina propria mucosae recovered histopathologically depending on the gradual decrease of the occlusal pressure result ing from bone resorption, whereas no quantitative recovery of the resorbed bone tissue was observed in the 100 and 50 μm subsidence groups. From the results observed in this study, a high correlation was observed between the histopathological changes under a denture base and the intensity of the occlusal pressure, and the possibility of the existence of the threshold for bone resorption induced by occlusal pressure was suggested.