Electrophysiological Effects of MS-551 in Humans: A Class III Antiarrhythmic Agent

To investigate the clinical effects of MS-551, a Class III antiarrhythmic agent, 11 patients underwent electrophysiological study. MS-551 was given intravenously as an initial dose of 0.2 or 0.3 mg/kg for 5 minutes followed by the continuous infusion at 0.2 or 0.3 mg/kg for 30 minutes, respectively, in all patients. The rate corrected QT interval increased significantly from 3 minutes after the beginning of MS-551 infusion. The sinus heart rate decreased significantly by 8% at 10 minutes after the drug administration (P ± 0.025). Mean PR and QRS intervals, and blood pressure were not significantly affected by the drug. Mean PA, AH, and HV intervals during sinus rhythm were also not affected. The effective refractory periods (ERPs) of the atrium and ventricle were significantly prolonged by 13% from 202 ± 24 ms to 231 ± 26 ms (P ± 0.0005), and by 7% from 238 ± 11 ms to 257 ± 13 ms (P ± 0.002), respectively, by MS-551. The ERP of the atrioventricular node and sinoatrial nodal recovery time were not changed significantly by the drug. This is a report of the effects of MS-551 in humans. This agent could be useful for treatment of tachyarrhythmias by prolongation of ERPs of the atrium and ventricle without significant variations of blood pressure and intracardiac conduction times. It is noteworthy that MS-551 slightly but significantly decreased heart rate.     

Kinetics of serum cytokines in adults undergoing peripheral blood progenitor cell transplantation

Summary. We investigated the serum cytokine levels (G-CSF, GM-CSF, IL-l/?, IL-3 and IL-6) using an ELISA in 14 patients with haematological malignancies undergoing peripheral blood progenitor cell transplantation (PBPCT). Serum G-CSF levels in all patients rose immediately after PBPCT, then gradually decreased as the neutrophil counts began to rise. No detectable serum levels of GM-CSF or IL-lp were observed, but serum levels of IL-3 rose transiently immediately following PBPCT. Serum levels of JL-6 rose transiently during a fever in four patients. These observations suggest that G-CSF and L 3 may contribute to the early haemopoietic reconstitution in PBPCT.     

Chemical modification of superoxide dismutase Extension of plasma half life of the enzyme through its reversible binding to the circulating albumin

Protection of organisms from oxidative stress is one of the major prerequisites for aerobic life. Since intravenously injected Cu⁺⁺/Zn⁺⁺ -type superoxide dismutase (SOD) rapidly undergoes renal glomerular filtration and appears in urine in its intact form, its clinical use as a scavenger for superoxide radicals has been highly limited. To test whether reversible interaction of SOD with plasma albumin might decrease the rate of disappearance of the enzyme from the circulation, the lysyl residues of the human erythrocyte-type enzyme were covalently linked with poly-(styrene-co-maleic acid) butyl ester (SMA) via amide linkage. Affinity chromatographic analysis by an albumin-Sepharose column revealed that the enzyme samples labeled with SMA (SMA-SOD) tightly bound to the column, while unmodified SOD was eluted in the unbound fractions. SMA-SOD bound to the column could be eluted by the buffer solution containing 0.1% sodium dodecylsulfate. In vivo analysis revealed that intravenously administered SMA-SOD circulated bound to albumin with an extremely long half-life (6 h), while unmodified SOD rapidly underwent renal glomerular filtration with a plasma half-life of 4min. Thus, SMA-SOD may effectively dismutate superoxide radicals in the circulation.     

Natural Killer Activity and Antibody-Dependent Cell-Mediated Cytotoxicity in Multiple Myeloma

Natural killer (NK) activity and antibody-dependent cell-mediatedcytotoxicity (ADCC) were studied by routine methods in 11 patientswith untreated malignant monoclonal gammopathy. NK and/or ADCCactivity was clearly reduced in three patients with advanceddisease. Moreover, sera from some myeloma patients impairedthe ADCC and NK activity. A large quantity of purified monoclonalIgG from one patient appeared to inhibit NK and ADCC activityas did high concentrations of pooled polyclonal immunoglobulinfrom healthy persons. In two of these 11 patients, other malignancieswere diagnosed prior to chemotherapy. One of these patients,who had nonsecretory myeloma, had marked impairment of NK andADCC activity; the other, with IgG myeloma, had normal NK andADCC activity.     

Localization of transglutaminase 1 mRNA in normal and psoriatic epidermis by non-radioactive in situ hybridization

We examined the expression of the transglutaminase 1 (TGase 1) gene IN frozen sections of normal and psoriatic epidermis by means of non-radioactive in situ hybridization with digoxigenin-labelied cRNA probes. TGase l mRNA was expressed in the granular layer of normal epidermis. regardless of ortho-or hyperkeratosis. However, in psoriatic epidermis. TGasel mRNA was detected in the suprabasal spinous layer, but not in the subcorneal layer. These results indicate that TGase 1 gene expression is limited to the last stage of keratinization in normal epidermis and this regulation is disturbed in psoriasis.     

Angiosarcoma of the scalp associated with renal transplantation

A case of cutaneous angiosarcoma occurring in a 51-year-old male renal transplant patient is reported. Multiple violaceous nodules surrounded by poorly demarcated red to purple discoloration were found on his scalp. Immunosuppressants consisting of azathioprine and prednisolone had been administered during the 12-year period since the renal transplantation. We diagnosed the lesion clinically as a cutaneous angiosarcoma and performed a wide surgical excision. The histopathological findings confirmed the diagnosis and showed tumour cells in the peripheral margin. Postoperatively, the patient started immunotherapy with systemic administration of recombinant interleukin-2 (rIL-2), but he refused to continue it because of the acute rejection of the transplanted kidney induced by the rIL-2. Instead he received radiation therapy (total 7000 rad) of the scalp. Although no recurrence was noticed for 15 months after the completion of radiation, he died due to lung metastasis from angiosarcoma. We review the seven cases, including ours, of angiosarcoma after renal transplantation that are reported in detail in the literature.     

Quantitative measurement of HCV RNA in the serum: A comparison of three assays based on different principles

Quantitative measurement of hepatitis C virus (HCV) RNA is useful in patients with chronic hepatitis C, especially with interferon treatment. We examined the clinical usefulness of the AMPLICOR monitor assay, a newly developed assay for quantitative measurement, by comparing it with two other assays with different principles. A total of 48 patients with chronic hepatitis C who were treated with interferon-α (IFN-α) were studied: 19 were complete responders and 29 were non-responders. Hepatitis C virus RNA was measured quantitatively by AMPLICOR, branched DNA (bDNA) probe, and competitive polymerase chain reaction (C-PCR) assays. An internal quantification standard was used in the AMPLICOR assay. A cDNA competitor with a deletion of 15 base pairs in the middle portion was used in the C-PCR method. The concentration of HCV RNA was significantly correlated between the three assays adopted in this study. Sensitivity of assays was 100% by C-PCR, 90% by AMPLICOR and 69% by bDNA assays. The active quantitative range was best with the C-PCR assay and worst with the bDNA assay. The bDNA assay had a tendency to exhibit lower values for patients with serotype 2 than did the other two assays. The predictive rate of the long-term response to IFN-α therapy, before its initiation, was over 75% in all three assays. The predictive rate just after completing IFN-α therapy was as high as 80% by C-PCR and the AMPLICOR assays, but was low (58%) with the bDNA assay. The handling of the bDNA and AMPLICOR assays was much easier than the C-PCR assay, which required time and skill. These results indicate that the AMPLICOR assay is a simple and reliable method for measuring the serum concentrations of HCV RNA, and thus is suitable for clinical application.     

HCV infection and its clinical features in recipients of blood screened for HCV (C100-3) antibody

Abstract After adoption of the anti-hepatitis C virus (C100-3) test, the incidences of definite and suspected cases of post-transfusional hepatitis (PTH) were 3.3% (7/209) and 7.2% (15/209), respectively. Four patients with definite PTH and seven patients with suspected PTH became positive for hepatitis C virus (HCV)-related antibodies or HCV-RNA after transfusion. These cases that became positive for anti-HCV or HCV-RNA showed a peak of alanine aminotransferase (ALT) more than 4 weeks after operation. Only rare cases that showed ALT peaks within 4 weeks after operation became positive for HCV-related antibodies or HCV-RNA. The peak ALT levels in cases showing positive conversion tended to be higher than those in cases showing no conversion. Judging from these results, cases of suspected PTH include those of transient liver disease attributable to surgery as well as clear cases of HCV infection. Thus new diagnostic criteria are required including data on HCV antibodies or HCV-RNA.     

METHIMAZOLE-INDUCED AGRANULOCYTOSIS IN JAPANESE PATIENTS WITH GRAVES'' DISEASE

We reviewed the records of approximately 7000 Japanese patients whose hyperthyroidism was treated with methimazole (MMI) alone. Four patients (Group I) developed agranulocytosis during a second course of MMI therapy and eight patients (Group II) during an initial course. Six patients (three in each group) received less than 30 mg MMI daily. Agranulocytosis occurred after more than 2 months of therapy (12 weeks-1 year) in five patients. Seven patients were less than 40 years of age. One patient displayed a gradual protracted development of agranulocytosis. These results indicate that agranulocytosis after MMI may occur irrespective of dose, age, duration of treatment, and with a second exposure.