Recombinant interferon-α-2a for treatment of chronic hepatitis C: results of a multicenter randomized controlled dose study

Abstract: To compare the efficacy of low and relatively high dosages of recombinant interferon (IFN)-α-2a in Japanese patients with chronic hepatitis C, as well as to characterize the type of patients who will respond well to a low-dosage treatment, 88 patients with histologically proven chronic hepatitis C were randomly assigned to two treatment groups; one treated with IFN-α-2a 6 MU daily for 2 weeks followed by 6 MU three times weekly for 22 weeks (6-MU group), and another given the same initial treatment followed by 3 MU three times weekly for 22 weeks (3-MU group). The rate of sustained normalization of ALT 6 months after the cessation of treatment was 33% in the 3-MU group and 40% in the 6-MU group (p=0.64). In addition, there was no difference in elimination of serum HCV-RNA 6 months after the cessation of treatment between the 3-MU group (26%) and 6-MU group (29%). Multivariate stepwise regression analysis revealed that serum HCV-RNA level (p=0.0035) and platelet count (p=0.0009) were independent variables useful in predicting a sustained response of ALT. The sustained response rate of ALT in patients with a serum HCV-RNA level less than 10⁵ copies/ml and serum platelet level above 15×10⁴/μl was 71%, whereas that in patients with a serum HCV-RNA level above 10⁵ copies/ml and serum platelet level less than 15×10⁴/μl was 12%. These results indicate that a high rate of sustained response to IFN therapy can be expected in chronic hepatitis C patients with a low serum level of HCV-RNA and a high level of platelets, even if treated with a low dose of IFN.     

Influence of surgery for ischemic heart disease on early postoperative left ventricular function

The pre- and postoperative systolic time intervals, hemodynamics and serum catecholamines were studied in 30 patients with successful myocardial revascularization surgery or left ventricular aneurysmectomy and the influence of the surgery on the left ventricular function was evaluated. 1. Significant depression of left ventricular performance was recognized in the group of patients with left ventricular aneurysm as compared to the patients with angina pectoris with or without previous myocardial infarction before the operation. 2. At 2 hours after the operation, signigicant decrease of ET/PEP, cardiac index and stroke work index and marked elevation of systemic vascular resistance were seen in the group of patients with aortocoronary bypass surgery who had previous myocardial infarction and with left ventricular aneurysmectomy as compared to the group of patients without previous myocardial infarction. 3. At 2 hours after the operation, ET/PEP seemed to reflect the left ventricular stroke work and the depression of the left ventricular function was mainly affected by the elevation of systemic vascular resistance due to the hypersecrection of serum catecholamines. 4. Reduction of systemic vascular resistance by vasodilator brought an improvement of EG/PEP, cardiac index and stroke work index.     

Adiponectin negatively correlates with alcoholic and non‐alcoholic liver dysfunction: Health check‐up study of Japanese men

Aim: Central obesity, insulin resistance and alcohol consumption are thought to be major risk factors for fatty liver formation. Adiponectin (APN) prevents fatty liver formation, and its serum levels are lower in subjects with central obesity and/or insulin resistance. The aim of this study was to explore the association among serum APN levels, central obesity, insulin resistance and liver dysfunction with or without fatty liver classified by alcohol consumption in healthy subjects. Methods: A total of 5588 Japanese male subjects who underwent a health check‐up were classified into three groups according to alcohol consumption: non‐ or light drinkers (15 g/day ≥ ethanol); mild drinkers (15 g/day < ethanol ≤ 30 g/day); and moderate‐ or heavy drinkers (30 g/day < ethanol). Central obesity and insulin resistance were assessed by waist circumference (WC) and Homeostasis Model of Assessment – Insulin Resistance (HOMA‐IR), respectively. Results: WC was significantly increased, while HOMA‐IR was significantly decreased according to the extent of alcohol consumption. Serum alanine aminotransferase levels were significantly lower and serum APN levels were significantly higher in mild drinkers than in the other two groups. Multiple linear regression analysis showed that serum APN level served as the significant and independent determinant for liver dysfunction in the subjects with fatty liver, irrespective of alcohol consumption. However, WC became a non‐significant determinant of liver dysfunction as alcohol consumption increased. Conclusion: Hypoadiponectinemia is a significant determinant for steatotic dysfunction for all levels of alcohol consumption, but central obesity was not a significant determinant for alcoholic fatty liver‐induced liver dysfunction.     

In vitro and in vivo selectin-blocking activities of sulfated lipids and sulfated sialyl compounds

There is accumulating evidence that sulfated lipids, sulfated oligosaccharides and other sulfated compounds are reactive with selectins in a manner that interferes with selectin interactions with their natural ligands. In the report we describe the ability of sulfated lipids (sulfatides and gangliosides) and multimeric forms of sulfated sialic acid to block binding of P- and E-selectin-Ig to neutrophils. The in vivo ability of these compounds to block lung injury in rats following i.v. infusion of purified cobra venom factor (CVF), which induces injury that is L- and P-selectin dependent, was also determined as well as effects on recruitment of neutrophils, as measured by lung myeloperoxidase. There was a significant correlation between the ability of sulfated lipids and sialyl compounds to interfere in vitro with P-selectin-Ig binding to neutrophils and to protect against P-selectin-dependent acute lung injury induced by CVF. The biological effects of these sulfated compounds were also associated with diminished accumulation of neutrophils. The protective effects of these compounds may be linked to their ability to interfere with P- selectin binding to counter-receptors on neutrophils.      

Analgesic and other pharmacological activities of an enkephalin analogue,syndyphalin (SD)-25

The pharmacological actions of Tyr-D-Met(O)-Gly-MePheol (syndyphalin (SD)-25) were compared with those of morphine after systematic administration. The analgesic potency of SD-25 was about 4 times that of morphine when administered s.c. to rats. SD-25 did not exhibit any narcotic antagonist activity. Subcutaneous administration of SD-25 produced a dose-dependent suppression of morphine withdrawal signs in morphine-dependent rats, typical morphine-like jumping in the mouse jumping test, and an increase in spontaneous locomotor activity in mice. These activities were 2–5 times those of morphine. In the anaesthetized dog, intravenous administration of SD-25 produced a 100–1000 times stronger increase in the amplitude of contractions of the jejunum than did morphine, a weaker depression in respiration than morphine, and a slight increase in blood pressure. These effects were reversed by naloxone. These results indicate that SD-25 possesses potent central nervous system actions closely similar to those of morphine, but its effect on blood pressure and respiration was weaker than that of morphine.     

Antiviral and immunomodulating activities of chemically synthesized lipid A-subunit analogues GLA-27 and GLA-60

Biological and antiviral activities of chemically synthesized lipid A-subunit analogues, GLA-27 and GLA-60, were investigated with respect to defense mechanisms such as macrophage and natural killer (NK) cell activation and interferon (IFN)-inducing activity. GLA-27, a 4-O-phosphono-D-glucosamine derivative carrying 3-O-tetradecanoyl (C14) and 2-N-3-tetradecanoyloxytetradecanoyl (C14-O-(C14] group, and GLA-60, a similar analogue carrying 3-O-linked C14-O-(C14) and 2-N-linked 3-hydroxytetradecanoyl (C14-OH) groups, strongly inhibited the formation of pox tail lesions and the growth of vaccinia virus at the tail lesion sites in infected mice. The antiviral activity of GLA-60 was about 1000-fold higher than that of muramyldipeptide (MDP), a representative immunomodulator. GLA-27 and GLA-60 had stronger immunomodulating activity than MDP in macrophage activation, NK cell activation and IFN-inducing activity, although it was weaker than natural lipid A. Toxic manifestations such as pyrogenicity, local Schwartzman reaction and lethality were far less pronounced for GLA-27 and GLA-60 than for natural lipid A.     

Antihepatotoxic actions of gingerols and diarylheptanoids

The antihepatotoxic effects of gingerols, shogaols, diarylheptanoids and related analogues were assessed utilizing carbon tetrachloride- and galactosamine-induced cytotoxicity in primary cultured rat hepatocytes. Most congeners exhibited significant actions in these assay methods. The carbon tetrachloride assay appeared to be most useful in defining structure-activity relationships. The antihepatotoxic activity of gingerols and shogaols was dependent on the length of the side chain with the [7]- and [8]-companions eliciting the strongest activity. The gingerols exerted more intense activity than the corresponding shogaols. In the diarylheptanoids, introduction of hydroxyl groupings on the phenyl rings caused increased activity; however, the effect of the positions and number of hydroxyls on activity was variable depending on the carbon skeleton.     

Antihepatotoxic actions of tannins

The antihepatotoxic effects of tannin analogues were examined utilizing carbon tetrachloride- and galactosamine-induced cytotoxicity in primary cultured rat hepatocytes. Most tannins showed significant antihepatotoxic effects in these two assay systems. Hydrolyzable tannins generally exhibited an intense enzyme inhibitory action on glutamic-pyruvic transaminase while condensed tannins exerted a much less inhibitory action, although variations were observed depending on structure. Structure-activity relationships are discussed.