Pharmacokinetics of hyperimmune anti-human immunodeficiency virus immunoglobulin in persons with AIDS

Hyperimmune anti-human immunodeficiency virus immunoglobulin (HIVIG) is an intravenous immunoglobulin prepared from HIV-infected asymptomatic donors with a CD4 cell count greater than 400 cells/microl and a high titer of antibody to HIV-1 p24 protein. Twelve persons with AIDS received four doses of HMG (two at 50 mg/kg of body weight and then two at 200 mg/kg) every 28 days. Pharmacokinetics were evaluated by measurement of anti-p24 antibody. HIVIG was well tolerated, and all participants completed the study. Three subjects who were not receiving Pneumocystis carinii pneumonia (PCP) prophylaxis developed PCP. The mean value for HIVIG clearance was 3.02 ml/kg/day at 50 mg/kg and 3.65 ml/kg/day at 200 mg/kg (P = 0.027); the mean trough antibody titers (reciprocal units) were 1,442 and 4,428, respectively. This study indicates that high titers of anti-p24 antibody can be maintained with a monthly administration schedule of HIVIG and that short-term safety is acceptable. Comparisons to evaluate the therapeutic potential of HIVIG are justified.     

Role of nitric oxide in the regulation of the hepatic microcirculation in vivo

BACKGROUND/AIMS: Nitric oxide (NO) is an important mediator in the regulation of vascular tone. However, no data exist on the physiological role of NO in the regulation of the hepatic microcirculation. This study was designed to evaluate the role of NO in the hepatic microcirculation in vivo under physiological conditions. METHODS: The hepatic microcirculation was investigated in anesthetized rats by intravital fluorescence microscopy after injection of fluorescein-isothiocyanate-labeled erythrocytes. Following assessment of baseline sinusoidal perfusion, animals were randomly treated with L-NMMA (n=6), L-arginine (n=6), nitroprusside sodium (NPS, n=5) or a comparable volume of NaCl (n=4). Drugs were given through a portal vein catheter at three doses (Dx), each followed by intravital microscopy. L-NMMA was given: 5 mg/kg (D1), 25 mg/kg (D2), 50 mg/kg (D3); L-arginine 30 mg/kg (D1), 150 mg/kg (D2), 300 mg/kg (D3); and NPS continuously 80 microg x kg(-1) x h(-1). RESULTS: L-NMMA induced a significant increase of mean arterial blood pressure (MAP) (114 vs. 129 mm Hg; p<0.05). In contrast, MAP of NPS-treated animals decreased (107 vs. 91 mm Hg; p<0.01) whereas MAP of animals receiving L-arginine did not significantly differ. Sinusoidal blood flow revealed dose-dependent changes: L-NMMA significantly decreased perfusion of sinusoids (D1: 65%, D2: 57%, D3: 50% of baseline, p<0.05). Injection of L-arginine increased the sinusoidal flow even with the lowest dose (D1: 137%, D2: 133%, D3: 123%, p<0.05). Continuous infusion of NPS had little effect on sinusoidal blood flow at the first and second times of microscopy but sinusoidal blood flow was significantly increased at the third time (D1: 103%, D2: 106%, D3: 122%). CONCLUSIONS: Inhibition of NOS results in a dose-dependent disturbance of the hepatic microcirculation despite significantly increased MAP, whereas L-arginine increases the sinusoidal blood flow. The results indicate an important role for NO in the regulatory mechanisms of hepatic sinusoidal perfusion under physiological conditions.     

YM-32890 A and B, new types of macrolide antibiotics produced by Cytophaga sp

Two new types of macrolide antibiotics, YM-32890 A and B, have been isolated from the fermentation broth of cytophaga sp. YL-02905S. In this paper, the taxonomy of the producing strain, fermentation, isolation, structure elucidation, and biological activity of the antibiotics are reported. YM-32890 A inhibits the growth of staphylococci including a macrolide-resistant strain, but shows no antimicrobial activity against other Gram-positive, Gram-negative bacteria and yeast.     

An exploration of the problems of using function points mark II

Abstract. This paper examines critically the function point analysis mark II (FPA mark II) method of measuring the functionality of information systems. Although the focus of the paper is on FPA mark II as devised by Symons, both this and the Albrecht method, from which the FPA mark II was developed, are briefly discussed. The published attempts to validate FPA mark II are reviewed and then the problems encountered by the author in applying the approach are described. The final part of the paper is concerned with the fit between SSADM and FPA mark II.     

A study of urinary dolichols as a biological marker for alcohol abuse. Report 2: Comparison of urinary dolichols/creatinine concentrations among non-drinkers, moderate-drinkers and heavy-drinkers

We report here the comparison of urinary dolichols/creatine (D/Cr) concentration ratios in male non-drinkers, moderate-drinkers and heavy drinkers at admission and during hospitalization, and also discuss its usefulness as a biological marker for alcohol abuse. Urine samples were collected from the following four experimental groups: non-(male and female) and moderate-drinker (male) volunteers, and alcoholic heavy-drinking patients (male) at admission for psychiatric treatment and after 9-15 days hospitalization (informed consent was obtained). Urinary dolichols were determined by high performance liquid chromatography after BondElutC18 (500 mg) extraction. Due to significant differences in urinary D/Cr concentrations between male and female groups in non-drinkers and because the heavy-drinkers available for this study were exclusively male, comparison of the value of urinary D/Cr concentration ratios was subsequently limited to male only. There were no statistical differences in urinary D/Cr concentrations in the male among non-drinkers, moderate-drinkers and heavy-drinkers at admission. The accuracy of urinary D/Cr as a biological marker for alcohol abuse, calculated using the mean +/- 2 s.d. in non- and moderate-drinkers as the normal range, is only 33.3% in heavy-drinkers at admission, while their value of gamma-GTP in serum was 88.3%.(ABSTRACT TRUNCATED AT 250 WORDS)     

Metabolism of tetramethrin isomers in rat: II. Identification and quantitation of metabolites

1. To examine the metabolic fate of (1RS, trans)- or (1RS, cis)-tetramethrin [3, 4, 5, 6-tetrahydrophthalimidomethyl (1RS, trans)- or (1RS, cis)-chrysanthemate], rat was administered a single oral dose of trans- or cis-[alcohol-14C]tetramethrin at dose levels of 2 or 250 mg/kg. 2. The radiocarbon was almost completely eliminated from rat within 7 days after administration in all groups. 14C-recoveries (expressed as percentages relative to the dosed 14C) in faeces and urine were 38-58 and 42-58% respectively in rat administrated trans-[alcohol-14C]tetramethrin, and in faeces and urine were 66-91 and 9-31% respectively in rat administered cis-[alcohol-14C]tetramethrin. 3. Fourteen metabolites found in excreta were purified by using several chromatographic techniques and identified by spectroanalyses (nmr and MS). Five sulphonate derivatives and three dicarboxylic acid derivatives were found. 4. The main metabolites were sulphonate derivatives in the faeces, and in the urine, alcohols, dicarboxylic acid and reduced metabolites derived from the 3,4,5,6-tetrahydrophthalimide moiety.     

Three-dimensional motion of the upper cervical spine in rheumatoid arthritis

Rheumatoid arthritis frequently contributes to instability of the upper cervical spine. Rotational instability of the upper cervical spine was evaluated in rheumatoid arthritis patients using biplanar x-ray photogrammetry. Three-dimensional cervical motion and the instantaneous axis of rotation of the atlas relative to the axis were evaluated in normal and rheumatoid arthritis patients during axial rotation in the horizontal plane. Anterior atlantoaxial subluxation did not increase during axial head rotation in either the atlantoaxial subluxation or the vertical subluxation groups, while the instantaneous axes of rotation were distributed posteriorly in the dens in the RA-normal group, but were widely scattered in the atlantoaxial subluxation group.     

Structural and electrophysiological analysis of annexin V mutants. Mutagenesis of human annexin V, an in vitro voltage-gated calcium channel, provides information about the structural features of the ion pathway, the voltage sensor and the ion selectivity filter

Annexin V binds to phospholipids in a calcium-dependent manner and exhibits calcium channel activity in vitro. We prepared a variety of mutants yielding information about the structure-function relationship of the ion channel activity. All mutants were characterized by X-ray crystallography, electron microscopy and electrophysiological measurements. Their structures are insignificantly changed whereas their electrophysiological properties are drastically different. Glu95, located in the central hydrophilic pore of the molecule, is crucial for the ion selectivity filter as its exchange leads to reduced calcium and increased sodium conductance. The removal of Glu17, located on the protein surface and far from the ion conduction pathway, leads to the appearance of a second conductance level of 9 pS in addition to the conductance level of about 30 pS in the wild-type molecule. This was also the case for Glu78, which is part of a weak calcium binding site. The exchange of Glu17 and Glu78 produced a mutant retaining only the smaller conductance level. We conclude that these two residues influence the angle between the two halves of the molecule, which determines the diameter of the ion conduction pathway, thereby leading to the occurrence of a second conductance level.