Interleukin-1-inhibitory IgG in sera from some patients with rheumatoid arthritis

Inhibition of interleukin-1 alpha (IL-1 alpha) activity was detected in 7 of 41 serum samples from patients with rheumatoid arthritis (RA). These 7 sera inhibited not only IL-1 alpha-induced endothelial cell adherence to neutrophils, but also IL-1 beta-induced endothelial cell adherence, although to a lesser extent. These sera showed no influence on tumor necrosis factor-induced endothelial cell adherence. No inhibitory activity was found in 40 sera from normal control subjects. Studies to further examine these effects included gel filtration analysis of 2 of the RA sera. The inhibitory activity was eluted near Mr 158 kd and above Mr 250 kd. Analysis by protein A affinity chromatography showed that IL-1-inhibitory activity was present in protein A-binding fractions. Purified IgG (by DE-52 column chromatography) from RA patients was found to be as potent an inhibitor as the protein A-binding fractions, which suggests that the major inhibitory activity in RA sera is attributable to IgG molecules. These purified IgG molecules also inhibited IL-1-induced proliferation of mouse thymocytes but did not influence IL-2-dependent proliferation of the CTLL-2 murine T cell line. The 7 patients whose sera showed IL-1-inhibitory activity had mild RA and low titers of rheumatoid factor. The findings, taken together, suggest a possible regulatory role of IL-1-inhibitory IgG in RA disease activity.     

Topics of glucocorticoids--centered on therapy for rheumatoid arthritis

Glucocorticoids (steroids) have been widely used for the treatment of patients with rheumatoid arthritis (RA) since Hench had attempted to administer cortisone (Kendall's compound E) to an active RA patient in 1948. Rheumatologists even in the 21st century can learn a lot from the history of steroid. In this feature article on steroid, a brief outline of 11β-hydroxysteroid dehydrogenase type 1, a tissue-specific regulator of steroid response, is presented. The isozyme re-activates inactive cortisone (compound E) to active cortisol (compound F), and seems to play an important role particularly in adipose tissue. In addition, I give an account of non-genomic mechanisms of steroid, which might be relevant to early and rapid effects during methylprednisolone pulse therapy. As for the field of practical rheumatology, rates and dosages of steroid administration for RA in Japan are shown, by looking into 3 large observational cohort researches and post-marketing surveillance programs for several biologics. The definition or an appropriate interpretation of medical/technical terms such as 'effectiveness' in the clinical setting and 'low-dose' steroid is also described.     

High P-selectin expression and low CD36 occupancy on circulating platelets are strong predictors of restenosis after coronary stenting in patients with coronary artery disease

Recent studies have shown that circulating platelets play an important role in the development of restenosis early after coronary stent implantation. We investigated P-selectin expression and CD36 blockade on platelets by flow cytometry in 48 consecutive patients who underwent coronary stenting. P-selectin expression was significantly higher 1 day after stenting in patients who had restenosis (n = 15) than in those who had no restenosis (n = 28), and the odds ratio for restenosis in patients with high P-selectin levels (MFI > 6.5) was 11.67 (P < 0.001) as compared with patients who had intermediate and low P-selectin levels. CD36 blockade was assessed with the use of two anti-CD36 antibodies, OKM5 and GS95 (our new anti-CD36 antibody), the binding of which indicates total CD36 amount and free CD36 unoccupied by lipid-related ligands, respectively. Binding of OKM5 to platelets was similar before and after stenting in both groups. CD36 blockade on platelets was seen 1 day after stenting in the non-restenosis group, and the odds ratio for restenosis in patients without CD36 blockade [GS95 binding ratio >0.8 as compared with binding before stenting] on day 1 was 28.60 (P < 0.001). P-selectin expression and unoccupied CD36 on platelets shortly after stenting may be strong predictors of post-stent restenosis.     

In Vitro penetration of a novel oxaborole antifungal (AN2690) into the human nail plate

Onychomycosis is a challenging fungal infection to treat topically, likely due to the unique properties of the nail plate. This seemingly impenetrable barrier has high resistance to the passage of antifungal drugs in sufficient concentrations to kill the causative fungi deep in the nail bed. Recently, a new class of antifungal agent was described, termed oxaboroles, which have broad-spectrum activity. These oxaboroles were designed with properties believed to be required to allow for easier transit through the nail plate. Herein, we report (i) the nail penetration results of four oxaboroles that led to the selection of AN2690, (ii) the results of the nail penetration of AN2690 from four vehicles, and (iii) the nail penetration of AN2690 in its chosen vehicle compared to a commercial control, ciclopirox. AN2690 has superior penetration compared to ciclopirox, and achieves levels within and under the nail plate that suggest it has the potential to be an effective topical treatment for onychomycosis.     

Pharmacogenetics of disease modifying anti-rheumatic drugs

There are large differences in the effectiveness of disease modifying anti-rheumatic drugs(DMARD) from one person to the next. Adverse drug reactions caused by DMARD can also occur to some patients, but do not occur to others. One possible cause of the differences in the effectiveness and adverse drug reactions is genetic variation in how individuals metabolize drugs. The Human Genome Project heralds new opportunities for using information about genetic variation to predict responses to drug therapies, called pharmacogenetics. Based on pharmacogenetics, tailor-made drug therapy is going to be realized. Our recent studies revealed the relationship between genetic polymorphisms of drug metabolizing enzymes and the efficacy of methotrexate or sulfasalazine in patients with rheumatoid arthritis, suggesting pharmacogenetics is applicable to the treatment of rheumatoid arthritis.     

Melatonin, a pineal secretory product with antioxidant properties, protects against cisplatin-induced nephrotoxicity in rats

In an attempt to define the role of the pineal secretory melatonin and an analogue, 6-hydroxymelatonin (6-OHM), in limiting oxidative stress, the present study investigated the cisplatin (CP)-induced alteration in the renal antioxidant system and nephroprotection with the two indolamines. Melatonin (5 mg/kg), 6-OHM (5 mg/kg), or an equal volume of saline were administered intraperitoneally (i.p.) to male Sprague Dawley rats 30 min prior to an i.p. injection of CP (7 mg/kg). After CP treatment, the animals each received indolamine or saline every day and were sacrificed 3 or 5 days later and plasma as well as kidney were collected. Both plasma creatinine and blood urea nitrogen increased significantly following CP administration alone; these values decreased significantly with melatonin co-treatment of CP-treated rats. In the kidney, CP decreased the levels of GSH (reduced glutathione)/GSSG (oxidized glutathione) ratio, an index directly related to oxidative stress. When animals were treated with melatonin, the reduction in the GSH/GSSG ratio was prevented. Treatment of CP-enhanced lipid peroxidation in the kidney was again prevented in animals treated with melatonin. The activity of the antioxidant enzyme, glutathione peroxidase (GSH-Px), decreased as a result of CP administration, which was restored to control levels with melatonin co-treatment. Upon histological analysis, damage to the proximal tubular cells was seen in the kidneys of CP-treated rats; these changes were prevented by melatonin treatment. 6-OHM has been shown to have some antioxidative capacity, however, the protective effects of 6-OHM against CP-induced nephrotoxicity were less than those of melatonin. The residual platinum concentration in the kidney of melatonin co-treated rats was significantly lower than that of rats treated with CP alone. It is concluded that administration of CP imposes a severe oxidative stress to renal tissue and melatonin confers protection against the oxidative damage associated with CP. This mechanism may be reasonably attributed to its radical scavenging activity, to its GSH-Px activating property, and/or to its regulatory activity for renal function.     

Glucocorticoid receptor in patients with lupus nephritis: relationship between receptor levels in mononuclear leukocytes and effect of glucocorticoid therapy.

We investigated the clinical significance of glucocorticoid receptor determination in 20 patients with systemic lupus erythematosus (SLE) who afterwards developed nephrotic syndrome. Glucocorticoid receptor concentrations in mononuclear leukocytes (MNL) in these patients were comparable with those in both other patients with SLE and healthy persons. Improvement in urinary protein excretion and in disease activity, which was scored according to the SLE Disease Activity Index system of the University of Toronto, closely related to the glucocorticoid receptor concentrations in MNL isolated from the corresponding patients. In summary, glucocorticoid receptor determination in patients with lupus nephritis may be a predictive clue for assessing responsiveness to glucocorticoid therapy.