Safety and pharmacokinetic study with escalating doses of 3-acetyl-7-oxo-dehydroepiandrosterone in healthy male volunteers

OBJECTIVES: To evaluate the safety and pharmacokinetics of 3-acetyl-7-oxo-DHEA (3beta-acetoxyandrost-5-ene-7,17-dione) given orally. DESIGN: A randomized, double blind, placebo-controlled, escalating dose study. SETTING: The Chicago Center for Clinical Research. PARTICIPANTS: Twenty-two healthy men. STUDY METHOD: The participants received placebo (n = 6) or 3-acetyl-7-oxo-DHEA (n = 16) at 50 mg/d for 7 days followed by a 7-day washout; 100 mg/d for 7 days followed by a 7-day washout; and 200 mg/d for 28 days. OUTCOME MEASURES: Safety parameters, evaluated at each dose level, included measurement of total testosterone, free testosterone, dihydrotestosterone, estradiol, cortisol, thyroxin and insulin levels. Analyses for 7-oxo-DHEA-3beta-sulfate (DHEA-S), the only detectable metabolic product of the administered steroid, were conducted on plasma drawn from all subjects at 0.25, 0.5, 1, 2, 4, 6 and 12 hours after the final 100 mg dose of 3beta-acetyl-7-oxo-DHEA. RESULTS: There were no differences in the clinical laboratory values or in reported minor adverse experiences, between treatment and placebo groups. In general, blood hormone concentrations were unaffected by the treatment with 3beta-acetyl-7-oxo-DHEA and remained within the normal range. No changes in vital signs, blood chemistry or urinalysis occurred during treatment with 3beta-acetyl-7-oxo-DHEA compared to placebo. The administered steroid was not detected in the blood but was rapidly converted to 7-oxo-DHEA-S, the concentrations of which were proportional to dose. This steroid sulfate did not accumulate; plasma concentrations 12 hours after the 3beta-acetyl-7-oxo-DHEA dose at 7 and 28 days on the 200 mg/d dose were 15.8 and 16.3 microg/L respectively. The mean time to peak plasma level of 7-oxo-DHEA-S was 2.2 hours; the mean half life was 2.17 hours. The apparent clearance averaged 172 L/h, and the apparent mean volume of distribution was 540 L. CONCLUSION: These results indicate that 3beta-acetyl-7-oxo-DHEA is safe and well tolerated in normal healthy men at doses up to 200 mg/d for 4 weeks.     

Cytokine gene polymorphisms in the Dutch population

Numerous studies have shown that variations in the production and activity of cytokines influence the susceptibility and/or resistance to various infectious agents, autoimmune diseases, and cancer, as well as the predisposition to allograft rejection. Differences in the production of cytokines between individuals are often caused by single nucleotide polymorphisms (SNP) in the promoter or coding regions of cytokine genes. The cytokine polymorphisms of 107 unrelated Caucasian individuals originating from various parts of the Netherlands were studied and compared with the results of two European (Czech and Italian) populations. Twenty-two SNPs of 13 different cytokine genes were analysed. To test the Hardy-Weinberg equilibrium, allele frequencies were estimated by direct gene counting. Evaluation of the allele frequencies of the Dutch, Italian and Czech populations showed that five SNPs were significantly different between the Dutch and the Italians, while these SNPs did not vary between the Dutch and the Czechs. This analysis, in combination with other types of immune profiling, may be helpful for prediction of the clinical outcome of various infectious and immune-related disorders, as well as for estimation of the risk for rejection and graft vs. host disease after organ or stem cell transplantation.     

Compressive chylothorax after lumbar spine fracture

A 14-year-old boy was admitted to the hospital after an episode of blunt trauma to the thorax, resulting in a Chance fracture of L1 and a compressive chylothorax 72 h after admission. After initial drainage in the operating room, conservative management was successful. This case study documents one of the rare complications of spinal fractures in the context of high-energy blunt trauma. It is the first detailing a noniatrogenic post-traumatic compressive chylothorax in pediatrics responding positively to conservative management. Drainage should be considered the first-line procedure for both therapeutic and diagnostic purposes. Surgery is required if the leakage is still present after parenteral feeding and the implementation of a fat-free diet for 5–7 days.     

Characterization of three new HLA-B alleles: B*35:05:03, B*52:29 and B*57:01:13

Three new HLA-B alleles were identified during routine sequence-based typing.     

Characteristics of alloreactive T cells measured before renal transplantation

Several assays to measure pre-existing allospecific T cell immunity in renal transplant candidates have been developed in the past years. In 46 patients, we used flow cytometry-based mixed lymphocyte culture to measure the precursor frequency and phenotype of alloreactive T cells before renal transplantation, using donor-specific or third-party cells for allostimulation. Allostimulation induced up-regulation of co-stimulatory molecules, chemokine receptors relevant for migration of T cells into the graft and effector proteins. Recipients prone for acute rejection had a higher precursor frequency of alloreactive CD8(+) T cells and a lower percentage of interleukin (IL)-7Rα expressing alloreactive CD8(+) T cells than non-rejectors. These data point to quantitative and qualitative differences between T cells of patients who will experience acute cellular rejection episodes from those who will not.     

Antinuclear antibody and HLA-B27 positive uveitis: combination of two diseases?

AIMS/BACKGROUND—Anterior uveitis associated with juvenile chronic arthritis concerns two different clinical entities: firstly, antinuclear antibody (ANA) positive patients who have a chronic anterior uveitis with severe complications and often a poor visual prognosis; secondly, usually HLA-B27 positive children, predominantly boys, with unilateral recurrent anterior uveitis. Three patients are described who had a combination of clinical and laboratory features of both diseases.
METHODS—Retrospective clinical and laboratory analysis of three patients.
RESULTS—Ocular features in the three patients combined the clinical picture of ANA positive chronic anterior uveitis during early childhood with the clinical features of HLA-B27 unilateral acute anterior uveitis during adolescence. The patients fulfilled the diagnostic criteria of juvenile chronic arthritis, and they had no ankylosing spondylitis. All three patients had the HLA-B*2705 subtype.
CONCLUSIONS—Whether the association of ANA positive chronic anterior uveitis and HLA-B27 unilateral acute anterior uveitis is a coincidence or represents a distinct clinical entity is not yet clear.

     

Enzymatic adaptation to physical training under beta-blockade in the rat. Evidence of a beta 2-adrenergic mechanism in skeletal muscle.

Nonselective and beta 1-selective adrenergic antagonists were tested for their effects on enzymatic adaptation to exercise training in rats as follows: trained + placebo (TC); trained + propranolol (TP); trained + atenolol (TA); and corresponding sedentary groups, SC and SP. Trained rats ran 1 h/d at 26.8 m/min, 15% grade, 5 d/wk, 10 wk. Both beta-antagonists were given at doses that decreased exercise heart rates by 25%. Training increased skeletal muscle citrate synthase, cytochrome c oxidase (Cyt-Ox), carnitine palmitoyltransferase (CPT), beta-hydroxyacyl coenzyme A dehydrogenase, mitochondrial malate dehydrogenase (MDH), and alanine aminotransferase (ALT) activities significantly in the TC group, but not in TP. These enzyme activities, except Cyt-Ox and CPT, were also significantly increased in TA. Hepatic phosphoenolpyruvate carboxykinase activity did not alter with training or beta-blockade. Fructose 1,6-bisphosphatase activity was lower in TC than in SC, but unchanged in TP or TA. Hepatic mitochondrial MDH and ALT activities increased with training only in TC. It is concluded that beta 2-adrenergic mechanisms play an essential role in the training-induced enzymatic adaptation in skeletal muscle.