Enantioselective sulfation of beta 2-receptor agonists by the human intestine and the recombinant M-form phenolsulfotransferase.

The beta 2-receptor agonist class of drugs is metabolized in humans almost exclusively by sulfate conjugation. The objective of this investigation was to determine the influence of chemical structure on the stereoselectivity of the sulfoconjugation of these chiral drugs. The pure enantiomers of six beta 2-agonists, including those clinically most widely used, were all effectively sulfated both by the cytosol of the human intestine and the recombinant human M-form phenolsulfotransferase (PST). Whereas the apparent Km values (Km,app) for the sulfation of the individual drug enantiomers by the intestinal cytosol varied widely, ranging from 4.8 microM for (S)-isoproterenol to 889 microM for (S)-albuterol, these Km,app values were highly correlated with those obtained with M-PST (correlation coefficient 0.994). In contrast, the M-PST Vmax,app values were similar for all drug enantiomers, ranging from 276 to 914 pmol min-1 mg-1 protein, implying that substrate binding to M-PST by far is the main determinant of the sulfation activity. For isoproterenol, the Km,app for M-PST was 6.1 times higher for the active (R)- than for the inactive (S)-enantiomer. For other beta 2-agonists, the stereoselectivity decreased towards unity as the Km,app increased. However, for albuterol, containing a hydroxymethyl substituent at the aromatic ring, the stereoselectivity was dramatically reversed, with 10 times higher Km,app for the inactive (S)- than for the active (R)-enantiomer.

Frequency of infections among rheumatoid arthritis patients, before and after disease onset.

The self-reported frequency of genitourinary and bronchopulmonary infections in postmenopausal women with rheumatoid arthritis (RA) and in postmenopausal women with osteoarthritis and/or soft tissue rheumatism was compared. Neither before, nor after the onset of joint disease was a higher frequency reported by the RA patients. The previously established increased mortality from infectious disease among RA patients might be due to a more severe infectious disease course, leading to an increased case-fatality rate.

Noncontraceptive hormones and rheumatoid arthritis in perimenopausal and postmenopausal women.

The use of noncontraceptive hormones before onset of joint disease was compared between 490 perimenopausal and postmenopausal women with rheumatoid arthritis and a control group of 659 women with soft-tissue rheumatologic disorders and/or osteoarthritis. Both groups were sampled randomly from the attendees of five rheumatologic clinics. A negative association was found between the onset of rheumatoid arthritis and the previous use of noncontraceptive hormones (odds ratio, 0.32; 95% confidence interval, 0.16 to 0.64). This association persisted on univariate and multivariate control of potentially confounding variables and on subgroup analysis. The protective effect of oral contraceptives on the development of rheumatoid arthritis was confirmed.

The occurrence of malignancies in patients with rheumatoid arthritis treated with cyclophosphamide: a controlled retrospective follow-up.

In a retrospective follow-up we compared the incidence of malignancies in patients with rheumatoid arthritis treated with cyclophosphamide with that in another group of patients with rheumatoid arthritis and also with the incidence of malignancies in the general population. Among 81 patients treated with cyclophosphamide in the past decade 15 malignancies occurred. This was 4.1 times the expected number obtained from a closely matched control group of patients with rheumatoid arthritis not treated with cytotoxic drugs (95% confidence interval 1.5 to 19.0), and 3.7 times the expected number calculated from general population rates (95% confidence interval 2.1 to 5.9). The increase in haematological and lymphoreticular malignancies was specially notable. The data also indicate that the development of malignancies after the start of cyclophosphamide therapy necessitates a certain induction time and that it is to some extent dose-dependent.