Circadian variations in the signs and symptoms of rheumatoid arthritis and in the therapeutic effectiveness of flurbiprofen at different times of day.

Abstract

1 Seventeen patients with rheumatoid arthritis were studied in a double‐ blind crossover trial contrasting three different times of administration of twice‐daily flurbiprofen. 2 Twelve of these patients were also studied when taking the same dose of flurbiprofen as a split dose four times a day. 3 Symptoms and signs of the disease were self‐ assessed throughout the day for several days on each regimen and the information was analysed for rhythmicity. 4 Twice a day flurbiprofen may be more effective than four times daily flurbiprofen, and the regimen without an evening dose was the least effective of three twice‐ daily treatments tested. 5 Circadian rhythms of grip strength and finger joint size were demonstrated, and were similar on all treatment regimens. 6 These rhythms have a similar pattern to those detected during studies of immune responses, and it is suggested that morning stiffness in rheumatoid arthritis is not only the result of nocturnal inactivity, and may respond to appropriately timed medication given to decrease inflammation or to suppress other aspects of the immune response.

Aspects of Human Chronopathology

“…Although the major symptoms of this common disease are pain, stiffness, and inflammation, systematic investigation of the temporal variation in these have been carried out only on a few occasions (Delbarre 1979;Kowanko et al 1981Kowanko et al , 1982bHarkness et al 1981Harkness et al , 1982. Circamensual and circannual studies using quantitative endpoints have never been conducted.…”

“…The symptoms and signs of rheumatoid arthritis vary within and between days (Scott 1960;Delbarre 1979;Kowanko et al 1981Kowanko et al , 1982aHarkness et al 1981Harkness et al , 1982. Although the major symptoms of this common disease are pain, stiffness, and inflammation, systematic investigation of the temporal variation in these have been carried out only on a few occasions (Delbarre 1979;Kowanko et al 1981Kowanko et al , 1982bHarkness et al 1981Harkness et al , 1982.…”

“…Circamensual and circannual studies using quantitative endpoints have never been conducted. The data of Kowanko et al (1981Kowanko et al ( , 1982a) are germaine to the discussion of circadian rhythms in the pain of rheumatoid arthritis. Figure 47 presents the data of a patient who self-monitored his rheumatoid arthritic symptoms 6 times daily (at approximately 3-hr intervals) during the waking span for 3 consecutive days while being treated with a nonsteroid antiinflammatory medication (100 mg flurbiprofen, Froben) daily at 1300 and 2300.…”

“…The acrophase of the rhythm in grip strength of the left and right hands was approximately 12 hr out of phase with those of the other circadian rhythms. Table 5 presents the data of another investigation (Kowanko et al 1981) in which 15 patients were studied while taking flurbiprofen at 1300 and 2300 daily for 14 days. Circadian variations in joint circumference (inflammation) were, as expected, greatest in the morning around 0700.…”

Predictable pulsatile release of tramadol hydrochloride for chronotherapeutics of arthritis

“…Finally, a controlled drug delivery system (CDDS) would be advantageous when a delay in absorption is desirable from a therapeutic point of view, particularly for the treatment of diseases that have peak symptoms in the early morning and that exhibit circadian rhythms, such as nocturnal asthma, angina, and rheumatoid arthritis (Kinget et al, 1998;Halsas et al, 1999;. In rheumatoid arthritis, symptoms are more exaggerated in the early morning (Scott, 1960;Kowanko et al, 1981) and night time medication is more beneficial (Schorn & Seymour, 1981). A pulsatile drug delivery system is helpful to avoid pharmacokinetic drug-drug interactions between concomitantly administered medications, to reduce dose size, to reduce dosing frequency so as to maximize patient compliance, to maximize desired effects, to minimize undesired effects, to localize drug at the right site in right quantity at right time, and to minimize systemic drug metabolism in the upper part of the gastrointestinal (GI) tract (Bussemer et al, 2001).…”