Dosing Time‐Dependent Effect of Raloxifene on Plasma Fibrinogen Concentration in Ovariectomized Rats

Abstract

The chronopharmacological effect of raloxifene, a selective estrogen-receptor modulator, was evaluated by repeated dosing of ovariectomized rats. Bilateral ovariectomy or sham operation was performed at age 12 wks, and animals were kept in rooms with a 12 h light-12 h dark cycle. Raloxifene (3 mg/kg, once daily for 10 wks) or vehicle was given repeatedly at either 2 h after lights-on (2 HALO) or 14 h after lights-on (14 HALO). Plasma fibrinogen concentration at the end of the study was reduced by the drug, and the reduction was significantly prominent in rats in whom the drug was dosed at 2 HALO rather than 14 HALO. Femur bone density decreased, and urinary excretion of deoxypyridinoline, an index of bone resorption capacity of osteoclasts, increased in ovariectomized animals at the end of the study. Treatment with raloxifene ameliorated these changes in a dosing time-independent manner. Serum calcium, ALT, and total protein concentrations at the end of the study also did not differ according to treatment regime, which indicates that protein synthesis and liver function may not contribute to the effects. This is the first study to determine dosing time-dependent changes in the efficacy of raloxifene in an animal model of osteoporosis. Because fibrinogen concentration is reported to be a marker of cardiovascular events, consideration of dosing time of raloxifene may be important to obtain a better cardioprotective effect of this medication when it is prescribed to postmenopausal women with osteoporosis.

Hemostatic Effects of Raloxifene in Ovariectomized Rats

“…In 2001, Cushman reported that Rx appears to have more positive effects than hormone replacement therapy in lowering fibrinogen [36]. Therefore, when Rx is prescribed to postmenopausal women with osteoporosis, it is fundamental to take into consideration the dosing times in order for plasma levels not to increase to a concentration where the cardioprotective effect is lost [37]. Our findings support past reports in mice that stated that 4 months of treatment with Rx attenuates intravascular thrombosis.…”

Ethics and Methods for Biological Rhythm Research on Animals and Human Beings

“…), timing (in reference to the wake-sleep or LD cycle), and dose/intensity of usual treatments. Research papers pertaining to chronopharmacology-administration-time (relative to the sleep-wake, menstrual, or annual cycle) differences in the pharmacokinetics and pharmacodynamics of chemical agents such as medications-are expected to state the rationale for the choice of the clock times, menstrual days, and/or months/seasons of treatment(s) (Bruguerolle, 2008;Dispersyn et al, 2008;Iurisci et al, 2009;Kawahara et al, 2008;Lemmer & Arraj, 2008;Tsuruoka et al, 2008). Finally, some research protocols may make use of special experimental designs involving forced-desynchrony, constant-routine, or timeisolation protocols, and these should be described in sufficient detail.…”

Do Restless Legs Syndrome (RLS) and Periodic Limb Movements of Sleep (PLMS) Play a Role in Nocturnal Hypertension and Increased Cardiovascular Risk of Renally Impaired Patients?

“…Chronomedicine is the study of the chronobiology of health and disease and the translation of applicable findings to clinical medicine (Portaluppi, 2007). In the past few years, in particular, a chronobiological approach has been extensively used in medical research, leading to a better understanding of the pathophysiological mechanisms and features of many medical conditions and public health problems (Burioka et al, 2008;Colognesi et al, 2007;Kawahara et al, 2008;Lee et al, 2008;Leibowitz et al, 2007;Leiza et al, 2007;Lin et al, 2008;Mbanu et al, 2007;Ohkura et al, 2007;Perez-Lloret et al, 2008;Sadick et al, 2007;Sallinen et al, 2008;Shah et al, 2007;Tsai et al, 2007) as well as greater insight of therapeutic issues (Boulamery et al, 2007;Bruguerolle, 2008;Coudert et al, 2008;Dispersyn et al, 2008;Dridi et al, 2008;Hermida, 2007;Hermida et al, 2007bHermida et al, , 2008Prados et al, 2007;Smolensky et al, 2007;Tsuruoka et al, 2008).…”