Raloxifene administration

Genazzani AR, Lombardi I, Borgioli G, di Bono I, Casarosa E, Gambacciani M, Palumbo M, Genazzani AD, Luisi M (2003) Adrenal function under long-term raloxifene administration. Gynecol Endocrinol 17 159-168... 

Colacurci N, Manzella D, Fornaro F, Carbonella M, Paolisso G (2003) Endothelial function and menopause effects of raloxifene administration. J Clin Endocrinol Metab 88 2135-2140... 

It is also important to note that, as happened with tamoxifen, this decrease in risk concentrated exclusively in ER(+) tumors. ER status was determined for 88 cases, and 75% of these were considered positive. The decrease in risk in-ducedby raloxifene administration during the total 8 years of MORE plus CORE reached 76% of the invasive ER(+) cases, compared with the placebo group (0.8 vs. 3.2 cases per 1000 woman-years HR=0.24 95% Cl = 0.15 to 0.40). There was no influence of the raloxifene treatment on the incidence of ER(-) invasive tumors (0.53 versus 0.51 cases per 1000 woman-years HR = 1.06 95% Cl = 0.43 to 2.59). This confirms the hypothesis that raloxifene exerts its protective effect through its binding to breast cell ERs, avoiding the proliferative effect of estrogens to take place. Consequently ER(-) tumors cannot be influenced by the presence of raloxifene in the blood, and no difference in its incidence should be expected between placebo and treated groups (Cauley et al. 2001) (Fig. 10.11). 

Palomba S, Orio F Jr, Morelli M, Russo T, Pellicano M, Zupi E, Lombardi G, Nappi C, Benedetti Panici PG, Zullo F (2002a) Raloxifene administration in premenopausal women with uterine leiomyomas a pilot study. J Clin Endocrinol Metab 87 3303-3308... 

Palomba S, Orio F Jr, Russo T, Falbo A, Cascella T, Doldo P, Nappi C, Lombardi G, Mastrantonio P, Zullo F (2004c) Long-term effectiveness and safety of GnRH agonist plus raloxifene administration in women with uterine leiomyomas. Hum Reprod 19 1308-1314... 

Fig. 14.7. Influence of raloxifen administration depends on age and time elapsed since menopause (redrawn from Davies et al. 1999 and Ettinger et al. 1999)...

To illustrate the different actions of both groups of antiestrogens, Table 6.1 presents the tissue-specific effects obtained with the administration of type I (tamoxifen and raloxifene) and type II (ICI 164384 and fulvestrant) antiestrogens in preclinical studies. 

Other SERMs are currently under development. Diaz Curiel et al. (1998) have proved that a raloxifene analog, LY117018 HC1, is effective in reducing bone loss in OVX rats. In addition, the administration of the substance permits a significant reduction in the minimal effective dose of human parathyroid hormone (PTHh) required in the treatment of osteopenic rats (Hodsman et al. 1999a,b). Two more compounds, FC1271a 41 and HMR-3339 (Ammann et al. 2004), show promising results in preclinical studies. 

Raloxifene seems to have pharmacological proprieties that make its administration useful in women with endometriosis. Raloxifene, in fact, has been investigated in animal models with good results. Furthermore, just as with the other novel therapies for endometriosis, original articles on the effect of raloxifene on this condition are still lacking. 

Raloxifene is actually used for the treatment and prevention of postmenopausal osteoporosis. Also, if raloxifene has been shown to have any effect on uterine leiomyomas in vitro and in animal models, to date no concrete efficacy has been demonstrated in normally cycled premenopausal women. Moreover, the addition of raloxifene to GnRH-a administration can be useful for limiting GnRH-a-related side effects and increasing the rate of reduction in tumor size. 

Absorption - Raloxifene is absorbed rapidly after oral administration with approximately 60% of an oral dose adsorbed. However, presystemic glucuronide conjugation is extensive and absolute bioavailability is only 2%. 

Alternatives to steroid hormone therapy for osteoporosis include raloxifene, bisphosphonates, sodium fluoride, vitamin D and calcium supplementation, calcitonin, and parathyroid hormone. Tamoxifen has estrogenic effects on bone and delays bone loss in postmenopausal women. However as a result of estrogenic activity in the uterus, long-term tamoxifen administration has been associated with an increased risk of... 

Thirty-seven weeks after ovariectomy, marked decreases of 73% (p <. 01) and 77% (p <. 01) in trabecular bone volume and trabecular bone number (data not shown), respectively, were observed at 1 to 5 mm of the growth plate metaphyseal junction of the proximal tibia. Simultaneously, a marked increase in trabecular bone separation from a control value in intact rats of 262 19 to 1486 236 pm (p <. 01) was observed in OVX animals. Treatment with 1 mg/kg of EM-800 and raloxifene resulted in 68% (p<. 01) and 64% (p <. 01) reversals, respectively, of the decrease in trabecular bone volume caused by ovariectomy. In fact, treatment with EM-800 and raloxifene at the daily 1 mg/kg dose increased trabecular bone volume of the proximal tibia from a control value of 5.8 0.9% in OVX animals to 16.4 0.4% and 15.8 1.0%, respectively. These stimulatory effects are not statistically different from the 53% reversal achieved with E2. At the lowest dose used (0.01 mg/kg), EM-800 already reversed by 34% (p <. 01) the elfect of OVX whereas raloxifene had no detectable effect. The administration of 0.1 mg/kg of EM-800 and raloxifene, on the other hand, resulted in 40% (p <. 01) and 24% (p <. 05) reversals, respectively, of the decrease in trabecular bone volume caused by OVX. 

Figure 27 (see color insert) illustrates the prevention of trabecular bone volume in the proximal tibial metaphysis induced by EM-800 and raloxifene in ovariectomized treated animals compared with OVX controls (Fig. 27B). The administration of 0.01 mg/kg of EM-800 (Fig. 27D) already prevented by 52% the OVX-induced osteopenia, whereas raloxifene had no detectable elfect at the same dose (Fig. 27F). Treatment...

We also compared the effect of increasing doses of EM-800 and raloxifene on serum cholesterol levels (Fig. 29). Thirty-seven weeks after ovariectomy, a 35% increase (p<. 01) in serum cholesterol was observed in OVX control rats compared with intact controls. The daily oral administration of even 0.01 and 0.03 mg/kg of EM-800 to OVX animals caused respective 54% (p <. 01) and 56% (p <. 01) reductions of serum cholesterol levels relative to OVX controls, raloxifene administered at the same doses caused respective 24% (p <. 01) and 41% (p <. 01) decreases in the same parameter. When administered in daily doses of 0.1, 0.3, and 1 mg/kg, EM-800 caused respective 58%, 58%, and 66% inhibitions (all p <. 01 versus OVX control rats) of serum cholesterol levels, and raloxifene caused respective 60%, 62%, and 65% decreases of this parameter at the same doses (all p <. 01). The E2 implant, on the other hand, only reduced serum cholesterol by 20% (p <. 01) compared with OVX control rats. 

Table 2 offers a summary of clinical parameters for several representative ER modulators, showcasing similarities and differences across scaffolds. Thus the benzothiophene molecule raloxifene (1) and both TPEs tamoxifen (4) and toremifene (6) provide oral bioavailability, while the steroid-like molecule fulvestrant (9) requires administration via intramuscular injection. On the other hand, all three oral treatments require daily dosing, in contrast with monthly administration for the injectable, consistent with the relative values of elimination half-life. 

Raloxifene is rapidly absorbed following oral administration. It then undergoes extensive first-pass metabolism (presystemic glucuro-nidation). 

ANION EXCHANGE RESINS RALOXIFENE Raloxifene levels may be i by coleslyramine Coleslyramine interrupts the enterohepatic circulation of raloxifene Avoid co-administration... 

In many studies the administration of estrogens has been shown to diminish infarct size in the rabbit model in which the LAD was ligated.157,158 This result has been ascribed to a Ca2+-activated potassium channel opening effect of these agents. These data may explain the relative immunity from the complications of CAD in women at the menstruating age. More recently, the synthetic estrogen-action product raloxifene has also shown favorable effects in the canine heart,159 despite its lack of effect in the rabbit.158... 

Calcitonin therapy results in decreased bone resorption. Osteoclasts have calcitonin receptors and calcitonin inhibits their activity. Sodium fluoride stimulates bone formation by unknown mechanisms. In women with osteoporosis, fluoride therapy produced an increased bone mineral density but no reduction in the rate of vertebral fractures. Other drugs known as selective estrogen receptor modulators (raloxifene, droloxifene, idoxifene, and levormeloxifene) may provide an alternative to estrogen replacement therapy (Chapter 34). Administration of low doses of PTH [or recombinant PTH( 1 -34)] does not affect serum calcium concentration, promotes bone formation, and increases mineral density. This anabolic action of PTH is probably mediated by decreasing osteoblast apoptosis. 

I Administration. Overall, raloxifene therapy is well tolerated, but hot flushes occasionally cause women to discontinue therapy (see Table 88-6). Raloxifene use is associated with a threefold increased risk of venous thromboembolism, similar to the increased risk seen in women taking estrogens. Raloxifene is contraindicated for those with active thromboembolic disease. Therapy should be stopped if a patient anticipates a signiflcant period (several hours or more) of immobility. Raloxifene does not induce endometrial bleeding. 

Raloxifene is adsorbed rapidly after oral administration and has an absolute bioavailability of about 2%. The drug has a half-life of about 28 hours and is eliminated primarily in the feces after hepatic glucuronidation it does not appear to undergo significant biotransformation by cytochrome p450s (CYPs). 

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