oh, sweet marie, I have no wordsI am surrendering you into God's loving hands and seeing you enfolded in His grace... and the doctors finding wisdom
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Fulvestrant AKA ICI 182,780 best given monthly as double dose in buttocks crosses BBB
ICI 182,780 Penetrates Brain and Hypothalamic Tissue and Has Functiona…ter Systemic Dosing -- Alfinito et al. 149 (10): 5219 -- Endocrinology
Articles by Alfinito, P. D. Articles by Deecher, D. C. Endocrinology, doi:10.1210/en.2008-0532 Endocrinology Vol. 149, No. 10 5219-5226 ICI 182,780 Penetrates Brain and Hypothalamic Tissue and Has Functional Effects in the Brain after Systemic Dosing Peter D. Alfinito, Xiaohong Chen, James Atherton, Scott Cosmi and Darlene C. Deecher Women’s Health and Musculoskeletal Biology (P.D.A., X.C., S.C., D.C.D.), Drug Safety and Metabolism (J.A.), Wyeth Research, Collegeville, Pennsylvania 19426 Address all correspondence and requests for reprints to: Darlene C. Deecher, Ph.D., Wyeth Research, RN 3164, 500 Arcola Road, Collegeville, Pennsylvania 19426. E-mail: deeched@wyeth.com. Previous reports suggest the antiestrogen ICI 182,780 (ICI) does not cross the blood-brain barrier (BBB). However, this hypothesis has never been directly tested. In the present study, we tested whether ICI crosses the BBB, penetrates into brain and hypothalamic tissues, and affects known neuroendocrine functions in ovariectomized rats. ICI crosses the BBB and penetrates into brain and hypothalamic tissues An earlier report suggested that ICI did not cross the BBB of OVX rats because it failed to block nuclear uptake of [3H]estradiol in hypothalamic tissue after once daily dosing at 1.0 mg/kg sc for 3 d (2). However, the ability of ICI to cross the BBB and penetrate brain tissues was not directly tested in these experiments. In the present study, the same dosing paradigm was followed as reported by Wade et al. (2) (Fig. 1A), and ICI levels were measured in plasma and brain (total brain minus hypothalamus and pituitary) and hypothalamic tissues over time. The ICI compound was detected in all samples and at all time points tested (Fig. 1B). The concentrations and pharmacokinetic profiles of ICI in plasma, brain, and hypothalamus were found to be similar (Fig. 1B and Table 1 ). ICI levels were stable in plasma and brain and hypothalamic tissues over the entire 24-h testing period, and the concentrations of ICI in plasma and hypothalamic tissue were similar at the 24-h time point. TABLE 1. Pharmacokinetic profile of ICI (1.0 mg/kg, sc, 3 d) in plasma and brain and hypothalamic tissues of OVX Sprague Dawley rats over time The ratio of brain to plasma exposure is an indication of a compound’s ability to cross the BBB. Based on 24-h exposure values, brain and hypothalamus to plasma ratios for ICI were 0.33 and 0.66, respectively (Table 1 ). These results demonstrate that ICI crosses the BBB, is present in brain and hypothalamic tissues, and persists at a constant level in plasma and brain and hypothalamic tissues for up to 24 h after systemic dosing. ICI blocks estrogenic actions in the MD model of hot flush but showed estrogenic-like effects when administered alone The MD model of hot flush is based on measuring naloxone-induced increases in TST in MD OVX rats (17, 23). Previous work indicates that estrogen’s ability to abate TST elevations in the MD model of hot flush occurs through its actions in the brain (18). To determine whether 11/6/08 8:20 AM ICI 182,780 Penetrates Brain and Hypothalamic Tissue and Has Functiona…ter Systemic Dosing -- Alfinito et al. 149 (10): 5219 -- Endocrinology P 3), these results demonstrate that ICI rapidly crosses the BBB and persists for an extended period of time in plasma and brain and hypothalamic tissues. Consistent with its ability to penetrate brain tissues, repeated systemic administration of ICI blocked the effects of EE on naloxone-induced TST elevations in the MD model of hot flush and on body weight change. Interestingly, ICI administration alone (1.0 or 3.0 mg/kg·d) demonstrated weak estrogenic-like activity in these models. We conclude that ICI is a brain-penetrable compound that can exert functional (antiestrogenic and estrogenic) effects in the CNS, and specifically the hypothalamus, after systemic dosing. Previous studies have concluded that ICI does not cross the BBB because at up to 1.0 mg/kg·d, it failed to block uptake of [3H]estradiol into nuclei of hypothalamic cells in OVX rats (2) and failed to mimic the effects of OVX on body weight gain and plasma gonadotropin levels in intact female rats (1). However, it is possible that these previous studies did not use a high enough dose to observe inhibitory effects on these endpoints. For example, despite the presence of ICI in brain and hypothalamic tissue after systemic administration of 1.0 mg/kg·d, we found that this dose of ICI did not inhibit the effect of EE on all functional endpoints. The 1.0 mg/kg·d dose of ICI did partially inhibit the effect of EE on TST increases in the MD model but did not block EE’s effect on body weight change. This functional selectivity may be explained by the fact that ICI’s inhibitory effect on different estrogen-mediated brain functions can vary depending on the endpoint being studied. For example, Steyn et al. (28) have shown that intracerebroventricular administration of ICI inhibited estrogen-induced GnRH pulse frequency but did not block estrogenic effects on progesterone receptor expression in the hypothalamus or on antepartum prolactin surges. The authors concluded that there might be a wide range of sensitivities to ICI in the brain that could cause variable results across different functional endpoints. Thus, it is possible that inhibition of [3H]estradiol uptake into nuclei of hypothalamic cells or blockade of estrogen’s effect on body weight change may require higher levels of ICI than other functional endpoints. This idea is supported by our results showing that ICI treatment at 3.0 mg/kg·d for 8 d did partially block the effect of EE on body weight change. Because some previous studies (1, 2) only tested ICI at up to 1.0 mg/kg·d, it is unknown if higher doses would have inhibited [3H]estradiol uptake into nuclei of hypothalamic cells in OVX rats, or induced body weight gain or increased plasma gonadotropin levels in intact female rats. Several lines of evidence suggest that estrogens regulate body weight primarily through central mechanisms that reduce meal size (15, 16, 29, 30, 31, 32). Lesions of the ventromedial nucleus of the hypothalamus blocked the effect of systemically administered EB on body weight change and food intake in OVX rats (29), infusion of estradiol directly into the paraventricular nucleus or medial preoptic nucleus of the hypothalamus reduced body weight and/or food intake in OVX rats (30, 31), and direct administration of EB to the hindbrain just above the nucleus 11/6/08 8:20 AM ICI 182,780 Penetrates Brain and Hypothalamic Tissue and Has Functiona…ter Systemic Dosing -- Alfinito et al. 149 (10): 5219 -- Endocrinology tractus solitarius reduced food intake in OVX rats (32). However, these results have not been reproduced in all laboratories (33), and several peripheral feedback mechanisms have been hypothesized. Therefore, it remains possible that the ability of ICI to block the effect of EE on body weight change in the present study could occur through peripheral not central mechanisms. However, direct involvement of peripheral mechanisms in mediating estrogens effect on body weight is lacking. It has been shown previously that estradiol treatment does not inhibit feeding by modulating orosensory stimuli (15, 16). Estradiol treatment can inhibit ghrelin-induced feeding, but this effect does not occur through reduction in meal size as is well established for estrogens (15). Estradiol does increase the satiating potency of cholecystokinin, but this effect likely occurs through an estradiol-induced increase in neuronal activity within the brainstem, not through regulation of signaling in the periphery (15, 16). Finally, leptin signaling does not appear to directly mediate estrogen’s effect on body weight because estradiol has reduced body weight and food intake in both leptin-deficient and leptin receptor-deficient mice (34). Thus, based on current evidence, estrogenic regulation of body weight appears to be mediated through central mechanisms, and is an appropriate endpoint for predicting whether ICI crosses the BBB and exerts functional effects in the CNS. The effect of ICI on body weight has been reported previously in intact cycling female rats and OVX estrogen-treated rats (2, 24). In these studies body weight changes were unaffected by daily ICI treatment at either 1 or 1.5 mg/kg·d (higher doses were not tested), and it was concluded that ICI did not cross the BBB. Our results are consistent with these studies because the ability of ICI to block EE’s effect on body weight change was not observed at the 1.0 mg/kg·d dose. However, at the higher dose (3.0 mg/kg·d), ICI treatment did block the effect of EE on body weight change. These data suggest that in previous studies in OVX rats, ICI may not have been administered at a high enough dose to block estrogenic effects on body weight regulation. The effect of ICI alone on body weight change in OVX rats has also been tested previously (2, 24). Results from these studies also suggest that body weight change is unaffected by ICI treatment at 1.0 or 1.5 mg/kg·d. These data are in contrast to our finding that ICI had weak estrogenic-like actions on body weight change at both 1.0 and 3.0 mg/kg·d. The discrepancy between the current work and previous studies is difficult to reconcile. There are several technical differences such as rat strain and vendor and total treatment length that might account for the discrepancy. One additional possibility is that the effect of ICI on body weight may vary depending on initial body weights. In the present work, initial body weights averaged 215 g, whereas in both other studies, initial body weights were approximately 270–276 g. It is possible that in heavier rats, ICI may have a greater volume of distribution, increased sequestration into adipose tissue, and/or increased plasma clearance. These possibilities are supported by studies showing that increased body mass can alter the pharmacokinetic properties of some drugs (35). 11/6/08 8:20 AM ICI 182,780 Penetrates Brain and Hypothalamic Tissue and Has Functiona…ter Systemic Dosing -- Alfinito et al. 149 (10): 5219 -- Endocrinology Therefore, the net result of these effects could be to reduce ICI exposure in brain tissue and limit its ability to stimulate ER signaling. Importantly, it is unlikely that rats in our study inadvertently received EE administration because uterine weights were similar to those from vehicle-treated rats (Fig. 4 ). Our results suggest that ICI has relatively low clearance in plasma and brain and hypothalamic tissues of OVX rats when administered at 1 mg/kg·d for 3 d, and can persist in all three compartments for at least 24 h after the last dose. In fact, the concentrations of ICI for each tissue were found to be similar at the 0.5 and 24-h time points (Fig. 1B). This relatively low clearance suggests that ICI could accumulate, particularly in lipid compartments such as brain and adipose tissues, after daily systemic administration. Although somewhat speculative, this type of accumulation could alter the pharmacokinetic and pharmacodynamic properties of ICI over time. Consistent with this idea, ICI treatment at 1 mg/kg·d for 2 d did not block the effect of EB on lordosis, ear wiggling, or hops and darts but reduced the effect of EB on all three parameters when administered at 1 mg/kg·d for 24 d (2). Thus, the potential functional effects of ICI on CNS-mediated endpoints may depend on both the doses tested and the time period over which dosing is conducted. A question that occurs is what are the relative roles of ER and β in mediating the effects of ICI on the endpoints measured in the current study (i.e. TST regulation in the MD model and body weight change). Because ICI binds to both receptors with similar affinities (36) and both receptors appear to have broad distribution in the brain, including the hypothalamus (37), the relative roles of the and β-subtypes are not easily discerned. Regarding body weight, several studies suggest that estrogen’s effect is ER mediated. In support of this idea, in two separate studies, the ER agonist 4,4',4''-(4-propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol decreased food intake and body weight in OVX rats, whereas the ERβ agonist 2,3-bis(4-hyroxyphenyl)- propionitrile had no effect (38, 39). In addition, EB had no effect on body weight and food intake in OVX ER knockout mice, suggesting that the β-subtype is insufficient to mediate the effect of estrogen on these endpoints (40). Finally, other studies have shown that estrogenic inhibition of feeding occurs through ER-expressing neurons located in the nucleus tractus solitarius (32). In contrast to these results, in a single study using oligonucleotide knockdown of ERs in the brain, only ERβ antisense probes blocked the effect of estradiol on body weight and food intake (41). However, the ability of their probes to reduce ER expression in the brain was not reported. Thus, based on current data, it appears that the effect of ICI on body weight change observed in the current study is mediated through the ER receptor subtype. However, this hypothesis will need to be confirmed in future studies. Less is known about the respective roles of the ER and β-receptor subtypes in temperature regulation. Both receptors have been implicated in the regulation of TST elevations in mice ICI 182,780 Penetrates Brain and Hypothalamic Tissue and Has Functiona…ter Systemic Dosing -- Alfinito et al. 149 (10): 5219 -- Endocrinology regulation. The antiestrogenic properties of ICI in the brain as well as uterine tissues have been well established (1, 28, 43, 44). However, results from our work and others suggest that ICI may not be a pure antiestrogen. Intrahippocampal infusion of ICI has mimicked the effect of EB on place learning in OVX rats (43). In addition, Sibonga et al. (24) have shown that, like 17 β- estradiol (45), ICI treatment (1.5 mg/kg·d) decreases the cancellous bone formation rate in OVX rats. Finally, in primary hippocampal neurons, both ICI and 17 β-estradiol promoted neuronal survival against excitotoxic- and β amyloid-induced cell death, induced rapid calcium influxes, increased spinophilin and Bcl-2 expression, and increased phosphorylation of ERK2 and Akt (25). Thus, ICI appears to have mixed antagonist and agonist properties, and its pharmacology now seems to be more similar to other selective ER modulators (SERMs), such as raloxifene and tamoxifen, then initially reported. The precise mechanisms supporting the mixed pharmacology of ICI are unknown, however, it may be related to the differential regulation of ER dimers in the absence or presence of an estrogen. It is well known that ER dimerization is a key step in the activation of estrogen signaling pathways. Using a yeast two- hybrid system, Wang et al. (46) found that ICI induced ER dimerization when given alone but destabilized ER dimers in the presence of an estrogen. Therefore, it is possible that ICI-induced receptor dimerization could lead to activation of estrogen responsive pathways, whereas destabilization of ER dimers in the presence of an estrogen would block signaling. In support of this idea, ICI was found to activate a subset of estrogen-responsive genes in MCF-7 cells, a breast cancer cell line, grown in hormone-depleted medium (47). Although this explanation might account for the antagonist and agonist-like effects of ICI observed in the MD model and on body weight change in the current study, it cannot be broadly applicable to all endpoints because ICI had no detectable estrogenic-like effect on uterine tissue. Currently, it is not well understood how the tissue-selective agonist/antagonist properties of SERMs, like ICI, tamoxifen, and raloxifene, manifest. It has been hypothesized that agonist/antagonist activities of SERMs result from specific ligand-induced conformational changes in ERs that alter coactivator/corepressor protein binding, and selectively influence different genomic and/or nongenomic signaling pathways (48). In addition, cell-specific promoter context could play a role in determining whether a SERM will elicit estrogenic or antiestrogenic actions. The clinical use of ICI is not likely to be altered significantly by the results from the present work. However, our results do offer a mechanistic explanation for the occurrence of hot flushes in premenopausal women treated with fulvestrant (8). In addition, the use of fulvestrant in premenopausal women would be expected to induce other CNS-related menopause-like 11/6/08 8:20 AM ICI 182,780 Penetrates Brain and Hypothalamic Tissue and Has Functiona…ter Systemic Dosing -- Alfinito et al. 149 (10): 5219 -- Endocrinology Psymptoms such as sleep disturbances, mood changes, loss of energy, weight gain, and decreased libido (49). Because most of these symptoms are not life threatening, it is unlikely that they would limit the use of fulvestrant for treating advanced breast cancer patients. Although we found that ICI has weak estrogenic-like activity on certain CNS-mediated functions, it is also unlikely that these results will affect the use of fulvestrant for treating breast cancer patients. Previous work has shown that ICI inhibits human breast cancer cell proliferation (1), and agonist-like activity would be inconsistent with the studies showing the utility of fulvestrant in treating ER-positive breast cancer (6, 7). In summary, we have shown that, in contrast to previous conclusions, ICI is capable of crossing the BBB, penetrating brain and hypothalamic tissues, and exerting functional effects on neuroendocrine endpoints after systemic administration. We have also found that ICI is not a pure antiestrogen, and may have a mix of both agonist and antagonist activities on certain CNS-mediated functions. Therefore, future studies should consider the potential for ICI to influence estrogen-related functions in the CNS after systemic dosing. |
this was the reference I was looking for
At the conference, Dr. Slamon said this man's results were the most amazing he had ever seen.
the most remarkable lecture I have heard in the last 5 years was the following Adoptive T-Cell Transfer for Metastatic Melanoma James Yang, MD National Institutes of Health at a conference in October hosted by Dr. Slamon He was, I believe, starting to try to do something simiilar with other cancers...or at least thinking of starting to as he stated he believed his method would be applicable to many other sorts of cancer. He only treats patients at the NIH and the patient's whose scans he showed and whose stories he told were widely metastatic. Perhaps trying to contact his office at the NIH??? |
Dear Marie,
I cannot stop my tears reading your post. I am praying for you and Mighty Oak. God has to guide you to the right doctors and give you both the strength to deal with this news and stay positive. Lots of love and peace, shobha |
Marie,
I'm just heartbroken to hear the news for Ed. I don't have any medical suggestions but I will certainly keep you two in my prayers. |
praying hard
Oh Marie, I have such a lump in my throat and an ache in my heart. You are the epitome of loving support and words will fall short of conveying my heartache at your saddness and today's new.
Sending you back all the loving support you have given out.....which is A LOT!!! Holding you in prayer tonight and always, Maureen p.s. I am such a rookie so I hope this is not a stupid question, but what about Tykerb (crosses the blood brain barrier)...? Is that an option? |
Marie,
I know where you have been living....in hope. Stay there. Stay there. |
Marie,
Please know that I am praying for you both. Keep believing in Ed's miracle. Begin to thank God already for delivering him. Kim |
Dear Marie - My body thinks I should be asleep now (9 time zones a lot to adjust in 2 days!), but I just had to check in. Your news jerked me right awake!
I am too dazed now to have any more ideas than Lani has put forward. The Boswellia was coming to mind as I read the start of this thread, but some of the other ideas may have an even better chance. Pattyz as usual has come through with her latest research. You have so much to come to grips with right now, so keep remembering we are sending you all the love and energy we can. We will all keep "watering" the Mighty Oak tree and try to see you both through this rough patch. Lots of love to you both. |
Marie,
My heart is breaking for you and Ed. Know that PRAYERS ARE COMING YOU'RE WAY. Eric |
Marie ~
I am so saddened to read this about Mighty Oak Ed...you both are in my thoughts and prayers. I wish I had some insight of what to do but just know how deeply you and Ed are loved. Ruth |
Marie, I so did not want to read this.
I am keeping you and Ed in my thoughts and prayers. I am praying for the doctors who will find the next right thing for Ed. |
Marie,
This is one of those times when words are not enough. Please tell Ed that we are all pulling for him. Stay strong. |
To Marie and Ed,
You are an inspiration in how to live. Your love for each other, and the caring you share here and, I'm sure, in the rest of your lives is amazing. Please know that I am praying for the greatest good for you both. Rebecca |
Marie, it just sickened me to read your post. We have all come to love and care about you and Ed so much. You know that you have my prayers always. Don't lose hope and never stop believing.
love and hugs to you both |
Marie
Holding you and Ed deep in my heart and in my prayers Keep on Believing! |
Hi Marie,
I am so sorry for the terrible news. I send my warm thoughts to you and the Mighty Oak. I took the liberty of doing some quick research on clinical trials for treating brain metastases from breast cancer. Links to a few that looked promising are set forth below. Most are in Massachussetts, with one at Dana Farber and another at Tufts. My guess is that you live in Mass. since you mentioned seeing a Dana Farber oncologist. The other one is at UCSF in San Francisco, where I am being treated. Other obvious treatment ideas are Tykerb and Xeloda, if the Mighty Oak hasn't tried them. Take care of yourself. Best, Jill http://www.clinicaltrials.gov/ct2/sh...astases&rank=4 http://www.clinicaltrials.gov/ct2/sh...stases&rank=15 http://www.clinicaltrials.gov/ct2/sh...stases&rank=20 http://www.clinicaltrials.gov/ct2/sh...stases&rank=42 |
You guys are simply the light in my life and add to the quality of my world, I am too without words. I was touched when I logged on and felt hope even though this looks terrible for him.
We went for a long ride to his Mom's old home to check the mail. Passing over the reservior tonight the sun went down behind giant patches of fog. I envisioned this as my mind and the voices that were screaming in it....cloudy but still able to see some sunshine through the haze.......the water was freakishly calm. Looking out at this calm water which I have passed hundreds of times made me think that this is how I need my mind to be. I am breathing and still numb but need you to know how I appreciate the way you can make me see. When finished we went to grab dinner, well he had Apple Pie w/extra vanilla ice cream, I had dinner (lol). He had to get some air so I stayed and followed his instructions to buy desserts for my Mom and Dad. Of course they got a visit and a dessert delivery, delivered by Sir Mighty Oak himself. Yes my Lovey's, this man is unreal. On the way home he asked me to call MD Anderson Monday (I will try online to contact tonight). He told me as he smiled and looked deep into my eyes, "I will have no one 'write me off'". Ed knows that OncoMan has not given up and there is much work to do, but he is gearing up with only prayers and hope in his pockets. Now that's my boy. He did let me know that now is the time I cannot push him. I will provide him with all his options, long shots and travel plans and await their approval. It is fruitless to ask you not to be so sad because I cry with your sagas also. I am asking for you all to just be the pure and loving friends you are and know I can only do this with your help. Prayers and positive thoughts, wish us one last miracle. Thank you so much for allowing me to be sad here and for the sadness I have passed to you.>>Marie PS: I Love You Santa Claus aka Lani, you are a gift in your own right. The hope and ammo you always supply in our war time allows us to be better Warriors. You have inspired me once more. |
what i meant
marie,I want you to know that when I said I was surrendering you, that did not mean I am giving up hope. merely acknowledging the enormity of what you and ed are dealing with, and that it is beyond my power to heal.I don' have the answers but I knew others would come forth with ideas.Miracles do not happen because of me but they do happen.love and prayers to both of you
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Oh Chrisy, knowing and loving you for 2 years has allowed me to know what you meant. Fret about those jelly fish getting too close to you instead. (smiling hard)>>Marie
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