Treatment To Lower Androgen Levels From Other Parts Of The Body
LHRH agonists and antagonists can stop the testicles from making androgens, but cells in other parts of the body, such as the adrenal glands, and prostate cancer cells themselves, can still make male hormones, which can fuel cancer growth. Some drugs can block the formation of androgens made by these cells.
Abiraterone blocks an enzyme called CYP17, which helps stop these cells from making androgens.
Abiraterone can be used in men with advanced prostate cancer that is either:
- Castration-resistant
This drug is taken as pills every day. It doesnt stop the testicles from making testosterone, so men who havent had an orchiectomy need to continue treatment with an LHRH agonist or antagonist. Because abiraterone also lowers the level of some other hormones in the body, prednisone needs to be taken during treatment as well to avoid certain side effects.
Ketoconazole , first used for treating fungal infections, also blocks production of androgens made in the adrenal glands, much like abiraterone. It’s most often used to treat men just diagnosed with advanced prostate cancer who have a lot of cancer in the body, as it offers a quick way to lower testosterone levels. It can also be tried if other forms of hormone therapy are no longer working.
Ketoconazole also can block the production of cortisol, an important steroid hormone in the body, so men treated with this drug often need to take a corticosteroid .
Bic Induces Late Apoptosis Of Rmc Cells
When viewed with combined Annexin V and 7-AAD staining, late apoptosis was seen to have occurred after treatment with Bic . The apoptotic population increased in a dose- and time-dependent manner. After 24h of treatment, the late apoptotic population had increased from 15.75% in the control to 26.03% and 32.36% at 30 and 60M, respectively. In contrast, after being treated for 48h, the corresponding values increased from 24.26% for the control to 53.36% and 58.95%, respectively, while no significant change was seen for early apoptosis , apparently supporting the occurrence of late apoptosis. Bic was implicated as an underlying cause of cancer cell apoptosis,. This is believed to be the first report about late apoptosis elicited by Bic in mesangial cells. On the other hand, Bic showed no apparent suppressive effect on the viability of NRK52E cells . We wondered could such a phenomenon as apoptosis be relevantly associated with an alternate cell protective effective that has always been called autophagy? Results seemed to make this unlikely, because that was no trace of LC3-phosphatidylethanolamine conjugate-II detected at 48h . Contrasting this phenomenon associated with NRK52E cells, Bic seemed to play a role of mainly inducing apoptosis of RMC cells. Speculating that such an apoptotic effect might be associated with the caspase signaling pathway, we performed the following study.
Figure 4
Safety Data From Clinical Studies Using Bicalutamide 150 Mg
Bicalutamide 150 mg is not approved for use either alone or with other treatments.
Two identical multi-center, randomized, open-label trials comparing Bicalutamide 150 mg daily monotherapy to castration were conducted in patients that had locally advanced or metastatic prostate cancer.
Monotherapy M1 Group
Bicalutamide 150 mg daily is not approved for use in patients with M1 cancer of the prostate. Based on an interim analysis of the two trials for survival, the Data Safety Monitoring Board recommended that Bicalutamide treatment be discontinued in the M1 patients because the risk of death was 25% and 31% higher in the Bicalutamide treated group compared to that in the castrated group, respectively.
Locally Advanced Group
Bicalutamide 150 mg daily is not approved for use in patients with locally advanced cancer of the prostate. Following discontinuation of all M1 patients, the trials continued with the T3-4, NX, M0 patients until study completion. In the larger trial , the risk of death was 25% higher in the Bicalutamide group and in the smaller trial , the risk of death was 36% lower in the Bicalutamide group.
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Medical And Dental Treatment
If you need medical treatment for any reason other than cancer, always tell the doctors and nurses you are having cancer treatment. Give them the contact details for your cancer doctor so they can ask for advice.
If you think you need dental treatment, talk to your cancer doctor or nurse. Always tell your dentist you are having cancer treatment.
When To Contact Your Team
Your doctor, nurse or pharmacist will go through the possible side effects. They will monitor you closely during treatment and check how you are at your appointments. Contact your advice line as soon as possible if:
- you have severe side effects
- your side effects arent getting any better
- your side effects are getting worse
Early treatment can help manage side effects better.
We haven’t listed all the side effects here. Remember it is very unlikely that you will have all of these side effects, but you might have some of them at the same time.
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Casodex And Other Medications
Below is a list of medications that can interact with Casodex. This list does not contain all drugs that may interact with Casodex.
Before taking Casodex, talk with your doctor and pharmacist. Tell them about all prescription, over-the-counter, and other drugs you take. Also tell them about any vitamins, herbs, and supplements you use. Sharing this information can help you avoid potential interactions.
If you have questions about drug interactions that may affect you, ask your doctor or pharmacist.
Casodex and warfarin
Warfarin is an anticoagulant drug thats used to treat or prevent blood clots. Casodex can increase the effect of warfarin in your body. This can raise your risk for bleeding.
If you take warfarin, youll need to have extra blood tests to check how long it takes your blood to clot. This test is called the international normalized ratio . Your INR will be checked when you start taking Casodex and regularly throughout your treatment. Based on your results, your doctor may need to lower your warfarin dose.
Casodex and certain drugs that are broken down in your liver
Certain drugs are broken down in your body by enzymes found in your liver. One important enzyme thats involved in breaking down several different drugs is called CYP3A4.
Examples of drugs that could have an increased risk of side effects when taken with Casodex include:
How Long Does It Take To Work
Casodex will start to block testosterone receptors as soon as you start to take it. However, its not known how quickly this affects the cancer cells. Each persons cancer is likely to respond slightly differently to the treatment.
Talk with your doctor about when you may start to see results from taking Casodex.
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What Are The Side Effects Of Bicalutamide
When bicalutamide and an LHRH analog are given together, the most common side effect is hot flashes and facial flushing. Alcohol may worsen this reaction, and so it should be cautiously consumed.
Other common side effects of the combination are:
LHRH analogs may increase blood glucose and worsen diabetes. Less common side effects are breast enlargement and breast pain, which may be due to the bicalutamide alone.
Drugs That Stop Androgens From Working
Anti-androgens
For most prostate cancer cells to grow, androgens have to attach to a protein in the prostate cancer cell called an androgen receptor. Anti-androgens are drugs that also connect to these receptors, keeping the androgens from causing tumor growth. Anti-androgens are also sometimes called androgen receptor antagonists.
Drugs of this type include:
They are taken daily as pills.
In the United States, anti-androgens are not often used by themselves:
- An anti-androgen may be added to treatment if orchiectomy or an LHRH agonist or antagonist is no longer working by itself.
- An anti-androgen is also sometimes given for a few weeks when an LHRH agonist is first started. This can help prevent a tumor flare.
- An anti-androgen can also be combined with orchiectomy or an LHRH agonist as first-line hormone therapy. This is called combined androgen blockade . There is still some debate as to whether CAB is more effective in this setting than using orchiectomy or an LHRH agonist alone. If there is a benefit, it appears to be small.
- In some men, if an anti-androgen is no longer working, simply stopping the anti-androgen can cause the cancer to stop growing for a short time. This is called the anti-androgen withdrawal effect, although it is not clear why it happens.
Newer anti-androgens
Enzalutamide , apalutamide and darolutamide are newer types of anti-androgens. They can sometimes be helpful even when older anti-androgens are not.
These drugs are taken as pills each day.
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Md And Fep Simulations
Following equilibration we used a variety of MD based simulations to explore the configurational landscape available to Bcu and the residues comprising the HBS. MD simulations were performed in an NVT ensemble with a cutoff of 12.0Å for coulombic interactions and 9.0Å for Van der Waals interactions. The pragmatic approach to the intractability of carrying out simulations with infinite cutoffs is problematic and has led to differing approaches and recommendations. Cheatham et. al. recommend the use of particle mesh Ewald as superior to a cutoff. However, Norberg, J., and Nilsson, L. point out these conclusions were drawn for a 9 Å cutoff and have shown results similar to PME are obtained with conditions used here without the introduction of the artifactual infinite lattice coulombic interactions of PME in a system designed to emulate solution conditions. The studies of ligand binding to AR by Bisson et. al. were performed using similar conditions to ours but with the somewhat smaller cutoff of 9 Å. Nevertheless this remains an open issue and is one of the reasons we have used multiple simulations and techniques. A timestep of 2fs was employed with a Nose-Hoover thermostat with a coupling parameter of 0.1 . After equilibration, the simulations were continued out to 5.3ns.
Side Effects And Risks
Casodex and Xtandi can cause some similar side effects and others that differ. Below are examples of these side effects.
More common side effects
These lists contain examples of more common side effects that can occur with Casodex, with Xtandi, or with both drugs .
- Can occur with Casodex:
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Functional Analysis Of Altered Protein
Bioinformatics analysis of the 1.8-fold differentially expressed proteins was performed using the Kyoto Encyclopedia of Gene and Genome enrichment analysis program. The apoptosis pathway was chosen in the KEGG category. Functional analysis of the 1.8-fold differentially expressed proteins was conducted using Metacore GeneGo software.
Advantage Over Antiandrogens And Other Agents
Enzalutamide lacks the partial agonist activity notable with other nonsteroidal antiandrogens, and, given its activity not just as an inhibitor of the androgen receptor, but preclinically to inhibit nuclear translocation of the AR and inhibit the association of AR with DNA, further differentiates it from other antiandrogens . Enzalutamide represents the third pharmaceutical agent to significantly increase survival in men with CRPC following docetaxel . While there have been no comparative studies between the other 2 agents, cabazitaxel and abiraterone acetate , the HRs are similar between all 3 of the agents. It is important to note that the abiraterone acetate and cabazitaxel studies had control arms that included agents with antitumor activity compared with placebo-controlled arm in the AFFIRM study. Approximately 30% of patients in both the AFFIRM enzalutamide and placebo arms were receiving corticosteroids at baseline, which was associated with reduced survival regardless of study treatment . Overall, enzalutamide has a favorable toxicity profile. Unlike cabazitaxel, enzalutamide was not reported to cause neuropathy or myelosuppression, 2 significant toxicities that can lead to morbidity and limit additional therapy in patients with CRPC .
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Protein Extraction And Sample Preparation And Tryptic Digestion
The cellular protein concentration was assessed using the Bradford assay . LNCaP and RWPE-1 cell protein samples were reduced using 5mM Trisphosphine for 30 min at 37°C. The samples were alkylated by treating them with 15 mM iodoacetamide and then they were left for 1 h at 25°C rotated at 300 r/min in the dark. The samples were then treated with mass-spectrometry grade Trypsin Gold overnight at 37°C. The chemical reagent was removed using C18 cartridges .
How Should This Medicine Be Used
Bicalutamide comes as a tablet to take by mouth. It is usually taken with or without food once a day, either in the morning or evening. Take bicalutamide at around the same time every day. You should begin taking bicalutamide on the same day you begin injecting the luteinizing hormone-releasing hormone. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Take bicalutamide exactly as directed. Do not take more or less of it or take it more often than prescribed by your doctor.
Bicalutamide along with the luteinizing hormone-releasing hormone may help stop the growth and spread of cancer cells but does not cure prostate cancer. Continue to take both bicalutamide and the luteinizing hormone-releasing hormone even if you feel better. Do not stop taking these medications without talking to your doctor.
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Early Versus Delayed Treatment
For men who need hormone therapy, such as men whose PSA levels are rising after surgery or radiation or men with advanced prostate cancer who dont yet have symptoms, its not always clear when it is best to start hormone treatment. Some doctors think that hormone therapy works better if its started as soon as possible, even if a man feels well and is not having any symptoms. Some studies have shown that hormone treatment may slow the disease down and perhaps even help men live longer.
But not all doctors agree with this approach. Some are waiting for more evidence of benefit. They feel that because of the side effects of hormone therapy and the chance that the cancer could become resistant to therapy sooner, treatment shouldnt be started until a man has symptoms from the cancer. This issue is being studied.
Are The Intrinsic And Er Stress Pathways Involved In The Process Of Renal Damage
Suspecting the possibility that the intrinsic pathway might be involved in Bic-induced RF,, we examined expressions of apoptotic and antiapoptotic proteins, and ER stress-related calpain-1 and caspase-12. Bic at a dose 15M seemed to have slightly upregulated the Bcl-2 and Bax protein . As a consequence, the Bax/Bcl-2 ratio remained unchanged . On the other hand, calpain-1, caspase-12 and cleaved caspase-12 proteins were entirely unaffected , implying that they obviously have no involvement in the intrinsic and ER stress pathways.
Figure 6
Effect of bicalutamide on expression of proteins related with the intrinsic and ER stress pathways. The intrinsic pathway related proteins Bcl-2 and Bax. The ERassociated calpain-1 and caspase-12 proteins. Western blots were performed in triplicate and quantified . LG: low glucose 5.5mM E: Etoptoside 2M.
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Financial And Insurance Assistance
If you need financial support to pay for Casodex, help is available.
Medicine Assistance Tool lists programs that may help lower the cost of Casodex. For more information and to find out if youre eligible for support, visit the program website.
You should take Casodex according to your doctors or healthcare providers instructions.
The Extrinsic Pathway Upregulated By Bic Is Attenuated By Co
As mentioned, Bic was able to inhibit both the cytosolic and nuclear AR so, we further examined whether testosterone could competitively and efficiently attenuate such a phenomenon and associated signaling pathways. As we found, TNF- and cleaved caspase-3 were all ameliorated by co-treatment with testosterone at a dose of 100nM, and it seemed that TNFR and p-PI3K were not significantly affected by testosterone . In contrast, p-Akt was prominently attenuated at a testosterone dose of 500nM.
Figure 9
Dose dependent effect of co-treatment with testosterone and bicalutamide on the survival and apoptotic pathways in the RMC cells. TNF- and TNFR. Total and phosphorated PI3K, PDGF-R, and Akt. Caspase-3 and cleaved caspase-3. Experiment was performed in triplicate and statistically treated . The symbol * compares within the same group and # compares among groups. *p< 0.05, **p< 0.01, ***p< 0.001. #p< 0.05, ##p< 0.01, ###p< 0.001.
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Recommended Dose And Schedule
The recommended dose for Bicalutamide therapy in combination with an LHRH analog is one 50 mg tablet once daily , with or without food. It is recommended that Bicalutamide tablets be taken at the same time each day. Treatment with Bicalutamide tablets should be started at the same time as treatment with an LHRH analog. If a dose of Bicalutamide tablets is missed, take the next dose at the scheduled time. Do not take the missed dose and do not double the next dose.
System Setup And Equilibration
The AR-ligand complexes were solvated with ~10,000 water molecules in a dodecahedral box extending 6Å around the receptor, using genbox . In addition five chloride counterions were added to neutralize the system . The solvated system was then minimized, with heavy atoms restrained to reorient hydrogen atoms. Following minimization we carried out 10ps of MD, at 0.1°K followed by 10ps at 306°K with restraints of 1000 kJ /nm2 on the protein heavy atoms to allow the solvent structure to accommodate to the protein complex. Further equilibration of the system for 200 ps at 306°K, using weaker restraints of the protein heavy atoms to their crystallographic positions, allowed distorted geometry and steric clashes in less well-determined regions of the protein to be relaxed.
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Plasticity Of The Hormone Binding Pocket Determining Ligand Functionality
In figure 6 we focus on the hormone binding site, to explore the detailed mechanism by which Bcu antagonizes the androgen response. Although the agonist activity of Bcu in the W741L mutant is fairly definitive in identifying W741 as playing a key role in the determination of a ligand’s functional consequences , it is not the sole determinant. This is demonstrated compellingly by the activity of the selective agonist S1 in WT AR . The substitution of anNO2 at the para position on the A-ring is unlikely to be related to the agonist activity of S1 as many, if not most, antiandrogens have this functional group . In addition, the B-ring is retained in S1. The result of structural studies, shown in Fig 6a, reveal how this is accomplished in the S1 complex but precluded with Bcu .
We also note the configuration of M745 found in the AR S1 and W741L Bcu complexes, which accommodates the rotation of Trp741 is incompatible with the A-ring axial methyl group in DHT . Thus we would surmise for example that a substitution on the A-ring of S1 occupying the C19 position of DHT might reposition M745 in turn forcing Trp back into the B-ring pocket and converting the S1 analog into an antagonist much as the sulfonyl linkage in bicalutamide does acting through M895.