Prostate Gland Protection and Natural Prostate Health

Prevent And Heal Prostate Problems

The Extensive Guide To Prevent And Heal Prostate Problems Including Prostate Cancer, Bph Enlarged Prostate And Prostatitis. This New Book Explains How To Cure Your Prostate Problem Naturally Without The Devastating Side Effects Of Medical Treatments. With Healthy Prostate at your fingertips, you'll quickly identify the best treatment option for whatever prostate condition you have. You'll gain a thorough understanding of the prostate, how it works, the disease conditions that can affect it and which one you have or how to prevent problems in the first place. You'll learn about toxins and other environmental factors in the food we eat, the air we breathe, even the water we drink that can have devastating effects on your prostate health and what you can do to combat them. Including: 12 warning signs that you may have benign prostatic hyperplasia. Which nation has the highest incidence of prostate cancer? The 11 healthiest foods you can eat and 10 foods you should avoid at all costs. How prostate illness increases your chance of urinary tract and kidney infection. 8 ways to treat prostatitis without prescription medications or surgery. 5 reasons why you should want to keep your prostate as healthy as possible. Why drinking milk may cause your prostate to become inflamed.

Prevent And Heal Prostate Problems Summary

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Prostate Cancer

Results from a second multicenter Phase II study of GVAX vaccine, designed for the treatment of prostate cancer, were recently reported. The trial found that for 22 patients with advanced hormone-refractory metastatic prostate cancer who were receiving the highest dose, the final median survival was not less than 24.1 months, compared with 18.9 months for patients treated with Taxotere and prednisone. A Phase III clinical trial is presently underway of GVAX in combination with Taxotere and prednisone.

Long Term Effects Tumorigenicity

A flare phenomenon is a well-documented effect of hormonal therapies and or hormone-responsive tumors. A prostate-specific antigen flare occurred in four of 28 patients who received liposomal doxorubicin (Caelyx) for symptomatic androgen-independent prostate cancer (40).

Combination of Radiation with Hormonal Ablation

A special situation emerges when the combination of radiation with a hormonal ablative measure is analyzed. As supported by several large randomized trials, the immediate combination of hormonal ablation with radiotherapy is of crucial value for the treatment of locally advanced high-risk prostate cancer (Boiia et al. 2002 RoACh et al. 2003). The underlying mechanisms of the interaction remain unclear so far. Initially, it was speculated that apop-tosis induction via hormone withdrawal is responsible for the efficacy of the combined treatment however, a detailed experimental analysis revealed that although a supra-additive induction of apop-tosis occurred after treatment of LNCaP cells with radiation and androgen deprivation (AD), this did not translate into an altered radiation sensitivity per se (Poiiack et al. 2001). The experimental setting used is this paper, however, does not allow the determination of the proportion of the clonogenic cells killed solely by the growth conditions...

Microscopic Evaluation

Quality control of herbal drugs has traditionally been based on appearance and today microscopic evaluation is indispensable in the initial identification of herbs, as well as in identifying small fragments of crude or powdered herbs, and detection of foreign matter and adulterants. A primary visual evaluation, which seldom needs more than a simple magnifying lens, can be used to ensure that the plant is of the required species, and that the right part of the plant is being used. At other times, microscopic analysis is needed to determine the correct species and or that the correct part of the species is present. For instance, pollen morphology may be used in the case of flowers to identify the species, and the presence of certain microscopic structures such as leaf stomata can be used to identify the plant part used. Although this may seem obvious, it is of prime importance, especially when different parts of the same plant are to be used for different treatments. Stinging nettle...

Inhibition Of Pi3k Signaling In Tumor Cells

A number of groups have used gene therapy approaches to demonstrate the relevance of PI3-K signaling in tumorigenesis. Adenoviral-mediated transfer of PTEN has been shown to inhibit proliferation and metastasis of orthotopic prostate tumor cells (100) and colorectal cancer cells (101). Treatment of bladder cancer cell models with adenoviral PTEN results in complete regression of the tumor (102). In addition, downregulation of VEGF and decreased microves-sel density was observed. Inhibition of PI3-K gene expression by RNA interference has also provided further evidence for the role of PI3-K in cancer cell proliferation and tumor growth. Transient transfection of HeLa cells with siRNA directed against p110p blocks HeLa cell growth on matrigel in vitro and tumor growth when transplanted in vivo (103). A stable, inducible shRNA system for studying PI3-K signaling has also been described (104). In a prostate tumor model, expression of shRNA directed against p110p reduced the formation of...

Animal and in vitro toxicology

Long-term toxicology studies with THC were carried out by the National Institute of Mental Health in the late 1960s (8). These included a 90-day study with a 30-day recovery period in both rats and monkeys and involved not only D9-THC but also D8-THC and a crude extract of marijuana. Doses of cannabis or cannabinoids in the range 50-500 mg kg caused reduced food intake and lower body weight. All three substances initially depressed behavior, but later the animals became more active and were irritable or aggressive. At the end of the study the weights of the ovaries, uterus, prostate, and spleen were reduced and the weight of the adrenal glands was increased. The behavioral and organ changes were similar in monkeys, but less severe than those seen in rats. Further studies were carried out to assess the damage that might be done to the developing fetus by exposure to cannabis or cannabinoids during pregnancy. Treatment of pregnant rabbits with THC at doses up to 5 mg kg had no effect on...

Nonanticoagulant uses

Both direct and indirect antitumor actions of anticoagulants have been postulated on the basis of experimental findings in animals (5). Warfarin given alone or in combination with cytostatic drugs reduces the size of fibrosarcomas in animals (5,6) and of osteosarcomas in man (7), and consequently prolongs survival times in both. The Cooperative Studies Program of the Veterans Administration Medical Research Service suggests that, among patients with various tumors, those with small-cell carcinoma of the lung had a significantly longer survival (about 4 years instead of 2) when warfarin was added to standard treatment (8). There were no differences in survival between warfarin-treated and control groups for advanced non-small-cell lung cancers, colorectal, head and neck, and prostate cancers (9). However, the contention that cancer morbidity and or mortality is reduced in anticoagulated patients is not substantiated by the results of a retrospective study of 378 patients who had been...

Family Cucurbitaceae A L de Jussieu 1789 nom conserv the Cucumber family

Pharmaceutical interest Classical examples of Cucurbitaceae are Cucumis sativus L. (cucumber), Cucumis melo L. (melon) and Citru-lus lanatus (Thunb.) Mansf. (Watermelon). Cucurbitaceae have attracted a great deal of interest on account of the production of cucurbitacins which are highly toxic (LD50 1 mg Kg in mice by intraperitonneal injection), and imparted to the plants that contain them bitterness, and drastic laxative and emetic properties. Examples of laxative drugs from Cucurbitaceae are Bryonia cretica L. subsp. dioica (Jacq.) Tutin (bryony), the dried pulp of Citrullus colocynthis (L.) Schrad. (bitter gourd) (Colocynth, British Pharmaceutical Codex, 1963) and the dried sediment which deposits in the juice of Ecballium elaterium (L.) A. Rich. (wild cucumber, squirting cucumber) (Elaterium, British Pharmaceutical Codex, 1934). The fresh seeds of Cucurbita pepo L. (pumpkin) (Cucurbita, British Pharmaceutical Codex, 1934) and Cucurbita maxima have long been used to expel...

Its getting harder every day

For most men sexual dysfunction in the form of erectile dysfunction comes without an effect on the desire to have sex. Simply put, they don't get their F-on because they can't get their F-on, not because they don't want to get their F-on. So, for many men, drugs like Viagra are real life-changers. Many doctors are concerned that the drug allows men to ignore the underlying cause of the problem though. This is of particular concern because erectile dysfunction can be a side-effect of serious blood pressure problems, heart disease and a host of other medical conditions. It is also common in men who have their prostate removed during cancer therapy.

Cannabinoid Receptor Agonists with Selectivity for CBX or CB2 Receptors

Although by far the highest concentrations of CB1 and CB1(a) mRNA are to be found in the CNS (Galiegue et al., 1995 Shire et al., 1995), it has been possible, largely by the application of reverse transcription coupled to the polymerase chain reaction, to demonstrate the presence of both these mRNAs in many peripheral tissues. Outside the CNS, the highest levels of human CB1 mRNA are in pituitary gland and immune cells, particularly B-cells and natural killer cells (Galiegue et al., 1995). As detailed by Pertwee (1997), other peripheral tissues of human, dog, rat and or mouse that contain CB1 mRNA include immune tissues (tonsils, spleen, thymus, bone marrow), reproductive tissues (ovary, uterus, testis, vas deferens, prostate gland), gastrointestinal tissues (stomach, colon, bile duct), superior cervical ganglion, heart, lung, urinary bladder and adrenal gland. CB1(a) mRNA is thought to exist as a minor transcript, the ratio of CB1(a) to CB1 mRNA in humans never exceeding 0.2 and, in...

Cannabinoid Binding Sites

Anterior pituitary gland although not in a wide range of other rat tissues including thymus, reproductive tissues (ovary, uterus, testis, vas deferens, prostate gland), gastrointestinal tract, heart, lung, urinary bladder and adrenal gland. Results from binding assays with 3H CP 55,940 using membrane preparations obtained from tissue homogenates have confirmed the presence of specifie cannabinoid binding sites in spleen cell membranes (Kaminski et al., 1992 Rinaldi-Carmona et al., 1994) and also demonstrated the presence of such binding sites in guinea-pig small intestine and pregnant mouse uterus (Paterson and Pertwee, 1993 Das et al., 1995). Most published binding data provide no information about the types of cannabinoid receptors present in peripheral tissues as they have been obtained with receptor probes that bind equally well to CB1 and CB2 receptors or whose relative affinities for CB1 and CB2 binding sites are unknown. An exception is an investigation carried out by...

Inhibitors of 14ademethylase and 17ahydroxylase

One procedure for the treatment of metastatic prostate cancers that do not respond to antiandrogens is the administration of ketoconazole, an imidazole derivative that is primarily used as an antifungal agent because it inhibits the biosynthesis of ergosterol, a key component of fungal membranes. Ketoconazole inhibits 14a-demethylase, a cytochrome P450 enzyme necessary for the conversion of lanosterol to ergosterol (in fungal cells) or to cholesterol (in mammalian cells), by coordination of the unsubstituted nitrogen atom to the iron atom in the active site. Since cholesterol is the precursor of all steroidal hormones, in a route that involves the participation of several other cytochrome P450 enzymes (Fig. 3.23), high doses of ketoconazole lead to androgen deprivation.38 The use of ketoconazole as an antiandrogen normally involves short treatments due to its toxicity, and normally it is associated with corticoids to prevent adrenal insufficiency. Another compound acting in this...

Organs and Systems Cardiovascular

In a randomized study of 180 patients with anemia due to hormone-refractory prostate cancer, who were treated with epoetin beta 1000 IU or 5000 IU subcutaneously 3 times a week for 12 weeks, cardiovascular events were more frequent with the higher dosage. Four patients had deep vein thrombosis and two had myocardial infarctions all were taking the higher dosage. However, only one of the patients with deep vein thrombosis had a high hemoglobin concentration (21).

General adverse effects

Men taking estrogens generally do so in the course of palliative treatment for malignancies (prostatic carcinoma), for which high doses have sometimes been used. Estrogen therapy in men with prostate cancer may be superior to castration in terms of efficacy, but orally administered estrogens are associated with adverse effects gynecomastia, loss of sexual function, and unacceptable cardiovascular toxicity (9). Low-dose estrogens in combination with anti-androgens or antithrombotic agents may be better tolerated.

Other features of the patient

Swedish workers have sought to develop a test system to define men who have a higher risk of cardiovascular complications when they take estrogens for cancer of the prostate (189). An investigational battery using exercise stress testing, evaluation of the peripheral circulation, blood volume estimation, chest X-ray, blood tests including hormonal status, lipoproteins, and antithrombin III, and history and physical examination taken by a cardiologist is claimed to make it possible to classify 84 of estrogen-treated patients as individuals with or without a particular risk of a cardiovascular complication and to identify an extremely high-risk subgroup.

Combinations of Cytotoxic Drugs Ionizing Radiation and EGFR Inhibitors

Overexpression of EGFR is sometimes associated with the expression of mutated species. One mutant EGFR, named EGFRvIII, lacks a portion of the extracellular ligand-binding domain, leading to a constantly active tyrosine kinase (HuANg et al. 1997). EGFRvIII is not found in normal tissues but is expressed on the cell membrane in certain tumours including gliomas, prostate, breast, non-small cell lung, colorectal and ovarian cancers (Mosc tEllo et al. 1995). Mutations of the EGFR kinase domain have also been reported, and recent studies indicate that its frequency is rare in most types of human cancer apart from that of lung adenocarcinoma (Sihto et al. 2005). Studies of a large number of lung tumour patients identified a frequency of 24 for EGFR mutations in the tyrosine kinase domain (exons 18-21) with a higher incidence for female, young, non-smoking patients. Importantly, these mutations seem to identify distinct subsets of lung cancer patients with an increased response to an...

Transcription Factors

Curcumin may operate through suppression of various transcription factors, including nuclear factor-kappa B (NF-kB), signal transducer and activator of transcription 3 (STAT3), early growth response protein 1, activator protein 1 (AP-1), peroxisome proliferators-activated receptor gamma (PPAR-y), and P-catenin 13, 14, 19 . These transcription factors play essential roles in various diseases. The constitutively active form of NF-kB has been reported in a wide variety of cancers. NF-kB is required for the expression of genes involved in cell proliferation, cell invasion, metastasis, angiogenesis, and resistance to chemotherapy. Bharti et al. demonstrated that curcumin inhibited IL-6-induced STAT3 phosphorylation and consequent STAT3 nuclear translocation 20 . Activation of PPAR-y inhibits the proliferation of nonadipocytes. Xu et al. demonstrated that curcumin dramatically induced expression of the PPAR-y gene and activated PPAR-y 21 . AP-1, another transcription factor that has been...

Overexpression of Protein Kinases

Expression of EGFR and its associated primary ligands epidermal growth factor (EGF) and transforming growth factor a (TGF-a) has been studied in several human malignancies with coexpression of EGFR and EGF observed to have both prognostic significance and a possible role in the pathogenesis of several human cancers. Specifically, overexpression of EGFR and EGF in several tumor types significantly reduces patient prognosis. For example, members of the EGFR kinase family (EGFR, ErbB-2, HER2 neu, ErbB-3, and ErbB-4) are known to be overexpressed in some types of breast tumors. The HER2 neu RTK has been found to be amplified up to 100 times in the tumor cells of approximately 30 of cancer patients with invasive breast disease, and its presence is also associated with poor prognosis. Similarly, overexpression of PDGF and PDGFR has been reported in meningioma, melanoma, and neuroendocrine cancers as well as tumors of the ovary, pancreas, stomach, lung, and prostate. Elevated levels of SRC...

Miscellaneous Drugs

That sometimes occur due to disorders such as cystitis, prostatitis, or other affected structures such as the kidney or the urethra. Overactive bladder is estimated to affect more than 16 million individuals in the United States. Symptoms of an overactive bladder include urinary urgency, frequent urination day and night, and urge incontinence, accidental loss of urine caused by a sudden and unstoppable need to urinate. These drugs also help control the discomfort associated with irritation of the lower urinary tract mucosa caused by infection, trauma, surgery, and endoscopic procedures. Other miscellaneous drugs are used to relieve the pain associated with irritation of the lower genitourinary tract (eg, phenazopyridine) caused by infection, trauma, surgery, and endoscopic procedures.

Comparative studies

Adverse effects and quality of life have been compared in 431 men with prostate cancer treated with a gonador-elin agonist or orchidectomy (3). Of the men who reported normal sexual function before treatment, 51 had reduced libido and 69 became impotent. Of those given gonadorelin, 57 had hot flushes. Breast swelling was more common in those given gonadorelin (25 compared with 10 after orchidectomy).

Pregnancy Category None

And halt progress of material through the intestines. Jimson weed should be avoided by persons with heart trouble, glaucoma, or slow bowels. Other body signs indicating that Jimson weed should be avoided include enlarged prostate, urination difficulty, fluid buildup in lung tissue, and obstruction that impedes movement of food from the stomach. The substance can raise blood pressure and body temperature while drying mucous membranes. Persons hospitalized following jimson weed ingestion have shown a flushed face, exaggerated reflexes, other reflexes consistent with a poison acting upon the brain, and changes involving prothrombin (a factor in blood clotting). Paranoia may be present. More than one report about jimson weed describes users with a saying such as this Blind as a bat, hot as a hare, dry as a bone, red as a beet, mad as a hatter, the bowel and bladder lose their tone, and the heart runs alone.

Pregnancy Category C

Levorphanol can cause dangerous and even fatal breathing difficulty. For that reason medical personnel are supposed to carefully adjust dosage to a patient's individual needs rather than depend upon customary amounts of the drug being safe. It is supposed to be used with special caution in patients with asthma, low thyroid function, urinary difficulty, or an enlarged prostate. Wariness is also prudent when using the substance to reduce heart pain, because the drug's influence on cardiac function has not been confirmed. The substance can lower blood pressure and may produce nausea, vomiting, and constipation. Levorphanol can make users woozy and harm skills needed for operating a car or other dangerous machinery. Although levorphanol is a depressant in humans, it increases leg activity in ponies an effect that may not have escaped notice by persons seeking ways to improve the animals' performance in races.

General Information

Mannitol is an osmotic diuretic that has been used in acute oliguric renal insufficiency, acute cerebral edema, and the short-term management of glaucoma, especially to reduce intraocular pressure before ophthalmic surgery. Other indications include promotion of the excretion of toxic substances by forced diuresis, bladder irrigation during transurethral resection of the prostate, and oral administration as an osmotic laxative for bowel preparation. Mannitol is used as a diluent and excipient in pharmaceutical formulations and as a bulk sweetener.

Pregnancy Category X

Researchers have noted liver cancer in mice that received methyl-testosterone. Other case reports indicate strong suspicion that the drug causes human liver cancer. The substance has been associated with a person's development of prostate cancer, but association is not the same as cause.

Inhibitors Of Farnesyldiphosphate Synthase And Geranylgeranyldiphosphate Synthase

Belonging to the third generation, such as risedronate, zoledronate, and minodro-nate, which contain a nitrogen heterocycle, have shown a dual anti-bone resorption and antitumor cell proliferation activity and are undergoing pre-clinical and clinical studies for several cancers including breast, prostate, lung, renal, osteo-sarcoma, and chondreosarcoma. The antitumor activity of these phosphonates is due to the inhibition of farnesyldiphosphate synthase (FPP) and geranylgeranyl-diphosphate synthase (GGPP) and hence the farnesylation or geranylgeranylation of small GTPases.84

Endocannabinoids in Reproductive Tract Fluids and Organs

Samples of human seminal plasma, midcycle oviductal fluid, and follicular fluid were analyzed by high-performance liquid chromatography mass spectrometry (Schuel, Burkman, Lippes, Crickard, Mahony, et al., 2002 Schuel, Burkman, Lippes, Crickard, Forester, et al., 2002) and quantitated by isotope dilution (Giuffrida et al., 2000). AEA, OEA, and PEA are present in human seminal plasma, midcycle oviductal fluid, and follicular fluid (Table 22.4). The levels of PEA and OEA are significantly higher than AEA in these reproductive tract fluids (p 0.005 to 0.001), and OEA was the most abundant NAE in follicular fluid (p 0.005). We also detected these NAEs in oviductal fluids collected from rabbits and goats at the time of ovulation. These findings are very different from those obtained with whole mouse uterus, in which AEA represents up to 95 of total NAEs (Schmid et al., 1997). Progesterone and prostaglandin E in follicular fluid are known to be produced by granulosa cells in ovarian...

Expression Of Target In Vivo

It may seem trivial to mention that therapy with a kinase inhibitor will be successful only if the target is present and it is functional. However, it has been noted that expression of a functional target will depend on the way the cells and or tumor are grown. Therefore, confirmation of expression and functionality in vitro may not translate into expression and functionality in vivo. Similarly, targets that are not expressed in vitro may be switched-on in response to the presence of growth factors in vivo. Lu et al. (61) have shown not only that expression of cyclin-dependent kinases is different between various cell lines but also that expression is often markedly different when the cells are grown in vitro as compared with the same cells growing as subcutaneous xenografts. The position of the tumor may also have a profound influence on the expression of genes. Uehara et al. (62) used immuno-histochemical detection of receptor (both native and phosphorylated) and ligand to...

Observational studies

Hormone-refractory prostate cancer The adverse effects of suramin that were reported in a group of 69 patients with hormone-refractory prostate cancer were anorexia (19 ), malaise and fatigue (40 ), paresthesia (10 ), weakness (9 ), and skin rash (6 ). In another group of patients there were higher frequencies of adverse effects fatigue occurred in 70 and neuropathy in 16 . Hematological abnormalities occurred often, but were mostly mild and consisted of neutropenia (30 ), anemia (74 ), thrombocytopenia (26 ), and coagulopathy (30 ). Other common adverse effects have included uremia (21 ), increased serum transaminase activities (19 ), nausea and vomiting (30 ), constipation (9 ), edema (33 ), dysrhythmias (7 ), mild hyperglycemia (86 ), and rash (60 ) (SEDA-20, 283). In 81 patients intravenous suramin (peak plasma concentration 300 mg ml trough concentration 175 mg ml) combined with aminoglutethimide 250 mg qds in patients with progressive androgen-refractory prostate cancer after...

Placebocontrolled studies

The antitumor effect of suramin has been evaluated in a prospective randomized trial in 458 patients with hormone-refractory prostate cancer and significant opioid analgesic-dependent pain (12). Reduction of pain and opioid requirements served as surrogates for tumor responsiveness. The patients were given either suramin (aiming at sustained plasma concentrations of 100300 mg ml) plus hydrocortisone (40 mg day) or placebo plus hydrocortisone. Patients treated with suramin plus hydrocortisone had greater reductions in combined pain and opioid analgesic intake. Suramin did not reduce the quality of life or performance status. However, overall survival was similar. Most of the adverse events were mild or moderate and were easily managed medically.

Organs and Systems Nervous system

In 24 patients with hormone-refractory prostate cancer given suramin twice weekly intravenously targeted to reach plasma concentrations of 50-100, 101-150, 151-200, or 201-250 mg ml plus doxorubicin, fatigue occurred in 18 and was dose-limiting in two (17). Eight developed neurological symptoms, of whom three, all receiving the highest dose, developed grade 3 toxicity. There were five cases of neuropathies. Two patients had evidence of a demyelinating neuropathy, one of whom developed a Guillain-Barre-like syndrome and inflammatory myopathy. A further patient had a mixed axonal and demyelinating peripheral neuropathy. Two patients developed a motor neuropathy that exacerbated pre-existing neurological defects. Other frequent adverse events were proteinuria, leukopenia, and alopecia. However, the respective roles of suramin and doxorubicin in causing these adverse effects were uncertain.

Dihydropyrimidine Dehydrogenase

Fected by the same genetic defect (68). In addition to metabolizing drugs, NAT2 is also known to catalyze both N-acetylation (usually deactivation) and O-acetylation (usually activation) of aromatic and heterocyclic amine carcinogens. Epidemiological studies suggest that the NAT2 acetylation polymorphisms modify risk of developing urinary bladder, colorectal, breast, head and neck, lung, and possibly prostate cancers. Associations between slow NAT2 acetylator genotypes and urinary bladder cancer and between rapid NAT2 acetylator genotypes and colorectal cancer are the most consistently reported (65). The importance of the NAT2 polymorphisms in clinical pharmacology and toxicology has been extensively reviewed (68, 69).

Serenoa repens saw palmetto

Hematologic A 53-year-old man, who had self-medicated with a saw palmetto supplement for benign prostatic hyperplasia, had profuse bleeding (estimated blood loss 2 liters) after resection of a meningioma and required 4 units of packed red cells, 3 units of platelets, and 3 units of fresh frozen plasma (61A). Postoperatively his bleeding time was 21 min (reference range 2-10 min) but all other coagulation tests were normal. He made an uneventful recovery. The authors concluded that the cyclo-oxygenase inhibitory activity of saw palmetto had caused platelet dysfunction, which had resulted in abnormal bleeding.

Synthesis Of Norfloxacin

Norfloxacin Synthesis

Bacteria are not sensitive to this drug, while enterococci and akinetobacter are not very sensitive. It is used for bacterial infections of the urinary tract, prostate gland, gastrointestinal tract, gonorrhea, and traveler's diarrhea. Synonyms of this drug are noroxin, barazan, fulgram, bacidal, and others. Ciprofloxacin is also effective for bacterial prostatitis, noncomplicated gonorrhea, osteomyelitis, and pulmonary infections. It is effective in treating acute infectious diarrhea, including traveler's diarrhea and enteritis. Side effects are rarely seen when taking this drug. Synonyms of this drug are ciproquin, ciprolet, cipropan, ciproxan, ciprocinal, and many others.

Identification And Profiling Of Biomarkers And Surrogate Markers

Biomarkers and surrogate markers for anticancer activity of new drugs are becoming a prerequisite for clinical testing (81). Whereas surrogate markers (markers for disease progression remission) can use well-established markers such as prostate-specific antigen for prostate cancer, biomarkers (indicators of drug activity) often must be newly developed and validated using animal models. Experiments by Bonasera et al. (82) suggested that use of 18F-labeled drugs in conjunction with positron emission tomography may be of limited value. Often immunohistochemical staining or Western blotting (see Tables 2, 4, and 5) are used to identify target activity and its inhibition in tumor tissue or other tissues. However, in a recent paper (83), peripheral blood leukocytes were used as a tissue source for p70S6 kinase (p70s6k), a downstream effector of mTOR, to monitor the effect of RAD001. Detailed biochemical profiling of mTOR signaling in tumors, skin, and peripheral blood mononuclear cells...

PDGF in Malignant Disease

Pdgf Signaling Dfsp

Pro-angiogenic effects of PDGF-BB, and to some extent of PDGF-AA and -AB, have been demonstrated in the chick chorioallantoic membrane assay (148,149). Interestingly, neovessels induced by PDGF-BB showed extensive branching and recruitment of smooth muscle a-actin expressing mural cells, in contrast to the brush-like vascular formations induced by VEGF-A (150,151). Recently, PDGF-CC and -DD were also shown to induce angiogenesis in the mouse corneal pocket assay (152). In experimental models of glioblastoma and murine melanoma, PDGF-BB and -DD production enhanced pericyte recruitment and thereby accelerated tumor growth (153,153a). Simultaneous inhibition of pericyte recruitment, using PDGF antagonists, was also shown to potentiate the anti-angiogenic effect of VEGF inhibition (154). Anti-angiogenic effects of Glivec, in combination with paclitaxel, were also obtained in a bone metastasis model of prostate cancer that had activated PDGF-P-receptors in the endothelium (155).

Diethylstilbestrol stilbestrol

Diethylstilbestrol continues to be recommended in some centers as one of the agents of last resort when prostate cancer proves refractory to steroid hormones or androgen deprivation therapy has done all it can (14cr). In a Japanese study in which 16 patients were given a daily intravenous injection of 250 mg of diethylstilbestrol diphosphate for 28 days the short-term response was favorable and the drug was well-tolerated (15c).

Mitoxantrone And Related Quinones

Mitoxantrone is active in breast cancer, acute promyelocitic or myelogenous leukemias, and androgen-independent prostate cancer. Although early reports seemed to indicate that its cardiotoxicity was lower than that of the anthracy-clines,56 this claim has been subsequently challenged.57 Mitoxantrone has been recently approved for treatment of secondary progressive multiple sclerosis (MS).58 The rationale for this application stems from the fact that MS is considered to be an autoimmune disease where a heightened immune action results in the destruction of the myelin of the central nervous system, causing nerve impulses to be slowed or halted and leading to the symptoms of MS. Since chemotherapeutic

Vaccinium macrocarpon cranberry

Hematologic After transurethral resection of his prostate, a 68-year-old man developed immune thrombocytopenic purpura (platelet count 1 x 109 l). He had self-medicated with cranberry juice for 10 days before the operation and had also taken amlodipine and aspirin (63A). He had oral petechiae, bleeding gums, hematuria, and bruises. He recovered within 3 days of being given human immunoglobulin and oral prednisolone, and 18 months later his platelet count was still normal. Cranberry juice may contain small amounts of quinine, which can cause immune thrombocytopenia.

Inhibition of Dihydrotestosterone Binding to the Androgen Receptor

MSC and two constituents of Cannabis, A9-THC and cannabinol, were tested for their ability to interact with the androgen receptor in rat prostate cytosol (32). The above-mentioned materials competitively inhibited the specific binding of dihydrotestosterone to the androgen receptor with a dissociation constant (Ki) of 2.1 x 10-7 M for CBN, 2.6 x 107 M for A9-THC, and 5.8 x 107 M for MSC. The data indicate that the antiandrogenic effects associated with marijuana use result, at least in part, from inhibition of androgen action at the receptor level.

Physiology and Pharmacology

Are present in the hair follicles and sebaceous glands of the scalp skin. Although testosterone acts directly on androgen receptors in several tissues such as skeletal muscles, male beard hair follicles, and male external genitalia, it has to be metabolized to the more potent androgen dihydrotestosterone to act on androgen receptors in the scalp hair follicles and prostate among other tissues. 5a-reductase is an important enzyme that mediates testosterone intracellular conversion to dihydrotestosterone (DHT). There are two types of 5a-re-ductase. Type I is primarily present in the skin, especially the sebaceous glands, epidermal and follicular keratinocytes, and sweat glands, as well as in the liver and kidneys. Type II is mainly found in the gonadal tissue (prostate, seminal vesicles, and fetal genital skin), dermal papilla, and in the liver and scalp hair follicles (91, 92). Recent evidence proved that type II exists in the root sheaths of the scalp hair follicles and predominates...

Steroids in sport 19451960

Similarly, Pat Lenehan argues that Zeigler only found out about Soviets using steroids in 1954 and that he then decided 'his own team needed to get even' (2003 64). It seems most reasonable to assume groups in both the USA and the USSR were developing knowledge on steroids from the early 1950s onwards. John Zeigler's partnership with CIBA to produce Dianabol had coincided with a boom in bodybuilding cultures (Woodland 1980). The quest for more strength and muscle mass quickly led to problems. Zeigler told the journalist Bil Gilbert in 1969, 'The trouble was that the users went crazy about steroids. They figured if one pill was good, three or four would be better, and they were eating them like candy. I began seeing prostate trouble, and a couple of cases of atrophied testes' (Gilbert 1969 70).

Transurethral resection syndrome

Systemic absorption of the fluid used for bladder irrigation during transurethral resection of the prostate can cause a variety of disturbances of the circulatory and nervous systems, which are often referred to as the transurethral resection syndrome. The lack of a consistent definition and varying degrees of awareness of mild forms of this complication probably explain the different figures given for the incidence of the syndrome in prospective studies, varying from 2 to 10 of all transurethral resections performed. Many urologists claim they have not encountered the transurethral resection syndrome for many years (1-3). However, the incidence and severity of symptoms of the transurethral resection syndrome on absorption of increasing volumes of glycine solution have been described (4). The fact that glycine can act as an inhibitory neuro-transmitter may explain why absorption of glycine-containing irrigating fluid from the pelvic cavity or directly into the blood during...

The science of performance effects and health

The knowledge base on health is especially curious. In 1972 The Times quoted from an IOC booklet called Doping in which it was claimed that steroids 'can severely harm the health, causing liver and bone damage, disturbances in the metabolic and sexual functions, and, among women, virilization and menstrual upset' (The Times, 21 April 1972). Such fears were also expressed by George Kaye, physiology editor of the American magazine Muscle Power who is quoted as saying 'How nutsy must one be to risk liver damage, testes atrophy, prostate and kidney cancer ' By contrast, the more rational scientific opinion was offered by Professor F. T. G. Prutny who was researching detection methods at St Thomas' Hospital, London, and funded by the Sports Council. He argued there was a lack of evidence, but risks of vascular disease and cancer were possible though liver cell changes would be reversible after discontinuation of the drugs.

Androgenrelated Antitumor Agents

Most prostatic tumors are androgen dependent, and for this reason hormone treatment of prostate cancer is based on the modulation of testosterone to achieve medical castration levels. This can be achieved directly by administration of antiandrogens or indirectly by inhibition of 5a-reductase, the enzyme responsible for the reduction of testosterone to its more active metabolite. Androgen production can also be controlled by inhibition of the release of LH (see Section 7).

Medical And Behavioral Toxicity Overview

These include cancer of the esophagus, oropharynx (mouth and throat), and liver. Other cancers possibly associated with alcohol consumption include cancer of the breast, stomach, prostate, and colon (Geokas, 1984). Alcohol plays a synergistic (multiplicative) role with smoking tobacco in the development of cancer, particularly with respect to the head, neck, and esophagus. There are several possible mechanisms through which alcohol enhances the onset of cancer. Alcohol appears to modify the immune response to cancers, facilitate delivery of carcinogens (substances which enhance cancer onset), and impair protective responses. Overall, alcohol is considered to act as a co-carcinogen for example, it increases the likelihood of certain smoking-induced cancers.

Structure Activity Relationships

Small Molecule Drugs

In vitro cytotoxicity studies with LI210 mouse leukemia cells were then extended to other cell lines, and subnanomolar potencies were also established against P388 mouse leukemia, A549 lung cancer, HT29 colon cancer, MEL-28 melanoma cells, and human tumors explanted from patients. In vivo activity was then evaluated in mouse tumor models and a variety of human tumors xenografted in nude mice. Complete regressions were observed in MEXF989 melanoma, MX-1 breast carcinoma, LXFL529 non-small cell lung carcinoma, and HOC22 ovarian carcinoma xenografts, and partial regressions were seen in renal MRIH121 and PC2 prostate carcinoma xenografts. Interestingly, changes in the C-subunit were seen to modulate the biological activity of both Et 736 and its N-12 demethylated analog Et 722, relative to Et 743, suggesting that this part of the molecule plays an important role in cytotoxicity. For example, Et 722 and Et 736 displayed a higher level of activity in vivo against P388 leukemia in mice,...

Vitamin Uptake and Metabolism

Calciferol function is complex and, with the exception of calcium transport from the intestinal tract, is poorly understood. Specific vitamin D receptors (VDRs) are found in 30 different tissues including bone, intestine, prostate, hemato that indicate that vitamin D has a cancer-preventive role. Populations living in areas with higher exposure to sunlight have lower incidence of prostate, breast, and colon cancers (26). Most of the calciferol analogs are based on modifications of the 17-alkyl side-chain. Modifications of the A-ring include 19-nor methylene and 3-nor hydroxy analogs with and without the 1-hydroxy moiety. The la-hydroxy-24-ethyl cholecalciferol analog (Fig. 8.15) was less calcemic in mice and inhibited the development of preneoplastic lesions in mammary glands (29). Unsaturation at position 16 (Fig. 8.16) provides modest antiproliferative effects on prostate cancer cells with little hypercalcemia (30). A series of...

Compounds Acting On Other Proteins Of The Nuclear Receptor Superfamily Retinoids

PPAR ligands have also been studied as antitumor agents. Promising results were obtained in initial clinical trials for liposarcoma and prostate cancers with the PPAR-g ligand troglitazone, normally employed as an oral antidiabetic. Unfortunately, more recent studies in colorectal and breast cancers have been disappointing.61

Mammalian Target of Rapamycin mTOR Inhibitors

Rapamycin B16

Preclinical studies have demonstrated efficacy of rapamycin analogs and the parent compound in multiple tumor types. In the National Cancer Institute (NCI) 60 tumor cell line panel, both rapamycin (NSC 226080) and CCI-779 (NSC 683864) demonstrated growth inhibitory activity against a broad spectrum of tumors with a subset of leukemia, lung, brain, prostate, breast, as well as renal and melanoma tumor cell lines being inhibited at low nanomolar concentrations (http dtp.nci.nih.gov ). Early animal studies at the NCI and at Ayerst Research Laboratories demonstrated modest growth inhibitory properties of rapamycin in murine tumor models of B16 melanoma, P388 lymphocytic leukemia, EM ependymo-blastoma, CD8F1 breast carcinoma, Colon 38, CX-1, and 11 A colon cancer models (Eng et al. 1984). Subsequently published studies have documented significant tumor growth inhibition with rapamycin or CCI-779 treatment of DAOY medulloblastoma, U251 or SF295 glioma, PC-3, DU-145, LAPC4, or LAPC9 prostate...

Anticancer Drugs Acting On Apoptotic Signalling Pathways

Cancer Drugs Pathways

Ultimate sensitivity or resistance of cells to a number of apoptotic stimuli (hypoxia, radiation, oxidants, Ca2+ overload, ceramide, and growth factor neurotrophin deprivation). BCL-2 proteins are over-expressed in a large number of cancers, including 90-100 of hormone-refractory prostate cancers, 90 of malignant melanomas, 80-90 of estrogen-positive breast cancer, and 50 of non-Hodgkin's lymphoma, among others. As a transcription factor, the p53 protein does not participate directly in the apopto-sis pathway, but it regulates a large number of other genes that lead to apoptosis, and indeed the tumor suppressor gene (TP53) is mutated in many cancers. Two TP53 gene therapy drugs that use an adenovirus as the delivery vehicle are in clinical trials. Thus, INGN201 (Ad-p53) has demonstrated broad-spectrum antitumor activity in many models of human cancer. Combining INGN201 trans-duction of established tumors with chemotherapy or radiotherapy in these models has resulted in enhanced...

Inhibitors of 5areductase

The androgenic activity in the prostate is due to 5a-dihydrotestosterone (DHT), since 95 of testosterone entering the prostate is converted to the more potent androgen DHT by the 5a-reductase enzyme of the type 2. Hence, blockade of that enzyme, whose expression is largely restricted to the prostate, facilitates the inhibition of testosterone action on urogenital sinus tissue derivatives, notably the prostate, without blocking peripheral androgenic action due to testosterone. Their main use so far is the treatment of alopecia and benign prostate hyperplasia, and there is interest in their potential use as cancer chemopreventive agents. Dutasteride (GI-198745) is an analog of finasteride that behaves as a dual inhibitor of 5-a-reductase type 1 and 2 isozymes. This compound is approved for benign prostate hyperplasia and has been proposed for the chemoprevention of prostate cancer in men at high risk.42

See also Antifungal azoles General Information

In man, higher doses of ketoconazole affect cortisol cortisone and androgen testosterone substrates. This finding has led to the use of ketoconazole in Cushing's disease and prostate cancer, but the phenomenon is also responsible for some of the adverse effects, especially those associated with higher doses and prolonged use (SED-12, 677). The potency of ketoconazole in inhibiting P450 isozymes (such as CYP3A4) is a cause of interactions with several other drugs.

General adverse reactions

Male hormone replacement therapy has been reviewed (11). Hypogonadism can be accompanied by hot flushes, similar to those seen in postmenopausal women, and gyne-comastia. The potential risks of testosterone replacement in adult men are precipitation or worsening of sleep apnea, hastened onset of clinical significant prostate disease, benign prostatic hyperplasia, prostatic carcinoma, gynecomastia, fluid retention, polycythemia, exacerbation of hypertension, edema, and an increased risk of cardiovascular disease.

Diagnosis And Screening

Screening programs can be highly effective in preventing late diagnosis. If tumors are diagnosed early (i.e., before they have metastasized), effective treatments can be initiated, often leading to cures. For example, cervical and breast cancer screening in women has become routine in several developed countries during the last decade, and prostate cancer screening for men is presently being introduced in many countries. In the U.K., a two-yearly check for bowel cancer in all men and women from age 60 onwards was introduced in the National Health Service (NHS) in 2006. Screening consists of a fecal occult blood test, in which patient-collected stool samples are examined. The samples are tested for minute traces of blood, a possible symptom of bowel cancer that affects around 34,000 Britons each year. (Prostate cancer is the U.K.'s second main cause of cancer deaths after lung cancer.) Research suggests that this screening may prevent at least 5,000 cases and 3,000 deaths per year....

See also Alphaadrenoceptor antagonists General Information

In a large database of 7093 patients with lower urinary tract symptoms related to benign prostatic hyperplasia treated for up to 3 years with alfuzosin in general practice, adverse events were reported in a very complex and uninformative way (2). In another paper, the same authors reported on a subcohort of 2829 patients, with special focus on effects on quality of life. Adverse events occurred in 15 of the patients, 1.7 died during the study, and 5.2 had serious effects, which the authors did not detail, but which they stated were not related to treatment. Most adverse effects occurred during the first 3 months of treatment (3). In another database of 3095 Spanish patients taking alfuzosin 5 mg bd for 60 days, adverse events were reported in 3.3 of the patients, and led to drug withdrawal in 1.6 postural hypotension occurred in 1.8 (4).

Overall level of evidence of adverse effects C

1274 Nakabayashi M, Xie W, Regan MM, Jackman DM, Kantoff PW, Oh WK. Response to low-dose ketoconazole and subsequent dose escalation to high-dose ketoconazole in patients with androgen-independent prostate cancer. Cancer. 2006 Sep 1 107(5) 975-81. English 1279 Aabo K, Kjaer M, Hansen HH. High-dose ketoconazole to untreated stage D prostate cancer. Eur J Cancer Clin Oncol. 1988 Mar 24(3) 431 -7. English

Outlook Src As A Target For Other Indications More Selective And Dual Src Inhibitors

Apart from a few isolated studies, the potential of Src inhibitors for inhibition of different tumors has not yet been extensively examined. A lack of enthusiasm in this area is certainly caused by a lack of convincing epidemiological studies implicating Src in the etiology of human tumors. Our preliminary studies with HT29 colon cancer xenografts in nude mice were not very encouraging (Fig. 5). However, recent in vitro data on potent effects of Src pyrrolopyrimidine inhibitors on prostate cell migration and invasion would warrant examination of existing compounds in suitable in vivo cancer metastases models. In accord with this notion, the Src inhibitors PP1 and herbimycin A have been shown to suppress collagen type I III-dependent decrease in cadherin E, coupled to changes in cell-cell adhesion, proliferation, and migration of pancreatic carcinoma cells (25). In another tumor type, malignant peripheral nerve sheath tumors, there is a correlation between Src activity, inhibition by a...

Overall level of evidence of adverse effects D

Cancer, prostate, treatment with bicalutamide Breast swelling 931 Boccardo F, Rubagotti A, Battaglia M, Tonno P di, Selvaggi FP, Conti G, Comeri G, Bertaccini A, Martorana G, Galassi P, Zattoni F, Macchiarella A, Siragusa A, Muscas G, Durand F, Potenzoni D, Manganelli A, Ferraris V, Montefiore F. Evaluation of tamoxifen and anastrozole in the prevention of gynecomastia and breast pain induced by bicalutamide monotherapy of prostate cancer. J Clin Oncol. 2005 Feb 1 23(4) 808-15. English Cancer, prostate, treatment with bicalutamide Breast swelling 930 Saltzstein D, Sieber P, Morris T, Gallo J. Prevention and management of bicalutamide-induced gynecomastia and breast pain randomized endocrinologic and clinical studies with tamoxifen and anastrozole. Prostate Cancer Prostatic Dis. 2005 8(1) 75-83. English

General Structure and Distribution

Cb1 Structure

The CB2 receptor was also isolated by its homology to other GPCRs, using a PCR-based approach in myeloid cells (Munro et al. 1993). The human CB2 receptor cDNA was isolated from the human promyelocytic cell line, HL60. The clone has 44 amino acid sequence identity overall with the CB1 clone, and percentage similarity rises to 68 in the TM domains. The amino acid residues conserved between CB1 and CB2 are shaded in Fig. 1. The localization of the CB2 receptor appears to be mainly in the periphery in the spleen and in low levels in adrenal, heart, lung, prostate, uterus, pancreas, and testis and in cells of immune origin, including microglia in the CNS (Munro et al. 1993 Galiegue et al. 1995 Walter et al. 2003). An alignment of human CB1 and CB2 is shown in Fig. 2. Using the numbering scheme of Ballesteros and Weinstein (Ballesteros and Weinstein 1995), each amino acid is given a number that begins with the helix number followed by

The Health Effects Of Chronic Cannabis

The results of epidemiological studies of upper respiratory tract cancers in cannabis users have been mixed. Sidney et al. (1997b) studied cancer incidence in an 8.6 year follow up of 64,855 members of the Kaiser Permanente Medical Care Program. There was no increased risk of respiratory cancer at follow-up among those who had ever used cannabis and current cannabis users. Males who had smoked cannabis had an increased risk of prostate cancer (RR 3.1), and so did current cannabis smokers (RR 4.7).

Second Generation Effects Teratogenicity

Diethylstilbestrol provides several illustrations of how societies cope with the risks of harm from a drug. Under different brand names diethylstilbestrol has been given to a wide range of patients over many years, mostly pregnant women and aging men with prostate cancer. The history of iatrogenic disease as a result of the use of diethylstil-bestrol in pregnant women shows that patients can play an important role in securing legitimacy for research and the publication of data on the harmful effects of a drug.

Physiology of Ejaculation

In the initial phase, emission, smooth muscles of the vas deferens, the seminal vesicles and the prostate, as well as their secretions, are involved. At the end, the mixture of spermatozoa from the epididymis and the vas deferens with the secretions of the seminal vesicles, forming about 50 of the ejaculate, and the prostate, which secretes nearly the other half of the semen, is made available in the prostatic (posterior) urethra. The sperm progression in the seminal tract during ejaculation, and the contractions of the epididymis, is supported by oxytocin, a potent stimulator of epididymis contractility. It also induces the release of another potent stimulator of epi-didymal contractility, endothelin-1 (Filippi et al. 2003). Fig. 1.3.1 Neural pathways controlling ejaculation. Sympathetic (Z), parasympathetic (PZ) and somatic nerves from lumbosacral spinal nuclei command anatomical structures responsible for ejaculation. Sensory afferent fibres from...

Mineral balance

A patient with androgen-independent prostate cancer developed hypocalcemia during treatment with estramus-tine (12). The total serum calcium concentrations before and after the initiation of estramustine were 2.1 and 1.1 mmol l respectively. This prompted a retrospective survey of hypocalcemia in 135 consecutive patients taking estramustine 20 were affected. The authors speculated that estramustine may cause hypocalcemia by inhibiting mobilization of calcium and the action of parathyroid hormone on the skeleton.

Animal toxicology

Long term toxicology studies with THC were carried out by the National Institute of Mental Health in the late 1960's (10ER). These included a 90-day study with a 30-day recovery period in both rats and monkeys and involved not only A9-THC but also A8-THC and a crude extract of marijuana. Doses of cannabis or cannabinoids in the range 50-500 mg kg caused reduced food intake and lower body weight. All three substances initially depressed behavior, but later the animals became more active and were irritable or aggressive. At the end of the study the weights of the ovaries, uterus, prostate, and spleen were reduced and the weight of the adrenal glands was increased. The behavioral and organ changes were similar in monkeys, but less severe than those seen in rats. Further studies were carried out to assess the damage that might be done to the developing fetus by exposure to cannabis or cannabinoids during pregnancy. Treatment of pregnant rabbits with THC at doses up to 5 mg kg had no...

Effects

In some organs, testosterone is reduced to 5-a-dihy-drotestosterone by the 5-a-reductase prior to the binding to the receptor. The enzyme 5-a-reductase is of relevance mainly in the skin and the prostate. There are two isoenzymes they show poor homology, and they have different chromosomal localization and different expression patterns in the prostate and skin. Substances which inhibit both types of the enzyme are known and clinically used in diseases of the prostate and skin (Occhiato et al. 2004). Men with 5-a-re-ductase-2 deficiency have ambiguous genitalia, but normal male libido with normal spermatogenesis, and may be able to father children by assisted reproduction (Imperato-Mc-Ginley 2002).

And Drugs

The descriptions of the effects of ADEs on male sexual function are generally scarce and restricted to few topics. Any intervention which influences the sexual hormone system obviously also influences male sexual functions, e.g. antian-drogenic compounds, which depress sexual libido and other sexual functions. In some circumstances, it may be questionable as to whether the effect of a drug on male sexual functions is a desired therapeutic effect, or whether it is an untoward effect. For example, the depression of pituitary hormone secretion by the gonadotropin-releasing hormone (GnRH) analogues in the treatment of prostate carcinoma is important in order to achieve androgen deprivation and prolong the remission of the disease. On the other hand, the depression of gonadotropin secretion in these men by GnRH leads to impotence and infertility, which is definitely an untoward effect.

Alcohol

Most laboratory tests give no indication that alcohol has a potential for causing cancer. Nonetheless, mice experimentation indicates that long-term use of alcohol can cause liver cancer. Human reports indicate an increased risk for prostate cancer. Women who take more than two drinks a day have an increased risk of breast cancer. A study of 8,006 Japanese men in Hawaii found an association between alcohol and cancer of the lungs and rectum, but association is not the same as cause and effect. Evidence indicates that saliva might transform alcohol in ways that promote oral cancer.

PI3K and Cell Growth

Cell growth is the mammalian target of rapamycin (mTOR), which activates p70S6 kinase and inhibits elongation-initiation factor 4E binding protein (4E-BP1), culminating in the stimulation of protein synthesis (71). Recently, the pathway linking PI3-K to p70S6 kinase has been further defined at the biochemical and genetic level following the elucidation of the function of two proteins, hamartin and tuberin, which are mutated in the genetic disorder tuberous sclerosis (72). These proteins form a complex, and tuberin acts as a GTPase-activating protein that inhibits the activity of the small GTPase, Rheb. Phosphorylation of tuberin by PKB inhibits GTPase activity. In its GTP-bound state, Rheb activates mTOR via an undefined mechanism (73). Bearing in mind that mTOR is upstream of p70S6kinase, rapamycin has emerged as a potential treatment for both tuberous sclerosis and cancer. An ester analog of rapamycin, CCI-779, inhibits growth of PTEN-deficient human myeloma cell lines (74) and...

Gastrointestinal

In 57 patients with advanced prostate cancer resistant to first-line hormonal therapy treated with estramustine and clodronate, the main adverse effect was nausea (33). Therapeutic efficacy was small. Reasons for premature withdrawal of clodronate in one study included refusal to continue treatment (five patients) and progressive disease of the bone (four patients) (34). One patient refused to take clodronate from the start seven discontinued clodronate after a median of 13 (range 0.2-23) months because of adverse events. In five patients the cause was nausea, combined with vomiting in four and diarrhea in one. After 0.9, 1.0, and 1.3 months the dosage of clodronate was reduced to 800 mg day in three patients (one had nausea, another dyspepsia, and a third had uncharacteristic sensations in the skeleton).

Target Marijuana

CB1 receptors are extraordinarily abundant in the brain. 18 They are particularly ubiquitous in the basal ganglia and the cerebellum, which regulate and coordinate body movements. CB1 receptors are also abundant in the hippocampus, which plays a central role in learning and memory, and in the cerebral cortex, which is involved in integrating higher cognitive functions. To a lesser extent CB1 receptors can also be found in the heart, lung, prostate, uterus, ovary, testis, bone marrow, thymus, tonsils, and adrenal gland.19

Prostaglandins

Before discussing some of the research on the mechanism of action of aspirin and other acidic NSAIDs, it is necessary to consider the fundamental chemistry of prostaglandins (PGs). Some early work with crude extracts from accessory genital glands (e.g., prostate, hence the name prostaglandins) established such physiological activities as vasodilation and muscle stimulation, as well as that the substance(s) were acidic lipids. However, the difficulties of isolating and identifying the responsible components took two decades and the development of sophisticated instrumentation such as gas chromatography and high-resolution mass spectrometry. Prostaglandins are a group of fatty acids derived from the hypothetical 20-carbon prostanoic acid. They are known to be ubiquitous, not localized in the prostate gland and

Tribulus

In rat studies, the administration of Tribulus extract heightened sexual behaviour and resulted in increased ICP. The authors claimed that this effect was due to increases in testosterone 53 . For this reason, Tribulus is contraindicated in pregnant women and men with prostate cancer. It has also been found to be toxic in sheep, eventually leading to death 54 , and there are reports of gynaecomastia in men taking Tribulus 55 .

Anandamide

Devane et al. (1992) isolated anandamide from pig brain lipid extracts by column chromatography, TLC, and HPLC. The structure of anandamide was confirmed by GC MS and 1H-NMR. They demonstrated that anandamide binds to the brain cannabinoid receptor with a high affinity (Ki 52 nM) and induces inhibition of the mouse twitch response. They also showed that anandamide elicits reduced spontaneous motor activities, immobility, hypothermia, and analgesia when administered to mice (Fride and Mechoulam, 1993). These observations were later confirmed by a number of investigators (e.g., Smith et al., 1994 Crawley et al., 1993). To date, it has been shown that anandamide exhibits diverse biological activities in vitro and in vivo, such as the inhibition of adenylyl cyclase, the inhibition of voltage-gated Ca2+ channels, the activation of an inwardly rectifying K+ current, the inhibition of neurotransmitter release, the stimulation of p5S GTPyS binding to G proteins, the activation of various...

Dipipanone

Persons are supposed to avoid the drug if they suffer from low thyroid activity or enlarged prostate. Dipipanone can make people sleepy, and users are supposed to be cautioned about operating dangerous machinery. Volunteers in one experiment experienced lower alertness after taking dipi-panone, but other experiments found the substance to lack sedative action. Study does show that sedation can occur when dipipanone is given together with the antihistamine triprolidine. Dipipanone can cause headache, tremors, nausea, and vomiting, impair vision, interfere with breathing, make urination difficult, lower blood pressure, and reduce production of saliva. Seizures have been reported. Euphoria may occur. A case study notes delusions and hallucinations caused by the drug. Paranoia has occurred occasionally. A case report tells of serious colon difficulty occurring after someone injected three dissolved oral Diconal tablets, a combination product containing dipipanone and the...

Review

Prostate cancer After external beam radiation in prostate cancer, a dose-dependent decrease of testosterone levels in a study with 666 patients was observed, and only 60 had recovery to their individual pretreatment level. The FSH and LH levels were increased. This alteration was less severe than in GnRH treatment. Smaller studies had the same results. If the total dose to the testis was

Birds vs bees

The physiological differences in drug response are a small part of the overall health differences between men and women. Besides the alarming lack of ovarian cancer in men and prostate trouble in women, common diseases are also disproportionately represented between the sexes. Here we encounter one of the most confounding elements in health environmental effects. For the most part, environmental factors like chemical exposure, cigarette smoking, and exposure to sunlight are really just triggers for genetic events. Each of them acts like a switch that causes the body to react. Sure, some environmental factors just cause gross damage and necrosis to tissue, but the majority of them just turn genes on and off.

Consequences

Cancer, prostate Hormones 2105 Shahidi M, Norman AR, Gadd J, Huddart RA, Horwich A, Dearnaley DP. Recovery of serum testosterone, LH and FSH levels following neoadjuvant hormone cytoreduction and radical radiotherapy in localized prostate cancer. Clin Oncol (R Coll Radiol). 2001 13(4) 291 -5. English Cancer, prostate Hormones 2103 Pickles T, Agranovich A, Berthelet E, Duncan GG, Keyes M, Kwan W, McKenzie MR, Morris WJ. British Columbia Cancer Agency, Prostate Cohort Outcomes Initiative. Testosterone recovery following prolonged adjuvant androgen ablation for prostate carcinoma. Cancer. 2002 Jan 15 94(2) 362-7. English Cancer, prostate Testicular histology 371 Lunglmayr G, Girsch E, Meixner EM, Viehberger G, Bieglmayer C. Effects of long term GnRH analogue treatment on hormone levels and spermatogenesis in patients with carcinoma of the prostate. Urol Res. 1988 16(4) 315-9. English Cancer, prostate T production in vitro Cancer, prostate Testicular histology

Selenium

Effects Selenium detoxifies heavy metals (such as arsenic, cadmium, lead, and mercury), alcohol, peroxidized fats, and some drugs reportedly slows down some of the aging processes, and inhibits the oxidation that leads to hardening of the tissues, keeping them more elastic. One study found that 200 micrograms day can protect against lung, colon, and prostate cancer, but appears to have no effect on skin cancer, though it may help eradicate moles and brown spots. Other studies have correlated high levels of selenium with a low incidence of leukemia and cancers of the rectum, pancreas, breast, ovary, bladder, skin, stomach, esophagus, liver, and gastrointestinal tract. Studies have shown that, when given in doses around 220 micrograms day, it improves moods and thinking, even in those who are not deficient, indicating most people do not get enough.

Receptors

Prostate cancer cell lines LNCaP and PC-3 were treated with curcumin, and its effects on signal transduction and expression of androgen receptor (AR) and AR-related cofactors were analyzed. The results showed that curcumin down-regulated transactivation and expression of AR and CREB (cAMP response element-binding protein-binding protein. It also inhibited the transforming activities of both cell lines as evinced by reduced colony-forming ability in soft agar. These findings suggest that curcumin has a potential therapeutic effect on prostate cancer cells through down-regulation of AR and AR-related cofactors 18 .

Anticancer Effects

Curcumin had synergic activity with chemotherapeutic agent vinorelbine in suppressing the growth of human squamous cell lung carcinoma H520 cells 53 . It significantly inhibited the growth of human gastric carcinoma AGS cells in a dose- and time-dependent manner 54 . Using time-lapse video and immunofluorescence labeling methods, Holy et al. demonstrated that curcumin significantly altered microfilament organization and cell motility in PC-3 and LNCaP human prostate cancer cells in vitro 55 . Chemoresistance is a major problem in the treatment of patients with multiple myeloma due to constitutive expression of NF-kB and STAT3. Bharti et al. showed that suppression of NF-kB and STAT3 activation in multiple myeloma cells by ex vivo treatment with curcumin resulted in decreases in adhesion to bone marrow stromal cells, secretion of cytokines, and viability of cells 56 . Curcumin decreases the proliferative potential and increases the apoptotic potential of both androgen-dependent and...

Hormonal Therapy

Hormones are naturally occurring substances produced by endocrine glands (e.g. testes, ovaries) that act as chemical messengers to influence the growth and activity of cells. Hormonal therapies act by altering the production or activity of particular hormones in the body. Hormonal therapy is most commonly used to treat breast and prostate cancer. Drugs used in hormone therapy for prostate cancer inhibit the action or block the production of testosterone and other male hormones, thereby slowing tumor growth (3). Medications include gonadotropin-releasing hormone agonists (block testosterone production) such as leuprolide acetate (Lupron ) goserelin acetate (Zolade ) an histrelin acetate (Vantas Implant). Androgen antagonists include flutamide (Eulexin ), bicalutamide (Casodex ) and nilutamide (Nilandron ). Alternatively, estrogen therapy involves the use of the female hormone diethylstilbestrol to suppress the production of testosterone.

Glutethimide

A test of the drug's influence on mental ability found little effect, but tobacco smokers seemed to be affected more than nonsmokers. A test of skills related to automobile driving found little influence from glutethimide. The drug produced inconsistent results in another experiment measuring alertness, reaction time, and decision making. Those tests, however, involve normal doses during relatively brief time spans. Generally people are advised to become aware of how the drug affects them before attempting to run dangerous machinery. Long-term heavy abuse can reduce mental skills in ways that resemble organic brain damage. Animal experiments suggest that the substance may worsen porphyria, a body chemistry disorder that can make a person violent. The drug can aggravate urinary tract blockage and should be used cautiously by persons with enlarged prostate. Eyesight difficulty and dry mouth are among typical unwanted effects.

Oxybutynin

Oxybutynin is contraindicated in patients with a hyper-sensitivity to the drug, those with glaucoma, partial or complete blockage of the gastrointestinal tract, myasthe-nia gravis, or urinary tract obstruction. The drug is used cautiously in patients with kidney or liver disease, heart failure, irregular or rapid heart rate, hypertension, or enlarged prostate and during pregnancy (Pregnancy Category C) and lactation. There is a decreased effectiveness of the phenothiazines when these drugs are administered with oxybutynin. A decreased response and increased risk of tardive dyskinesia may occur when haloperidol is administered with oxybutynin.

Native Distribution

Two cannabinoid receptor types have been identified in various cells and tissues of the immune system (Table 1). The first of these, the CB1 receptor, was cloned originally from a cDNA rat library by Matsuda et al. (1990). Munro et al. (1993) reported on the cloning of the second receptor for cannabinoids, designated the CB2 receptor, which was not expressed in the brain but rather in the immune system. Recent studies suggest the existence of a third cannabinoid receptor, tentatively designated as non-CB non-CB2 (Breivogel et al. 2001 Fride et al. 2003 Wiley and Martin 2002). Cannabinoid receptor CB1 mRNA is found primarily in brain and neural tissue but can be found also at lower levels in peripheral tissues including the adrenal gland, bone marrow, heart, lung, prostate, testis, thymus, tonsils, and spleen (Bouaboula et al. 1993 Galiegue et al. 1995 Kaminski et al. 1992 Noe et al. 2000). Messenger RNA for the CBi receptor has been identified also in microglia from the brain (Sinha...

Estrogen Therapy

Estrogen is rarely used to treat prostate cancer because of its adverse reactions but is occasionally used to treat breast cancer in postmenopausal women if no other options are available. In prostate cancer, an estrogenic agent such as DES works by inhibiting the hypothalamic-pituitary system through a negative feedback (shut off) mechanism. A shortage of testosterone DHT reaching the cells signals of an increased production of testosterone by the testes (some of which will reach cells and occupy receptors) which results in a fall of output of LH from the pituitary of LH and a subsequent decrease in testosterone synthesis by the testes (an outcome known as chemical castration ).

Others

Phenoxodiol, a synthetic analogue of diadzein, an isoflavone present in members of the family Fabaceae (Pueraria tuberosa, Glycine max), is being developed for the treatment of cervical, ovarian, prostate, renal and vaginal cancers 109 . Phe-noxodiol is a broad-spectrum drug that induces cancer cell death through inhibition of anti-apoptopic proteins, including XIAP and FLIP 110 . The drug is in phase II and phase III clinical trials in the USA and Australia, respectively 111 .

Meperidine

Cally toward driving skills, however, led researchers to conclude that people should not operate a motor vehicle for 24 hours after an intramuscular injection of meperidine. Anyone with enlarged prostate, urinary difficulty, Addison's disease, or underactive thyroid should be wary about using the drug. An unusual case report tells of a patient developing Parkinson's disease symptoms from meperidine more commonly such reports arise from contaminated illicit substances related to meperidine. Another illicit peril occurs when persons grind up and inject oral meperidine tablets the talc in those tablets can block tiny blood vessels throughout the body and also cause those vessels to bleed serious business in the eyes or brain. Illicit intramuscular injection of the drug over a period of years can cause muscle damage. Injecting into an artery can lead to gangrene.

Estrogens

Estrogen is a general term used to describe compounds that possesses estrogenic activity. However, they in turn can be subdivided into two groups estrogens, which are functionalized derivatives of a steroid structure, and compounds that do not contain a steroid ring.

Summary

For the past several years marijuana has been the most commonly abused drug in the United States, with approx 6 of the population 12 years and older having used the drug in the month before interview. The use of marijuana is not without significant health risks. Marijuana is associated with effects on almost every organ system in the body, ranging from the central nervous system to the cardiovascular, endocrine, respiratory pulmonary, and immune systems. Research shows that in addition to marijuana abuse dependence, marijuana use is associated with serious health consequences in some studies with impairment of cognitive function in the young and old, fetal and developmental consequences, cardiovascular effects (heart rate and blood pressure changes), respiratory pulmonary complications such as chronic cough and emphysema, impairment of immune function, and risk of developing head, neck, and or lung cancer. In general, acute effects are better studied than those of chronic use, and...

Oxandrolone

Nausea and diarrhea are among the less serious reports of unwanted effects. The substance can masculinize female users and interfere with menstrual periods. In immature rats oxandrolone has drastically interfered with the male reproductive system, a finding that may be relevant to young athletes using the compound without medical supervision. In humans the substance can promote prostate disease and should be avoided by men with breast cancer and generally by anyone with kidney disease (although doctors sometimes give oxandrolone to dialysis patients). The drug has been used to treat hepatitis in alcoholics despite its ability to interfere with bile flow and to cause jaundice or liver malfunction. Fluid retention can occur and be a serious problem for heart patients. Other unwanted effects may include overall higher cholesterol levels (accompanied by reduction of the HDL good cholesterol ), although unlike some other drugs of this type, oxandrolone has been seen to reduce...

Colorectal Cancer

Endocannabinoids are known to inhibit the proliferation of breast cancer cells, prostate cancer cells, and rat thyroid cancer cells (Bifulco and Di Marzo 2002). Ligresti and colleagues (2003) showed that the levels of anandamide and 2-AG were increased relative to controls in adenomatous polyps and carcinomas, but there appeared to be no differences in the expression of CB1 and CB2 receptors or FAAH levels among the tissues. To determine if cannabinoids affect colorectal cancer cell growth, the authors used CaCo-2 (which express CB1 receptor) and DLD-1 cells (which express both CB1 and CB2 receptors, with CB1 receptor less expressed than in CaCo-2 cells). Anandamide, 2-AG and HU-210, as well as an inhibitor of anandamide inactivation, potently inhibited CaCo2 cell proliferation (relative potencies HU-210 anandamide 2-AG), while DLD-1 cells were less responsive to cannabimimetics than CaCo-2 cells (Ligresti et al. 2003). Such data suggest that CB1 receptors are more important than CB2...

Finasteride

Finasteride is likely to be used less intensively in benign prostatic hyperplasia than in malignancies. In one study in 3040 men with benign prostatic hyperplasia the effects of fi-nasteride 5 mg day for 4 years were compared in men over and under 65 years (110C). In both groups the drug was effective and there were no significant differences in cardiovascular adverse events between placebo- and finasteride-treated patients. There were significant differences between placebo and finasteride in the incidence of typical drug-related adverse events, but there were no specific differences associated with age. The principal events were impotence (8.8 ), reduced libido (6.8 ), reduced volume of ejaculate (3.5 ), other ejaculation disorders (1.5 ), rash (0.6 ), breast enlargement (0.5 ), and breast tenderness (0.2 ). There were no drug interactions of clinical importance with finasteride.

Tetracyclines

Chlorotetracycline, an antibiotic with a broad spectrum of action, causes a bacteriostatic effect with respect to Gram-positive (staphylococci, including those that produce penicillinase streptococci, pneumococci clostridia, listeria, and anthrax bacillus) and Gram-negative microorganisms (gonococci, whooping cough bacillus, colon bacillus, enterobacteria, klebisella, salmonella, shigella), as well as Rickettsia, chlamydia, mycoplasma, and spirochaeta. Blue-pus bacillus, proteus, serracia, most strains of Bacteroides fragilis, most fungi, and small viruses are resistant to this drug. It is used for pneumonia, bronchitis, empyema of the lungs, angina, cholecystitis, whooping cough, endocarditis, endometritis, intestinal infections, prostatitis, syphilis, gonorrhea, brucellosis, osteomyelitis, purulent infections of soft tissues, and others caused by microorganisms sensitive to this drug. Synonyms of this drug are aureomycin, biomycin, xanthomycin, and others.

Cell Growth Arrest

Cannabinoids have been shown to induce cell cycle arrest in breast carcinoma (De Petrocellis et al. 1998), prostate carcinoma (Melck et al. 2000) and thyroid epithelioma cells (Bifulco et al. 2001). In breast carcinoma cells this has been ascribed to the inhibition of adenylyl cyclase and the cAMP protein kinase A (PKA) pathway (Table 1). PKA phosphorylates and inhibits Raf-1, so cannabinoids prevent the inhibition of Raf-1 and induce prolonged activation of the Raf-1 MEK ERK signalling cascade (Melck et al 1999). Cannabinoid-induced inhibition of thyroid epithelioma cell proliferation has been attributed to the induction of the cyclin-dependent kinase inhibitor p27kip1 (Portella et al. 2003). It has been suggested that cannabinoids produce their growth-inhibiting effects on skin and prostate cancer cells at least in part by attenuating epidermal growth factor receptor tyrosine kinase activity (Casanova et al. 2003) and or by lowering epidermal growth factor receptor expression...

Cancer Stem Cells

The concept of cancer stem cells has been around since the 1950s. Only recently has evidence started to accumulate that supports the hypothesis regarding cancer stem cells. For example, a decade ago, it was shown that when cancer cells were harvested from patients with leukemia and implanted into rodents, only a select number of blood cells from the harvested population could successfully grow. Similarly, for solid tumors, it was more recently demonstrated that when tumor cells from human breast cancers are implanted into mice, approximately only 1 in 100 successfully form tumors. Therefore, it is now thought that cancer stem cells may play a role in most (or perhaps all) types of cancers (both solid and blood-related), and a significant research effort is now underway to identify tumor stem cells in all the various tumor types, including skin, lung, pancreatic, ovarian, and prostate cancer. A great deal of research into the origin of cancer stem cells is also ongoing. One possibility...

Phytoestrogens

Cancer (breast and prostate cancer in particular), heart disease (antioxidant activity), osteoporosis, menopause, cognitive function and diabetes are major points of focus for the potential health benefits of phytoestrogens. Much interest has been shown in their potential anticancer activity, spurred on by the observation that Japan, whose population consumes large quantities of phytoestrogens, has one of the lowest breast cancer rates in the world. Similarly, there is a very low incidence of prostate cancer among Asian men. Interestingly, when members of these groups migrate to Northern America or Europe, their risk of developing cancer increases to a level similar to the general population of their newly adopted country, suggesting that an environmental factor such as diet may be important. The dietary consumption of phytoestrogens is known to be 30 times higher in Japan than in the U.K. In 1994, the total isoflavone intake of Japanese residents was estimated to be 150 to 200 mg...

COX2 Inhibitors

In addition to the genetic evidence implicating COX-2 in carcinogenesis, numerous pharmacological studies have suggested that COX-2 is a viable therapeutic target. In particular, selective inhibitors of COX-2 reduce the formation, growth, and metastases of experimental tumors, and decrease the number of intestinal tumors in familial adenomatous polyposis (FAP) patients. However, the antitumor effects of selective COX-2 inhibitors may reflect mechanisms operating in addition to inhibition of COX-2. For example, recent studies of the expression of COX-2 in human prostate cancer have provided conflicting results several have suggested that COX-2 is commonly overexpressed in prostate cancer, whereas others have found low levels of expression or none at all. However, even if COX-2 overexpression proves to be uncommon in prostate cancer, selective COX-2 inhibitors could still be useful if the COX-2-independent effects are proven to be clinically important. In this context, researchers...

Lycopene

Lycopene is a powerful carotenoid antioxidant that neutralizes free radicals, thus preventing them from damaging cells and particularly their genomes. The accumulation of lycopene in body tissues is higher than for any other carotenoid, and it is deposited in high concentrations in the skin, colon, liver, prostate gland, and lungs. Epidemiological studies show that a high intake of lycopene-containing fruits can reduce the risk of developing certain types of tumors. For example, a study by Harvard's School of Public Health and Medical School on the diets of more than 47,000 men over a 6-year period found that, out of 46 vegetables and fruits evaluated for a possible association with health, only tomato-based foods that contained the highest amounts of lycopene showed any measurable effect. For example, a relationship was identified between a decreased risk of prostate cancer and a greater than average consumption of tomato-based foods, with resulting higher blood levels of lycopene....

Androgens

The male hormone testosterone and its derivatives actuate the reproductive potential in the adolescent boy. From puberty onward, androgens continue to aid in the development and maintenance of secondary sex characteristics facial hair, deep voice, body hair, body fat distribution, and muscle development. Testosterone also stimulates the growth in size of the accessory sex organs (penis, testes, vas deferens, prostate) at the time of puberty. The androgens also promote tissue-building processes (anabolism) and reverse tissue-depleting processes (catabolism). Examples of androgens are flu-oxymesterone (Halotestin), methyltestosterone (Oreton Methyl), and testosterone. Additional examples of androgens are given in the Summary Drug Table Male Hormones.

Ephedrine

Food and Drug Administration (FDA) became particularly alarmed at the prevalence of medical problems developed by young healthy users, and regulatory efforts were increasing when this book was written. Some scientists say the FDA's concerns are unfounded and that many physical problems after ephedrine ingestion derive from a person's prior medical history or massive overdose. Nonetheless, the FDA believes that ephedrine may harm people who already have the following conditions prostate trouble, psychological afflictions (including depression and nervousness), high blood pressure, diabetes, glaucoma, and ailments of thyroid, kidney, or heart.