Silibinin
Silibinin is the major active flavolignan constituent of silymarin, which is a combination of flavonolignans extracted from Silybum marianum (milk thistle). Other flavolignans found in silymarin are isosibilinin A and B, silicristin, and silidianin. In vitro and animal in vivo demonstrations both consistently suggest that silibinin has hepatoprotective/antihepatotoxicity properties[1][2] Silibinin has also demonstrated cancer-fighting effects against human prostate adenocarcinoma cells, estrogen-dependent and estrogen-independent breast carcinoma cells, human ectocervical carcinoma cells, human colon cancer cells, and both types of human lung carcinoma cells.[3][4][5][6] Chemically modified silibinin, silibinin dihydrogen disuccinate disodium, is injected in treatment of severe intoxications with hepatotoxic substances.
A complex of silymarin and phosphatidylcholine (lecithin), is about ten times more bioavailable than silymarin. Silymarin complexed with beta-cyclodextrin is much more soluble than silymarin by itself.
Wagoner et al demonstrate and report silibinin's profound effects on Hepatitis C: Silymarin, an extract from milk thistle (Silybum marianum), and its purified flavonolignans have been recently shown to inhibit hepatitis C virus (HCV) infection, both in vitro and in vivo. In the current study, we further characterized silymarin's antiviral actions. Silymarin had antiviral effects against hepatitis C virus cell culture (HCVcc) infection that included inhibition of virus entry, RNA and protein expression, and infectious virus production...Although inhibition of in vitro NS5B polymerase activity is demonstrable, the mechanisms of silymarin's antiviral action appear to include blocking of virus entry and transmission, possibly by targeting the host cell.[7]
Amazingly, Neumann et al achieved successful prevention of Hepatitis C reinfection-via-liver-graft with silibin mono-therapy.[8]
Polyak et al comment that silibinin and related flavolignans are so effective in hepatitis C treatment and intervention, more research to establish therapeutic modalities is "urgently needed": Silymarin, also known as milk thistle extract, inhibits hepatitis C virus (HCV) infection and also displays antioxidant, anti-inflammatory, and immunomodulatory actions that contribute to its hepatoprotective effects. In the current study, we evaluated the hepatoprotective actions of the seven major flavonolignans and one flavonoid that comprise silymarin.The most potent compounds across multiple assays were taxifolin, isosilybin A, silybin A, silybin B, and silibinin, a mixture of silybin A and silybin B. The data suggest that silymarin- and silymarin-derived compounds may influence HCV disease course in some patients. Studies where standardized silymarin is dosed to identify specific clinical endpoints are urgently needed.[9]
Tamoxifen is absorbed more effectively when coadministerered with silibinin and silibinin-containing compounds: The enhanced bioavailability of tamoxifen by silybinin might be due to the promotion of intestinal absorption in the small intestine and the reduction of first-pass metabolism of tamoxifen in the small intestine and in the liver. If these results are confirmed in clinical trials, the tamoxifen dosage should be adjusted when tamoxifen is administered with silybinin or silybinin-containing dietary supplements.[10]
Cheung et al describe silibinin as a promising adjunct therapy for, potentially, many forms of cancer: Silymarin and its major constituent, Silibinin, are extracts from the medicinal plant Silybum marianum (milk thistle) and have traditionally been used for the treatment of liver diseases. Recently, these orally active, flavonoid agents have also been shown to exert significant anti-neoplastic effects in a variety of in vitro and in vivo cancer models, including skin, breast, lung, colon, bladder, prostate and kidney carcinomas. The aim of the present review is to examine the pharmacokinetics, mechanisms, effectiveness and adverse effects of silibinin's anti-cancer actions reported to date in pre-clinical and clinical trials. The review will also discuss the results of current research efforts seeking to determine the extent to which the effectiveness of silibinin as an adjunct cancer treatment is influenced by such factors as histologic subtype, hormonal status, stromal interactions and drug metabolising gene polymorphisms. The results of these studies may help to more precisely target and dose silibinin therapy to optimise clinical outcomes for oncology patients.[11]
Wang et al observed protective superoxide generation in human breast cancer cells via silibinin administration: The pharmacological activity of polyphenolic silibinin from milk thistle (Silybum marianum) is primarily due to its antioxidant property. However, this study found that silibinin promoted sustained superoxide (O(2)(.-)) production that was specifically scavenged by exogenous superoxide dismutase (SOD) in MCF-7 cells, while the activity of endogenous SOD was not changed by silibinin. Previous work proved that silibinin induced MCF-7 cell apoptosis through mitochondrial pathway and this study further proved that O(2)(.-) generation induced by silibinin was also related to mitochondria. It was found that respiratory chain complexes I, II and III were all involved in silibinin-induced O(2)(.-) generation. Moreover, it was found that silibinin-induced O(2)(.-) had protective effect, as exogenous SOD markedly enhanced silibinin-induced apoptosis.[12]
Haddad et al extol the therapeutic potential of silibinin in treating nonalcoholic steatohepatitis (NASH): Nonalcoholic steatohepatitis (NASH) is a progressive liver disease related to the metabolic syndrome, obesity and diabetes. The rising prevalence of NASH and the lack of efficient treatments have led to the exploration of different therapeutic approaches. Milk thistle (Silibum marianum) is a medicinal plant used for its hepatoprotective properties in chronic liver disease since the 4th century BC...Silibinin also decreased O(2)(*-) release and returned the relative liver weight as well as GSH back to normal. Our results suggest that milk thistle's extract, silibinin, possesses antioxidant, hypoinsulinemic and hepatoprotective properties that act against NASH-induced liver damage. This medicinal herb thus shows promising therapeutic potential for the treatment of NASH.[13]
Lu et al found dramatic reversals in methamphetamine-induced cognitive impairment in mice treated first with methamphetamine, then with silibinin: Cognitive deficits are a core feature of patients with methamphetamine (METH) abuse....Silibinin dose-dependently ameliorated the impairment of recognition memory caused by METH treatment in mice. Silibinin significantly attenuated the decreases in the dopamine content of the prefrontal cortex and serotonin content of the hippocampus caused by METH treatment. We also found a correlation between the recognition values and dopamine and serotonin contents of the prefrontal cortex and hippocampus. The effect of silibinin on cognitive impairment may be associated with an amelioration of decreases in dopamine and serotonin levels in the prefrontal cortex and hippocampus, respectively. These results suggest that silibinin may be useful as a pharmacological tool to investigate the mechanisms of METH-induced cognitive impairments. [14]
Silymarin may help patients with type II diabetes by assisting in blood sugar control similarly to the way therapeutic insulin is used in insulin-dependent type II diabetics.[15]
Cititations: [1]Al-Anati L, Essid E, Reinehr R, Petzinger E. Silibinin protects OTA-mediated TNF-alpha release from perfused rat livers and isolated rat Kupffer cells. Mol Nutr Food Res 53 (4): 460–6. [2]Jayaraj R, Deb U, Bhaskar AS, Prasad GB, Rao PV. Hepatoprotective efficacy of certain flavonoids against microcystin induced toxicity in mice. Environ. Toxicol. 22 (5): 472–9. 2007. [3]Mokhtari MJ, Motamed N, Shokrgozar MA. Evaluation of silibinin on the viability, migration and adhesion of the human prostate adenocarcinoma (PC-3) cell line. Cell Biol. Int. 32 (8): 888–92. 2008. [4]Bhatia N, Zhao J, Wolf DM, Agarwal R. Inhibition of human carcinoma cell growth and DNA synthesis by silibinin, an active constituent of milk thistle: comparison with silymarin. Cancer Lett. 147 (1-2): 77–84. 1999. [5]Hogan FS, Krishnegowda NK, Mikhailova M, Kahlenberg MS. Flavonoid, silibinin, inhibits proliferation and promotes cell-cycle arrest of human colon cancer. J. Surg. Res. 143 (1): 58–65. 2007. [6]Sharma G, Singh RP, Chan DC, Agarwal R. Silibinin induces growth inhibition and apoptotic cell death in human lung carcinoma cells. Anticancer Res. 23 (3B): 2649–55. 2003. [7]Wagoner J, Negash A, Kane OJ, Martinez LE, Nahmias Y, Bourne N, Owen DM, Grove J, Brimacombe C, McKeating JA, Pécheur EI, Graf TN, Oberlies NH, Lohmann V, Cao F, Tavis JE, Polyak SJ. Multiple effects of silymarin on the hepatitis C virus lifecycle. Hepatology. 2010 Jun;51(6):1912-21. [8]Neumann UP, Biermer M, Eurich D, Neuhaus P, Berg T. Successful prevention of hepatitis C virus (HCV) liver graft reinfection by silibinin mono-therapy. J Hepatol. 2010 Jun;52(6):951-2. [9]Polyak SJ, Morishima C, Lohmann V, Pal S, Lee DY, Liu Y, Graf TN, Oberlies NH. Identification of hepatoprotective flavonolignans from silymarin. Proc Natl Acad Sci U S A. 2010 Mar 30;107(13):5995-9. [10]Kim CS, Choi SJ, Park CY, Li C, Choi JS. Effects of silybinin on the pharmacokinetics of tamoxifen and its active metabolite, 4-hydroxytamoxifen in rats. Anticancer Res. 2010 Jan;30(1):79-85. [11]Cheung CW, Gibbons N, Johnson DW, Nicol DL. Silibinin--a promising new treatment for cancer. Anticancer Agents Med Chem. 2010 Mar;10(3):186-95. [12]Wang HJ, Jiang YY, Wei XF, Huang H, Tashiro S, Onodera S, Ikejima T. Silibinin induces protective superoxide generation in human breast cancer MCF-7 cells. Free Radic Res. 2010 Jan;44(1):90-100. [13]Haddad Y, Vallerand D, Brault A, Haddad PS. Antioxidant and Hepatoprotective Effects of Silibinin in a Rat Model of Nonalcoholic Steatohepatitis. Evid Based Complement Alternat Med. 2009 Nov 1. [14]Lu P, Mamiya T, Lu L, Mouri A, Niwa M, Kim HC, Zou LB, Nagai T, Yamada K, Ikejima T, Nabeshima T. Silibinin attenuates cognitive deficits and decreases of dopamine and serotonin induced by repeated methamphetamine treatment. Behav Brain Res. 2010 Mar 5;207(2):387-93. [15]Huseini HF, Larijani B, Heshmat R, et al. The efficacy of Silybum marianum (L.) Gaertn. (silymarin) in the treatment of type II diabetes: a randomized, double-blind, placebo-controlled, clinical trial. Phytother Res 20 (12): 1036–9. 2006.
*The latter article is intended for educational / informational purposes only. THIS PRODUCT IS INTENDED AS A RESEARCH CHEMICAL ONLY. This designation allows the use of research chemicals strictly for in vitro testing and laboratory experimentation only. Bodily introduction of any kind into humans or animals is strictly forbidden by law.
Exemestane
Exemestane, sold as Aromasin, is a steroidal aromatase inhibitor (AI) primarily administered in the adjuvant treatment of hormonally responsive breast cancer in postmenopausal women. In that type of cancer, higher estrogen levels are correlated with recurrence of cancer and with more severe manifestations. Exemestane renders the aromatase enzyme permanently inactive by binding permanently to circulating aromatase in the body. Estrogen in pre-menopausal women originates from the ovaries primarily, while in post-menopausal women aromatase converts steroidal compounds reversed from the adrenal glands into estreogen.[1] Exemestane is what is referred to as an irreversible steroidal aromatase inactivator or "suicide inhibitor". Exemestane is structurally similar to the target of the enzymes, and thus permanently binds to those enzymes which disrupts their task of converting androgens into estrogens.[1]
Data comparing exemestane with tamoxifen indicates that exemestane is as effective in the primary adjuvant treatment of early-stage breast cancer in postmenopausal women.[1]
Maurus writes of use of aromatase inhibitors in treatment of childhood growth deficiency: The approach to the child with growth retardation who is in puberty remains an important clinical challenge. The use of high-dose growth hormone (GH), suppression of puberty with GnRH analogs in combination with GH, and the use of selective inhibitors of the aromatase enzyme with aromatase inhibitors (also in combination with GH) are all therapeutic choices that have been studied. Aromatase blockade effectively blocks estrogen production in males with a reciprocal increase in testosterone, and a new generation of aromatase inhibitors, including anastrozole, letrozole and exemestane, is under investigation in adolescent subjects with severe growth retardation. This class of drugs, if judiciously used for a window of time, offers promise as an adjunct treatment of growth delay in pubertal patients with GH deficiency, idiopathic short stature, testotoxicosis, and other disorders of growth. These evolving uses of aromatase inhibitors, however, represent off-label use of the product, and definitive data on their efficacy are not available for each of the conditions mentioned. Safety issues regarding bone health also require further study.[2]
Exemestane and all AIs are eventually prone to down regulation in effect on the human body with human use. This can be a major detriment to their use as long-term treatments for cancer:
Clinical trials have demonstrated the importance of aromatase inhibitor (AI) therapy in the effective treatment of hormone-dependent breast cancers. Yet, as with all prolonged drug therapy, resistance to aromatase inhibitors does develop. To date, the precise mechanism responsible for resistance to aromatase inhibitors is not completely understood. ... several mechanisms of de novo/intrinsic resistance and acquired resistance to AIs are [worthy of further discussion]...tudies will generate important information on the mechanisms of AI resistance. Such information can be valuable for the development of treatment strategies against AI-resistant breast cancers.[3]
Exemestane is a teratogen, known for causing birth defects; thus exemestane "is marketed for use only in postmenopausal women. Its labeling includes a contraindication to use in pregnant or lactating women."[4]
Exemestane is not well studied as a monotheray for hypogonadal men or men with such pathologies as azoospermia, but other aromatase inhibitors with comparable effects are frequently used and have been shown to be clinically effective in treating hormonal deficiencies, either alone or with more direct (i.e., testosterone) hormone application.
Citations [1]Coombes RC et al. Survival and safety of exemestane versus tamoxifen after 2–3 years' tamoxifen treatment (Intergroup Exemestane Study): a randomised controlled trial. Lancet 369 (9561): 559–70. 2007. [2]Mauras N. Strategies for maximizing growth in puberty in children with short stature.Endocrinol Metab Clin North Am. 2009 Sep;38(3):613-24. [3]Chen S, Masri S, Wang X, Phung S, Yuan YC, Wu X. What do we know about the mechanisms of aromatase inhibitor resistance? J Steroid Biochem Mol Biol. 2006 Dec;102(1-5):232-40. [4]Beltrame D, di Salle E, Giavini E, Gunnarsson K, Brughera M. Reproductive toxicity of exemestane, an antitumoral aromatase inactivator, in rats and rabbits. Reprod Toxicol. 2001 Mar-Apr;15(2):195-213.
*The latter article is intended for educational / informational purposes only. THIS PRODUCT IS INTENDED AS A RESEARCH CHEMICAL ONLY. This designation allows the use of research chemicals strictly for in vitro testing and laboratory experimentation only. Bodily introduction of any kind into humans or animals is strictly forbidden by law.
Clenbuterol HCl
Clenbuterol HCl belongs to a class of drugs known as beta-2 adrenergic agonists. Its primary known mechanism of action is on the beta-2 adrenergic receptor, also known as ADRB2. [1] Beta-2 adrenergic agonists are primarily used to treat asthma and other pulmonary/respiratory disorders. Other long-acting beta-2 adrenergic agonists include salmeterol, formoterol, and bambuterol. Clenbuterol has been popularized in the public mind recently by media portrayals of off-label use for fat loss, as well as some professional athlete doping scandals involving the drug.
Clenbuterol has diverse effects, some of them through unknown mechanisms. In a study undertaken by Ngala, et al, on knockout mice with no beta-2 adrenergic receptor gene, various doses of clenbuterol stimulated glucose uptake as measured in the soleus muscle independent of any beta-2 adrenergic agonist activity. [2] Yimlamai et al write that clenbuterol not only increases skeletal muscle hypertrophy, it also attenuates muscle-wasting from disuse; this effect is apparently not mediated by locally produced IGF1. [6]
According to Spurlock et al, "Beta-adrenergic receptor agonists (BA) induce skeletal muscle hypertrophy, yet specific mechanisms that lead to this effect are not well understood." [3] Research into the matter by Spurlock et al concluded that the documented BA-induced skeletal muscle hypertrophy occurs through a complex and diverse array of pathways: Global evaluation of gene expression after administration of clenbuterol identified changes in gene expression and overrepresented functional categories of genes that may regulate BA-induced muscle hypertrophy. Changes in mRNA abundance of multiple genes associated with myogenic differentiation may indicate an important effect of BA on proliferation, differentiation, and/or recruitment of satellite cells into muscle fibers to promote muscle hypertrophy. Increased mRNA abundance of genes involved in the initiation of translation suggests that increased levels of protein synthesis often associated with BA administration may result from a general up-regulation of translational initiators. Additionally, numerous other genes and physiological pathways were identified that will be important targets for further investigations of the hypertrophic effect of BA on skeletal muscle. [3]
Daubert et al write on the anabolic and lipolytic properties of clenbuterol: Although clenbuterol is not a steroid hormone, it possesses anabolic properties that increase muscle mass. Its longer duration of action compared to other beta2-agonists (such as albuterol) make it a desired agent for body-building because of its high and prolonged serum level. The mechanism for the short and long-term cardiovascular complications of clenbuterol is complex. The anabolic effects of clenbuterol are associated with its beta2-adrenoreceptor agonist activity on striated skeletal muscles. In addition, clenbuterol promotes lipolysis through adipocyte beta3-adrenoreceptors. [5] This conclusion from a study performed by Kammalakkannan et al on convalescing heart patients gives a glimpse into clenbuterol's temptation as a performance-enhancing drug for professional athletes:
Clenbuterol, a beta(2)-agonist with potent anabolic properties, has been shown to improve skeletal muscle function in healthy subjects, and in high doses, promotes cardiac recovery in patients with left ventricular assist devices. In a small, randomized controlled study, we investigated the effect of clenbuterol on skeletal muscle function, cardiac function, and exercise capacity in patients with chronic heart failure. Clenbuterol was well tolerated and led to a significant increase in both lean mass and the lean/fat ratio. Maximal strength increased significantly with both clenbuterol (27%) and placebo (14%); however, endurance and exercise duration decreased after clenbuterol. Prior data support combining exercise training with clenbuterol to maximize performance, and on-going studies will evaluate this approach. [4]
...however, any off-label use, particularly without the supervision of a medical professional, carries with it a significant risk of misapplication, overdose, or inability to manage or mitigate undesirable effects. Partly because clenbuterol is dosed in micrograms, emergency room reports of the aforementioned problems abound; this, and the doping potential, have resulted in numerous FDA reports on the drug. The following is excerpted from a report by Daubert et al on a bodybuilder who checked himself into the emergency room after a "ten-fold dosing error" of Ventipulmin, a veterinary brand of clenbuterol syrup: His electrocardiogram (ECG) demonstrated supraventricular tachycardia with a ventricular rate of 254 bpm. Esmolol was recommended for rate control after the unsuccessful use of adenosine and diltiazem. ...The patient's urine was negative for any drugs of abuse. Clenbuterol levels were not obtained. A second ECG, 16 hours post ingestion, reflected atrial fibrillation with a ventricular rate of 125 to 147 bpm. On hospital day 3, he was electively cardioverted to sinus rhythm; heart rate and rhythm returned to normal, and he was discharged with oral metoprolol. [5]
The long duration of these effects is, of course, due to clenbuterol's 39-hour half-life in the body, another aspect likely to be overlooked by those casually using or abusing the drug without proper medical knowledge or support from a professional.
Conclusion: Because long-term administration of clenbuterol and some other beta-agonists results in various detrimental effects, these drugs offer a potent approach for shorter-term treatment as long as the side-effects are managed and taken into account. Ironically, they are probably not suitable for asthma treatment in most patients, at least not as a stand-alone option, a first choice or, preferably for long-term use. Prather et al write that "If this category of drugs does preserve lean mass in humans, there are legitimate medical applications. Trials of efficacy and safety are needed," but also that "[t]he rate of extrapolation from animal studies to unsupervised human usage is alarming." [7]
On management of skeletal muscle-wasting, the most compelling but least-studied (in actual human subjects), Ryall and Lynch write: Stimulation of the pathway with beta-adrenoceptor agonists (beta-agonists) has therapeutic potential for muscle wasting disorders including: sarcopenia, cancer cachexia, disuse and inactivity, unloading or microgravity, sepsis and other metabolic disorders, denervation, burns, HIV-AIDS, chronic kidney or heart failure, and neuromuscular diseases. However, there are also pitfalls associated with beta-agonist administration and clinical applications have so far been limited, largely because of cardiovascular side effects. In rats and mice, newer generation beta-agonists (such as formoterol) can elicit an anabolic response in skeletal muscle even at very low doses, with reduced effects on the heart and cardiovascular system compared with older generation beta-agonists (such as fenoterol and clenbuterol). However, the potentially deleterious cardiovascular side effects of beta-agonists have not been obviated completely and so it is important to refine their development and therapeutic approach in order to overcome these obstacles. [8]
Citations: [2] Ngala RA, O'Dowd J, Wang SJ, Stocker C, Cawthorne MA, Arch JR. Br J Pharmacol. Beta2-adrenoceptors and non-beta-adrenoceptors mediate effects of BRL37344 and clenbuterol on glucose uptake in soleus muscle: studies using knockout mice. 2009 Dec;158(7):1676-82. [3] Spurlock DM, McDaneld TG, McIntyre LM. Changes in skeletal muscle gene expression following clenbuterol administration. Department of Animal Sciences, Iowa State University, Ames, IA, USA. moodyd@iastate.edu[4] Kamalakkannan G, Petrilli CM, George I, LaManca J, McLaughlin BT, Shane E, Mancini DM, Maybaum S. Clenbuterol increases lean muscle mass but not endurance in patients with chronic heart failure. J Heart Lung Transplant. 2008 Apr;27(4):457-61. [5] Daubert GP, Mabasa VH, Leung VW, Aaron C. Acute clenbuterol overdose resulting in supraventricular tachycardia and atrial fibrillation. J Med Toxicol. 2007 Jun;3(2):56-60. [6] Yimlamai T, Dodd SL, Borst SE, Park S. Clenbuterol induces muscle-specific attenuation of atrophy through effects on the ubiquitin-proteasome pathway. J Appl Physiol. 2005 Jul;99(1):71-80. Epub 2005 Mar 17. [7] Prather ID, Brown DE, North P, Wilson JR. Clenbuterol: a substitute for anabolic steroids? Med Sci Sports Exerc. 1995 Aug;27(8):1118-21. [8] Ryall JG, Lynch GS. The potential and the pitfalls of beta-adrenoceptor agonists for the management of skeletal muscle wasting. Pharmacol Ther. 2008 Dec;120(3):219-32. Epub 2008 Sep 16.
*The latter article is intended for educational / informational purposes only. THIS PRODUCT IS INTENDED AS A RESEARCH CHEMICAL ONLY. This designation allows the use of research chemicals strictly for in vitro testing and laboratory experimentation only. Bodily introduction of any kind into humans or animals is strictly forbidden by law.
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