March 2015

  1. What is BPC 157?

    The effect of BPC157, with or without growth hormone (GH), on proliferating cell nuclear antigen (PCNA) gene expression (dRn) in rat tendon fibroblasts. Asterisks indicate significant effects. From Chang et al., Pentadecapeptide BPC 157 enhances the growth hormone receptor expression in tendon fibroblasts, Molecules (Basel, Switzerland). 2014;19(11):19066-19077.

    The effect of BPC157, with or without growth hormone (GH), on proliferating cell nuclear antigen (PCNA) gene expression (dRn) in rat tendon fibroblasts. Asterisks indicate significant effects. From Chang et al., Pentadecapeptide BPC 157 enhances the growth hormone receptor expression in tendon fibroblasts, Molecules (Basel, Switzerland). 2014;19(11):19066-19077.

      BPC157 is a 15-amino acid peptide compound linked to a number of medical and scientific applications1. It is associated with protective effects against stomach ulcers, as assessed by clinical models of this disorder (i.e. 96% ethanol-induced lesions)2. BPC157 is also associated with beneficial effects on blood pressure. The mechanisms of action of BPC157 are not completely understood, but may be indirectly linked to endothelial (cells in the linings of many organs and systems, including the gut) nitric oxide (NO) production. BPC157 has demonstrated an ability to generate NO comparable to that of similar doses of L-arginine in in vitro studies using samples of rat gastric mucosa. Studies using stomach ulcer models have found that the anti-ulcer effects of the NO precursor, L-arginine, are reversed by N(G)-nitro-L-arginine methylester (L-NAME), which inhibits NO production2. However, L-NAME may only attenuate (slow down or partially reverse) the effects of BPC157 on lesions2. Another study investigated the effect of BPC157, alone or combined with L-arginine (200 mg/kg), L-NAME (5 mg/kg), or both, on experimental colonic fistulas (severe gastrointestinal lesions that may connect the colon to other surfaces, including skin) in rats. 10 μg/kg doses of this peptide, intraperitoneally or in drinking water, resulted in rapid healing of these lesions, leading to their closure3. Groups receiving BPC157 with L-NAME, L-arginine or both also exhibited fistula healing, despite the detrimental effect of L-NAME administration (without BPC157 or L-arginine) on the same3. BPC157 may also have a role in the healing of other tissue types, including muscle, ligaments and tendons4. Intraperitoneal or cutaneous (i.e. as a cream) administrations of this peptide improved markers of healing (e.g. reduced edema or hematoma and enzymes such as alanine aminotransferase or creatine kinase) in a rat model of muscle injury5. BPC157 may also affect the central nervous system. A single 10 μg/kg intraperitoneal dose of this peptide resulted in reductions in the synthesis of serotonin in several rat brain regions, including the thalamus, hypothalamus and hippocampus compared to control rats1. However, this also resulted in increased synthesis of the same neurotransmitter in other brain regions, such as the substantia nigra1. A seven-day regimen of subcutaneous BPC157 (10 μg/kg per dose) resulted in significant increases of serotonin synthesis in the substantia nigra, nucleus accumbens and lateral caudate. This indicates that BPC157 may have the potential to affect memory, emotional responses and/or processing and homeostatis1. BPC157 may also be applied to the treatment of alcohol withdrawal and toxicity. A study used a mouse model of toxicity (i.e. acute intoxication with ethanol) to investigate this possibility. A 10 μg/kg intraperitoneal dose of BPC157 quickly reversed the symptoms of acute intoxication (e.g. anesthesia, hypothermia, absence of self-righting reflex and increased risk of mortality)6. This study also assessed the effect of BPC157 on withdrawal after access to 20% ethanol for thirteen days. The same dose of the peptide also resulted in reduced symptoms of this (e.g. seizure). Rats and mice treated with BPC157 showed decreases in clinical biomarkers following experimentally-induced congestive heart failure7. BPC157 (at the doses as above) has also demonstrated beneficial effects on increased portal pressure and liver damage in animal models of chronic alcohol intake7. 1. Tohyama Y, Sikiric P, Diksic M. Effects of pentadecapeptide BPC157 on regional serotonin synthesis in the rat brain: alpha-methyl-L-tryptophan autoradiographic measurements. Life sciences. 2004;76(3):345-357. 2. Sikiric P, Seiwerth S, Grabarevic Z, et al. The influence of a novel pentadecapeptide, BPC 157, on N(G)-nitro-L-arginine methylester and L-arginine effects on stomach mucosa integrity and blood pressure. European journal of pharmacology. 1997;332(1):23-33. 3. Klicek R, Sever M, Radic B, et al. Pentadecapeptide BPC 157, in clinical trials as a therapy for inflammatory bowel disease (PL14736), is effective in the healing of colocutaneous fistulas in rats: role of the nitric oxide-system. Journal of pharmacological sciences. 2008;108(1):7-17. 4. Chang CH, Tsai WC, Hsu YH, Pang JH. Pentadecapeptide BPC 157 enhances the growth hormone receptor expression in tendon fibroblasts. Molecules (Basel, Switzerland). 2014;19(11):19066-19077. 5. Novinscak T, Brcic L, Staresinic M, et al. Gastric pentadecapeptide BPC 157 as an effective therapy for muscle crush injury in the rat. Surgery today. 2008;38(8):716-725. 6. Boban-Blagaic A, Blagaic V, Romic Z, et al. The influence of gastric pentadecapeptide BPC 157 on acute and chronic ethanol administration in mice. The effect of N(G)-nitro-L-arginine methyl ester and L-arginine. Medical science monitor : international medical journal of experimental and clinical research. 2006;12(1):Br36-45. 7. Lovric-Bencic M, Sikiric P, Hanzevacki JS, et al. Doxorubicine-congestive heart failure-increased big endothelin-1 plasma concentration: reversal by amlodipine, losartan, and gastric pentadecapeptide BPC157 in rat and mouse. Journal of pharmacological sciences. 2004;95(1):19-26.
  2. What is Toremifene Citrate?

    toremifene

    "Toremifene" by Fvasconcellos. Licensed under Public Domain via Wikimedia Commons - https://commons.wikimedia.org/wiki/File:Toremifene.svg#mediaviewer/File:Toremifene.svg

      Toremifene Citrate and its Applications in Animal Studies This is a selective estrogen receptor modulator currently associated with the treatment of metastatic breast cancer and disorders associated with menopause in humans. Toremifene is associated with a reduced potential for genotoxicity in comparison to other similar drugs such as tamoxifen1. It is in common use as a standard against which new estrogen receptor modulators (or other agonists/antagonists) are compared in animal trials2. Toremifene was also recently used to validate a transgenic rat assay designed to detect the carcinogenicity of chemicals under evaluation3. Female transgenic rats were given 40mg/kg toremifene by gavage every day for three weeks, to simulate a repeated-dose regimen3. This was found not to result in mutations in comparison to the same dose of tamoxifen at the same frequency3. The transgenic adenocarcinoma of the mouse prostate model is a model of cancer in this organ. Toremifene was found to protect against cancer development in studies using this model4. This drug is also incorporated into animal studies of combined cancer therapies. Toremifene alone and in combination with atamestane (an irreversible estrogen synthesis blocker) were associated with significant decreases in the low-density lipoprotein and serum cholesterol of ovarectomized rats (a model of estrogen-blocking therapy in breast cancer)5. It was also associated with significant positive effects on bones in these rats5. This combination (1mg toremifene plus 1mg atamestane per day) was found to be equal in effect to toremifene alone in reducing uterine tumor growth in mice injected with Ac1 cancer cells6. A combination of 30 or 120mg/day toremifene and local hyperthermia in nude mice injected with MCF-7 breast cancer line cells found that the anti-tumor effects were significantly greater in the groups receiving these treatments than groups receiving either dose of toremifene alone7. Toremifene as an Anti-Infective Toremifene has been shown to prevent the formation of biofilms associated with micro-organisms including several subspecies of Staphylococcus (including S. aureus) and Candida, as well as Pseudomonas aeruginosa8. A rat model of subcutaneous catheter placement demonstrated the efficacy of toremifene against the biofilm formation of S. aureus and C. albicans8. This may indicate the potential role of toremifene in preventing infection in porous implants incorporating metal and other materials9. The pre-incubation of subinhibitory concentrations of toremifene also significantly enhanced the inhibition of C. albicans and C. glabrata biofilms by the classic antifungals caspofungin and amphotericin B10. This also enhanced the inhibition of mixed S. epidermis and C. albicans biofilms by caspofungin10. Toremifene may also be a potent anti-Ebola virus drug11. An in vivo mouse model found that this drug inhibited Ebola virus infection, even in the absence of estrogen receptors11. Toremifene inhibited viral entry after internalization. These findings indicate that the drug may act through alternative pathways to prevent infection11. References: 1. Kim SY, Suzuki N, Laxmi YR, Umemoto A, Matsuda T, Shibutani S. Antiestrogens and the formation of DNA damage in rats: a comparison. Chemical research in toxicology. 2006;19(6):852-858. 2. Kangas L, Harkonen P, Vaananen K, Keskitalo J, Eigeliene N. Effects of ospemifene on breast tissue morphology and proliferation: a comparative study versus other selective estrogen receptor modulators in ovariectomized rats. Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme. 2014;46(5):328-332. 3. Kawamura Y, Hayashi H, Kurata Y, Hiratsuka K, Masumura K, Nohmi T. Evaluation of the genotoxicity of tamoxifen in the liver and kidney of F344 gpt delta transgenic rat in 3-week and 13-week repeated dose studies. Toxicology. 2013;312:56-62. 4. Nguewa PA, Calvo A. Use of transgenic mice as models for prostate cancer chemoprevention. Current molecular medicine. 2010;10(8):705-718. 5. Goss PE, Qi S, Hu H. Comparing the effects of atamestane, toremifene and tamoxifen alone and in combination, on bone, serum lipids and uterus in ovariectomized rats. The Journal of steroid biochemistry and molecular biology. 2009;113(3-5):233-240. 6. Sabnis GJ, Macedo L, Goloubeva O, Schayowitz A, Zhu Y, Brodie A. Toremifene-atamestane; alone or in combination: predictions from the preclinical intratumoral aromatase model. The Journal of steroid biochemistry and molecular biology. 2008;108(1-2):1-7. 7. Kanaya Y, Doihara H, Shiroma K, Ogasawara Y, Date H. Effect of combined therapy with the antiestrogen agent toremifene and local hyperthermia on breast cancer cells implanted in nude mice. Surgery today. 2008;38(10):911-920. 8. De Cremer K, Delattin N, De Brucker K, et al. Oral administration of the broad-spectrum antibiofilm compound toremifene inhibits Candida albicans and Staphylococcus aureus biofilm formation in vivo. Antimicrobial agents and chemotherapy. 2014;58(12):7606-7610. 9. Braem A, De Cremer K, Delattin N, et al. Novel anti-infective implant substrates: Controlled release of antibiofilm compounds from mesoporous silica-containing macroporous titanium. Colloids and surfaces. B, Biointerfaces. 2015. 10. Delattin N, De Brucker K, Vandamme K, et al. Repurposing as a means to increase the activity of amphotericin B and caspofungin against Candida albicans biofilms. The Journal of antimicrobial chemotherapy. 2014;69(4):1035-1044. 11. Johansen LM, Brannan JM, Delos SE, et al. FDA-approved selective estrogen receptor modulators inhibit Ebola virus infection. Science translational medicine. 2013;5(190):190ra179.

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