Fagron North America, IACP, NCPA: Nominators
Pharmacy Compounding Advisory Committee review of Chrysin
June 23, 2016 Chrysin
• Naturally occurring bioflavonoid and polyphenolic compound
• Found in passion flower indian trumpet flower, honeycomb, chamomile and oyster mushrooms Chrysin
• Bioflavonoids such as chrysin can act as chemical messengers
• Necessary in the production of plant pigmentations
• Involved in UV filtration
• Influence the symbiotic relationships of nitrogen fixation Chrysin
• FDA has stated that it is a small molecule, can be characterized easily, and is relatively stable under ordinary storage conditions
• Chrysin actually has a molecular size of 254.2375 g/mol
• Molecular weight consistent with that of steroid hormones Oral supplement dosing
• Because of low bioavailability oral dosing is typically referenced at 400 mg – 3 g
Br J Clin Pharmacol. 2001 Feb; 51(2): 143–146. Disposition and metabolism of the flavonoid chrysin in normal volunteers T Walle, Y Otake, J A Brubaker, U K Walle, and P V Halushka Conculsion
Even though the systemic availability of chrysin appears to be low, this does not exclude the occurrence of local biological effects of the flavonoid, particularly in the intestine. In summary, this study supports the view that the bioavailability of chrysin, and possibly other flavonoids, in humans is very low, due to extensive presystemic intestinal as well as hepatic glucuronidation… Topical administration feasibility • It has been shown in the study of trans dermal drug delivery systems that one of the main criteria for feasibility of drug delivery through the skin is small molecular size of 500 Daltons or less
• Other references states that unionized entities have better absorption. chrysin is non polar.
ABSTRACT Transdermal drug delivery is the application of drug on the skin surface so that it can permeate through the skin and reaches the systemic circulation. Skin contains 10-70 hair follicles and 200-250 sweat ducts per cm2 of the skin so it is easily accessible by drugs and provides a mean of drug delivery via the skin. It was recognized as drug delivery route several decades ago but stratum corneum of the skin poses a problem in permeation of drugs. Transdermal route have a number of advantages over conventional drug delivery routes such as avoidance of first pass effect, enhanced bioavailability, patient compliance, steady state plasma drug level, painless delivery of drugs, ease of application and easy removal of patch in case of toxicity…
Jhawat VC, Saini V, Kamboj S, Maggon N. Transdermal Drug Delivery Systems : Approaches and Advancements in Drug Absorption through Skin. 2013;20(1):47-56. Chrysin efficacy potential
Environ Health Perspect. 1998 Feb;106(2):85-92. Molecular basis of the inhibition of human aromatase (estrogen synthetase) by flavone and isoflavone phytoestrogens: A site-directed mutagenesis study. Kao YC1, Zhou C, Sherman M, Laughton CA, Chen S. Abstract Flavone and isoflavone phytoestrogens are plant chemicals and are known to be competitive inhibitors of cytochrome P450 aromatase with respect to the androgen substrate. Aromatase is the enzyme that converts androgen to estrogen; therefore, these plant chemicals are thought to be capable of modifying the estrogen level in women. In this study, the inhibition profiles of four flavones [chrysin (5, 7- dihydroxyflavone), 7,8-dihydroxyflavone, baicalein (5,6,7-trihydroxyflavone), and galangin (3,5,7-trihydroxyflavone)], two isoflavones [genistein (4,5,7- trihydroxyisoflavone) and biochanin A (5,7-dihydroxy-4-methoxyisoflavone)], one flavanone [naringenin (4, 5,7-trihydroxyflavanone)], and one naphthoflavone (alpha-naphthoflavone) on the wild-type and six human aromatase mutants (I133Y, P308F, D309A, T310S, I395F, and I474Y) were determined. In combination with computer modeling, the binding characteristics and the structure requirement for flavone and isoflavone phytoestrogens to inhibit human aromatase were obtained. These compounds were found to bind to the active site of aromatase in an orientation in which rings A and C mimic rings D and C of the androgen substrate, respectively. This study also provides a molecular basis as to why isoflavones are significantly poorer inhibitors of aromatase than flavones. Chrysin efficacy potential
J Endocrinol. 2008 May;197(2):315-23. doi: 10.1677/JOE-07-0282. Chrysin, a natural flavonoid enhances steroidogenesis and steroidogenic acute regulatory protein gene expression in mouse Leydig cells. Jana K1, Yin X, Schiffer RB, Chen JJ, Pandey AK, Stocco DM, Grammas P, Wang X. Abstract During the aging process of males, testosterone biosynthesis declines in testicular Leydig cells resulting in decreases in various physiological functions. To explore the possibility of delaying the decline using food supplements, we have studied steroidogenic effects of a natural flavonoid, chrysin, in mouse Leydig cells. Chrysin dramatically increased cyclic AMP (cAMP)-induced steroidogenesis in MA-10 mouse Leydig tumor cells. This result was confirmed using Leydig cells isolated from mouse testes. The steroidogenic effect of chrysin is not associated with an increase in expression of the P450 side-chain cleavage enzyme, required for the conversion of cholesterol to pregnenolone. In addition, when 22(R)hydroxylcholesterol was used as a substrate, chrysin induced a non-significant increase in steroid hormone, suggesting that the majority of the observed increase in steroidogenesis was due to the increased supply of substrate cholesterol. These observations were corroborated by showing that chrysin induced a marked increase in the expression of steroidogenic acute regulatory (StAR) protein, the factor that controls mitochondrial cholesterol transfer. Also, chrysin significantly increased StAR promoter activity and StAR mRNA level. Further studies indicated that this compound depressed expression of DAX-1, a repressor in StAR gene transcription. In the absence of cAMP, chrysin did not increase steroidogenesis. However, when a sub-threshold level of cAMP was used, StAR protein and steroid hormone were increased by chrysin to the levels seen with maximal stimulation of cAMP. These results suggest that while chrysin itself is unable to induce StAR gene expression and steroidogenesis, it appears to function by increasing the sensitivity of Leydig cells to cAMP stimulation. Chrysin efficacy potential
J Med Food. 2002 Spring;5(1):43-8. Beneficial effects of chrysin and benzoflavone on virility in 2-year-old male rats. Dhawan K1, Kumar S, Sharma A. Abstract This work describes the potential usefulness of bioflavonoids for countering the deleterious effects of aging on male sexuality in 2-year-old rats. A flavone chrysin from Passiflora caerulea Linn. and a benzoflavone moiety (BZF) recently isolated from Passiflora incarnata Linn. were administered to 2-year-old male rats for a period of 30 days. After cessation of these treatments, there was a significant improvement in overall sexual functions in the rats given bioflavonoids, compared with control rats. The rats receiving chrysin (1 mg/kg) and BZF (10 mg/kg) exhibited increased libido when they were allowed to interact with nonestrous female rats. Additionally, both treated groups had increased sperm count, greater fertilization potential, and greater litter size when they were allowed to interact with proven proestrous female rats of a similar strain. BZF was more potent than chrysin as an antiaromatase agent and exhibited better effects on the sexual system of the 2- year-old male rats. Plant flavonoids have great potential for clinical and therapeutic applications against the physiological and biochemical effects of aging. Chrysin efficacy potential
Andrologia. 2012 Jun;44(3):181-6. doi: 10.1111/j.1439-0272.2010.01127.x. Epub 2011 Mar 7. Beneficial effects of chrysin on the reproductive system of adult male rats. Ciftci O1, Ozdemir I, Aydin M, Beytur A.
Abstract In this study, the beneficial effect of chrysin, a natural flavonoid currently under investigation due to its important biological activities, on reproductive system of rats was investigated. Rats (n = 16) were divided randomly into two equal groups. Rats in control group were given corn oil as carrier. Chrysin was orally administered at the dose of 50 mg kg(-1) per day by gavages, and it was dissolved in corn oil for 60 days. Tissue thiobarbituric acid reactive substances (TBARS) and glutathione (GSH) levels, antioxidant enzyme activity (CAT, SOD and GSH-Px), sperm parameters (motility, concentration and abnormal sperm rate), reproductive organ weight (testes, epididymis, vesicula seminalis, prostate) and serum testosterone levels were determined in the rats. Our results indicated that chrysin significantly increased GSH, CAT, GSH-Px and CuZn-SOD levels, but did not change the formation of TBARS significantly. In addition, sperm motility, sperm concentration and serum testosterone levels significantly increased, whereas abnormal sperm rate significantly decreased with chrysin treatment. In conclusion, it is suggested that treatment with chrysin can positively affect the reproductive system in rats, and it can be used for the treatment of male infertility. Mutagenicity
• FDA points to study in bacteria strains using the Ames test.
• Within the study below referenced chrysin showed Negative mutagenicty across every strain tested.
• The Ames test has been shown to have greater sensitivity, specificity, and predictability over other forms of mutagenic testing in various carcinogen testing.
D. Kirkland, M. Aardema, L. Henderson, L. Müller Evaluation of the ability of a battery of three in vitro genotoxicity tests to discriminate rodent carcinogens and non-carcinogens I. Sensitivity, specificity and relative predictivity Mutat Res, 584 (2005) 1–256 P. Steinberg (editor), High-throughput Screening Methods in Toxicity Testing, p. 213–69, Copyright 2013, Hoboken (NJ): John Wiley & Sons, Inc., Mutagenicity
Molecules. 2012 May 7;17(5):5255-68. doi: 10.3390/molecules17055255. Mutagenicity of flavonoids assayed by bacterial reverse mutation (Ames) test. Resende FA1, Vilegas W, Dos Santos LC, Varanda EA.
Abstract The mutagenicity of ten flavonoids was assayed by the Ames test, in Salmonella typhimurium strains TA98, TA100 and TA102, with the aim of establishing hydroxylation pattern- mutagenicity relationship profiles. The compounds assessed were: quercetin, kaempferol, luteolin, fisetin, chrysin, galangin, flavone, 3-hydroxyflavone, 5-hydroxyflavone and 7-hydroxyflavone. In the Ames assay, quercetin acted directly and its mutagenicity increased with metabolic activation. In the presence of S9 mix, kaempferol and galangin were mutagenic in the TA98 strain and kaempferol showed signs of mutagenicity in the other strains. The absence of hydroxyl groups, as in flavone, only signs of mutagenicity were shown in strain TA102, after metabolization and, among monohydroxylated flavones (3-hydroxyflavone, 5-hydroxyflavone and 7-hydroxyflavone), the presence of hydroxyl groups only resulted in minor changes. Luteolin and fisetin also showed signs of mutagenicity in strain TA102. Finally, chrysin, which has only two hydroxy groups, at the 5-OH and 7-OH positions, also did not induce mutagenic activity in any of the bacterial strains used, under either activation condition. All the flavonoids were tested at concentrations varying from 2.6 to 30.7 nmol/plate for galangin and 12.1 to 225.0 nmol/plate for other flavonoids. In light of the above, it is necessary to clarify the conditions and the mechanisms that mediate the biological effects of flavonoids before treating them as therapeutical agents, since some compounds can be biotransformed into more genotoxic products; as is the case for galangin, kaempferol and quercetin. Neuroprotective effects Neurochem Int. 2015 Nov;90:224-31. doi: 10.1016/j.neuint.2015.09.006. Epub 2015 Sep 18. Neuroprotective effects of chrysin: From chemistry to medicine. Nabavi SF1, Braidy N2, Habtemariam S3, Orhan IE4, Daglia M5, Manayi A6, Gortzi O7, Nabavi SM8.
Abstract The World Health Organization estimated that the proportion of older people (over 60 years) will increase from 11% to 22% during next 40 years throughout the world. With respect to this, the morbidity and mortality rates of age-related diseases will increase. Mental diseases are the most common and important health problems among elderly people. Therefore, much attention has been paid to the discovery of neuroprotective drugs with high efficacy and negligible adverse effects. A growing body of scientific evidence has shown that phytochemicals possess neuroprotective effects and also mitigate neurodegeneration under both in vivo and in vitro conditions. Polyphenolic compounds, especially flavonoids, are known as most common chemical class of phytochemicals which possess a multiple range of health promoting effects. Chrysin, belonging to the flavone class, is one of the most important bioactive constituents of different fruits, vegetables and even mushrooms. Chrysin possesses potent neuroprotective effects and suppress neuroinflammation. In addition, chrysin improves cognitive decline and possesses a potent anti- amyloidogenic and neurotrophic effects. Furthermore, beneficial effects of chrysin on both depression and epilepsy have been reported. The present paper aimed to critically review the available literature data regarding the neuroprotective effects of chrysin as well as its chemistry, sources and bioavailability. Elmore, M.R.P., Lee, R.J., West, B.L., Green, K.N., 2015. Characterizing newly repo- pulated microglia in the adult mouse: impacts on animal behavior, cell morphology, and neuroinflammation. PLoS One 10, e0122912. Hepatoprotective effects
Eur J Pharmacol. 2010 Apr 10;631(1-3):36-41. doi: 10.1016/j.ejphar.2009.12.031. Epub 2010 Jan 6. Effect of chrysin on hepatoprotective and antioxidant status in D- galactosamine-induced hepatitis in rats. Pushpavalli G1, Kalaiarasi P, Veeramani C, Pugalendi KV.
Abstract Chrysin is a natural, biologically active compound present in many plants and possesses potent anti-inflammatory, anticancer and antioxidation properties. This work was designed to investigate the effect of chrysin, on the hepatoprotective efficacy in d-galactosamine-intoxication rats. d-galactosamine-induced toxicity was manifested by the elevation of serum hepatic marker enzyme activities (aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase and gamma-glutamyl transpeptidase) and the lipid peroxidation process and by decreasing the antioxidant capacity of the plasma, erythrocyte and tissues. Treatment with chrysin (25, 50 and 100mg/kg body weight) decreased hepatic marker enzyme activities and lipid peroxidation products such as thiobarbituric acid reactive substances, lipid hydroperoxides and conjugated dienes, increased the activities of free-radical scavenging enzymes superoxide dismutase, catalase and glutathione peroxidase and the levels of non-enzymatic antioxidants reduced glutathione, vitamin C and vitamin E. These findings demonstrate that chrysin acts as a hepatoprotective and antioxidant agent against d-galactosamine-induced hepatotoxicity. Hepatoprotective effects
Food Chem Toxicol. 2010 Jun;48(6):1654-9. doi: 10.1016/j.fct.2010.03.040. Epub 2010 Mar 31. Influence of chrysin on hepatic marker enzymes and lipid profile against D- galactosamine-induced hepatotoxicity rats. Pushpavalli G1, Veeramani C, Pugalendi KV. Abstract Chrysin is a flavonoid that exists in nature and is the major component of some traditional medicinal herbs. We investigated the hepatoprotective and antihyperlipidaemic potential of chrysin against D- galactosamine (a single intraperitoneal injection 400 mg/kg BW) induced hepatotoxicity in male albino Wistar rats. D-GalN rats exhibited an increased hepato and nephro toxicity marker activities aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase and gamma glutamyl transpeptidase and total bilirubin level while urea, uric acid and creatinine and lipid profile. It also negatively affected the serum total protein, albumin and A/G ratio. Rats treated with chrysin at different concentrations (25, 50 and 100 mg/kg BW) caused a significant improvement in serum protein level, decreased hepato and nephro toxicity markers. It also decreased the levels of very low density lipoprotein cholesterol and low density lipoprotein cholesterol while high density lipoprotein cholesterol significantly increased. It also decreased the levels of total cholesterol, phospholipids, triglycerides, free fatty acids in the plasma and tissues of liver and kidney. The effect of chrysin (25 mg/kg) is comparable with silymarin, a known hepatoprotective drug. Chrysin thus exhibits hepatoprotective and antihyperlipidaemic activity. Chemoprotective effects
Oncol Rep. 2006 May;15(5):1169-73. Preventive effects of chrysin on the development of azoxymethane-induced colonic aberrant crypt foci in rats. Miyamoto S1, Kohno H, Suzuki R, Sugie S, Murakami A, Ohigashi H, Tanaka T.
Abstract The modifying effects of dietary feeding with chrysin (5,7-dihydroxyflavone) on the development of azoxymethane (AOM)-induced colonic aberrant crypt foci (ACF) were investigated in male F344 rats. We also assessed the effect of chrysin on mitosis and apoptosis in 'normal appearing' crypts. To induce ACF, rats were given two weekly subcutaneous injections of AOM (20 mg/kg body weight). They also received an experimental diet containing chrysin (0.001 or 0.01%) for 4 weeks, starting 1 week before the first dose of AOM. AOM exposure produced a substantial number of ACF (73+/-13/rat) at the end of the study (week 4). Dietary administration of chrysin caused significant reduction in the frequency of ACF: 0.001% chrysin, 37+/-17/rat (49% reduction, P<0.001); and 0.01% chrysin, 40+/-10/rat (45% reduction, P<0.001). In addition, chrysin administration significantly reduced the mitotic index and significantly increased the apoptotic index in 'normal appearing' crypts. These findings might suggest a possible chemopreventive activity of chrysin in the early step of colon tumorigenesis through modulation of cryptal cell proliferation activity and apoptosis. Chemoprotective effects
Toxicol In Vitro. 2011 Apr;25(3):630-5. doi: 10.1016/j.tiv.2010.12.013. Epub 2010 Dec 30. Chrysin promotes tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) induced apoptosis in human cancer cell lines. Li X1, Wang JN, Huang JM, Xiong XK, Chen MF, Ong CN, Shen HM, Yang XF. Abstract Chrysin exists widely in plants, honey and propolis. The anti-cancer property of chrysin has been demonstrated though the molecular mechanism is not clear. In this study, we found that pre- treatment with chrysin could promote the cell death induced by TRAIL according to the morphological changes and appearance of sub-G1 peak in four human cancer cell lines. In HCT-116 cells, the results of flow cytometry analysis showed that the percentage of sub-G1 reached (38.89 ± 3.78) % when pre-treatment of chrysin was used at 40 μM, but that was only (2.53 ± 0.10) % in the untreated group and (13.22 ± 0.20) % in TRAIL alone group. The differences between the combination and the untreated or TRAIL alone group were all significant (P<0.05) and dose-dependent effect was obvious. Similar results were obtained in CNE1 cells. In the search of molecular mechanisms, we found that pre-treatment with chrysin could increase TRAIL- induced degradation of caspase 3, caspase 8, PARP proteins. Z-VAD-fmk, which is a pan-caspase inhibitor, could inhibit the apoptosis enhanced by the combination of chrysin and TRAIL. All data indicate that chrysin can enhance the apoptosis induced by TRAIL, and the apoptosis is caspase-dependent and related to the activation of caspase 8. Conclusion
• In referenced study chrysin exhibited stronger aromatase inhibition then other flavonoids tested
• Chrysin is a good candidate for topical or transdermal delivery and historically has been effectively used at much lower doses then what is commonly used orally because of low bioavailability
• Animal studies suggest that chrysin supplementation will improve sperm count and fertility, suggesting that is it improves or increases free testosterone levels
• In the Ames testing referenced chrysin did not induce mutagenic activity in any of the bacterial strains compared
• Studies show that chrysin has neuroprotective, chemoprotective, and hepatoprotective effects Cesium chloride:
Inclusion in the list of bulk drug substances that can be used in compounding under section 503A of the FD&C Act
Dr. Paul S. Anderson Seattle, WA Presented to the Food and Drug Administration June 2016 A brief note on the presenters background:
• The committee has my CV • My personal clinical experiences come from University based clinical interventional human research as well as private clinical practice. • I have been involved in the following, beyond private clinical practice: • NIH funded Integrative Oncology Study (2009-2014) in collaboration with University of Washington, Fred Hutchinson Cancer Research Center and the Bastyr Integrative Oncology Research Center (BIORC) clinics. • Chief of parenteral medicine • Coordinator of parenteral medicine unit • Canadian Foundation funded multi University / Multi Clinic human trial “Canada-US-Integrative Oncology Study” (CUSIOS) trial – ongoing now. • Site director for US Site-1
PS Anderson - 2016 2 Efficacy:
PS Anderson - 2016 3 Where did the Idea Start?
Sartori HE. Cesium therapy in cancer patients. Pharmacol Biochem Behav. 1984;21 Suppl 1:11-3. PMID: 6522427 • The effect of cesium therapy on various cancers is reported. A total of 50 patients were treated over a 3 year period with CsCl. The majority of the patients have been unresponsive to previous maximal modalities of cancer treatment and were considered terminal cases. The Cs-treatment consisted of CsCl in addition to some vitamins, minerals, chelating agents and salts of selenium, potassium and magnesium.
PS Anderson - 2016 4 Sartori – Continued:
Sartori HE. Cesium therapy in cancer patients. Pharmacol Biochem Behav. 1984;21 Suppl 1:11-3. PMID: 6522427 • “There was an impressive 50% recovery of various cancers, i.e., cancer of unknown primary, breast, colon, prostate, pancrease, lung, liver, lymphoma, ewing sarcoma of the pelvis and adeno-cancer of the gallbladder, by the Cs-therapy employed. There was a 26% and 24% death within the initial 2 weeks and 12 months of treatment, respectively. A consistent finding in these patients was the disappearance of pain within the initial 3 days of Cs-treatment. The small number of autopsies made showed the absence of cancer cells in most cases and the clinical impression indicates a remarkably successful outcome of treatment.”
PS Anderson - 2016 5 Safety:
PS Anderson - 2016 6 Recent Data Regarding Safety:
“Cesium is relatively safe; signs of its mild toxicity are gastrointestinal distress, hypotension, syncope, numbness, or tingling of the lips.”
Melnikov P, Zanoni LZ. Clinical effects of cesium intake. Biol Trace Elem Res. 2010 Jun;135(1-3):1-9. doi: 10.1007/s12011-009-8486-7. Epub 2009 Aug 5. PMID: 19655100
PS Anderson - 2016 7 Adverse Events in the Literature:
•Three primary sources describing four adverse events are listed below.
•All four events have one critical factor in common.
PS Anderson - 2016 8 Three Adverse Event Reports 2003 & 2008:
• Centeno JA, Pestaner JP, Omalu BI, Torres NL, Field F, Wagner G, Mullick FG. Blood and tissue concentration of cesium after exposure to cesium chloride: a report of two cases. Biol Trace Elem Res. 2003 Aug;94(2):97-104. PMID: 12958400 Cesium (Cs) levels from human tissue were measured to determine exposure to an alternative medical treatment. Cesium levels are reported from two patients who were administered cesium chloride in conjunction with aloe vera as part of an alternative cancer treatment.
• O'Brien CE, Harik N, James LP, Seib PM, Stowe CD. Cesium-induced QT-interval prolongation in an adolescent. Pharmacotherapy. 2008 Aug;28(8):1059-65. doi: 10.1592/phco.28.8.1059. PMID: 18657021 We describe a 16-year-old girl with metastatic hepatocellular carcinoma who experienced cesium-induced QT-interval prolongation after the start of a cesium chloride-based alternative treatment regimen.
PS Anderson - 2016 9 One Fatality 2013:
• Sessions D, Heard K and Kosnett M Fatal Cesium Chloride Toxicity After Alternative Cancer Treatment. JOUURNAL OF ALTERNATIVE AND COMPLEMENTARY MEDICINE. Volume 19, Number 12, 2013, pp. 973– 975. DOI: 10.1089/acm.2012.0745
“The evening before presentation, upon advice from a nutritionist, her husband injected approximately 9mL of an oral CsCl preparation (concentration unknown) into and around the lump. Her nausea, headache, and malaise began immediately thereafter.”
PS Anderson - 2016 10 What is the commonality in all adverse events?
All four were NOT under the care of a qualified physician and none of the protocols were designed nor monitored as such.
PS Anderson - 2016 11 Alternatives:
PS Anderson - 2016 12 Palliative and Experimental Oncology:
• Cesium Chloride is one of many drug products that has promise in the palliative and experimental oncology setting.
• It can be used safely if ordered and monitored by a qualified physician or prescriber.
• Its unique properties make it unlike other drug products and so there are no adequate replacement drugs in this setting.
PS Anderson - 2016 13 Summary:
PS Anderson - 2016 14 Personal use: Clinical and Research venues:
• My personal experience with Cesium Chloride has been in researching palliative and experimental oncology strategies in humans.
• These have been under the NIH study protocols (BIORC) and the new Canada-US-Integrative Oncology Study (CUSIOS) auspices.
• In this setting physician collaborators, using appropriate dosing and monitoring of patients, have administered thousands of doses of Cesium Chloride without high grade adverse event, and overall extremely good safety.
PS Anderson - 2016 15 Safety as a prescribed medication:
• Cesium is quite safe when ordered, monitored by and managed by a qualified physician or appropriate prescriber. • Inclusion in 503(a) would assure this is the case. • The only adverse events reported were when a qualified physician did not order or manage the drug.
• Removal from 503(a) and reliance on application for 503(b), IND and or emergency IND status would unduly restrict access to the drug for salvage chemotherapy, research and appropriate use.
PS Anderson - 2016 16 Thank you.
PS Anderson - 2016 17 Dichloroacetate sodium:
Inclusion in the list of bulk drug substances that can be used in compounding under section 503A of the FD&C Act
Dr. Paul S. Anderson Seattle, WA Presented to the Food and Drug Administration June 2016 Efficacy and Current Human Use:
PS Anderson - 2016 2 Current Human Data:
•A concern has been raised that DCA has no place nor human data supporting its use in oncology and research.
•The following is intended to assist in updating that idea.
PS Anderson - 2016 3 Current Human Data:
• The following papers are human case reports and trials published between 2010 and 2016 – listed in descending order. • These data show: • Efficacy in quality of life, extension of life and tumor response parameters • Very low side effect profile • Very high safety index
PS Anderson - 2016 4 Human Data – DCA:
• Lemmo W and Tan G. Prolonged Survival After Dichloroacetate Treatment of Non-Small-Cell Lung Carcinoma-Related Leptomeningeal Carcinomatosis. J Med Cases. 2016;7(4):136-142 • Chu QS, Sangha R, Spratlin J, Vos LJ, Mackey JR, McEwan AJ, Venner P, et al. A phase I open-labeled, singlearm, dose-escalation, study of dichloroacetate (DCA) in patients with advanced solid tumors. Invest New Drugs. 2015;33(3):603-610. • Dunbar EM, Coats BS, Shroads AL, Langaee T, Lew A, Forder JR, Shuster JJ, et al. Phase 1 trial of dichloroacetate (DCA) in adults with recurrent malignant brain tumors. Invest New Drugs. 2014;32(3):452- 464.
PS Anderson - 2016 5 Human Data – DCA:
• Khan A, Marier D, Marsden E, Andrews D, Eliaz I. A novel form of dichloroacetate therapy for patients with advanced cancer: a report of 3 cases. Altern Ther Health Med. 2014;20(Suppl 2):21-28.
• Strum SB, Adalsteinsson O, Black RR, Segal D, Peress NL, Waldenfels J. Case report: Sodium dichloroacetate (DCA) inhibition of the "Warburg Effect" in a human cancer patient: complete response in non- Hodgkin's lymphoma after disease progression with rituximab-CHOP. J Bioenerg Biomembr. 2013;45(3):307-315.
PS Anderson - 2016 6 Human Data – DCA:
• Strum S, Adalsteinsson O, Black R, Segal D, Peress N, Waldenfels J. Erratum to: Case Report: Sodium dichloroacetate (DCA) inhibition of the 'Warburg Effect' in a human cancer patient: complete response in non-Hodgkin's lymphoma after disease progression with rituximab- CHOP. J Bioenerg Biomembr. 2013;45(3):317. • Khan A. Case Report of Long Term Complete Remission of Metastatic Renal Squamous Cell Carcinoma after Palliative Radiotherapy and Adjuvant Dichloroacetate. Advances in Cancer: Research & Treatment http://www.ibimapublishing.com/journals/ACRT/acrt.html. Vol. 2012 (2012), Article ID 441895, 7 pages DOI: 10.5171/2012.441895
PS Anderson - 2016 7 Human Data – DCA:
• Khan A. Use of oral dichloroacetate for palliation of leg pain arising from metastatic poorly differentiated carcinoma: a case report. J Palliat Med. 2011;14(8):973-977.
• Flavin DF. Non-Hodgkin's Lymphoma Reversal with Dichloroacetate. J Oncol. 2010;2010
• Flavin D. Medullary thyroid carcinoma relapse reversed with dichloroacetate: A case report. Oncol Lett. 2010;1(5):889-891.
PS Anderson - 2016 8 Human Data – DCA:
•The presenter has other human trial data which will be shared later in this presentation.
•This also shows similar safety and efficacy of DCA in humans.
PS Anderson - 2016 9 Other active research and support for unique mechanism of action in cancer:
•The following are a sample of recent papers showing the basis of use for DCA, its unique role in metabolic therapies and potentials for therapeutic benefit.
PS Anderson - 2016 10 Current Research:
• Ohashi T, Akazawa T, Aoki M, Kuze B, Mizuta K, Ito Y, Inoue N. Dichloroacetate improves immune dysfunction caused by tumor- secreted lactic acid and increases antitumor immunoreactivity. Int J Cancer. 2013;133(5):1107-1118. • Garon EB, Christofk HR, Hosmer W, Britten CD, Bahng Kankotia S, Stacpoole PW. Dichloroacetate and cancer: new home for an orphan drug? Biochim Biophys Acta. 2014;1846(2):617-629. • Heshe D, Hoogestraat S, Brauckmann C, Karst U, Boos J, Lanvers- Kaminsky C. Dichloroacetate metabolically targeted therapy defeats cytotoxicity of standard anticancer drugs. Cancer Chemother Pharmacol. 2011;67(3):647- 655.
PS Anderson - 2016 11 Current Research:
• Lin G, Hill DK, Andrejeva G, Boult JK, Troy H, Fong AC, Orton MR, et al. Dichloroacetate induces autophagy in colorectal cancer cells and tumours. Br J Cancer. 2014;111(2):375-385.
• Shahrzad S, Lacombe K, Adamcic U, Minhas K, Coomber BL. Sodium dichloroacetate (DCA) reduces apoptosis in colorectal tumor hypoxia. Cancer Lett. 2010;297(1):75- 83.
PS Anderson - 2016 12 Safety:
PS Anderson - 2016 13 Safety: Common Concern
The most common toxicity is a dose dependent reversible peripheral neuropathy. Other reactions appear to be mediated by a slowing of glutathione activity via the GSTz pathway: “From the Abstract: Dichloroacetate (DCA) inhibits its own metabolism and is converted to glyoxylate by glutathione S-transferase zeta (GSTz). … Moreover, DCA- induced inhibition of tyrosine catabolism may account for the toxicity of this xenobiotic in humans and other species.” Cornett R, James MO, Henderson GN, Cheung J, Shroads AL, Stacpoole PW. Inhibition of glutathione S-transferase zeta and tyrosine metabolism by dichloroacetate: a potential unifying mechanism for its altered biotransformation and toxicity. Biochem Biophys Res Commun. 1999 Sep 7;262(3):752-6. PMID: 10471397
PS Anderson - 2016 14 Safety: In Current Use
• The presenter has administered over 10,000 doses of DCA and has not had one case of neuropathy develop. (More information on this use later in the presentation). • The research colleagues of the presenter have administered over 10,000 additional doses of DCA and report the same lack of peripheral neuropathy and other high grade adverse events. • This lack of adverse event occurrence is due to proper dosing and administration of the drug as outlined in the monograph for DCA authored by the presenter.
PS Anderson - 2016 15 Alternatives:
PS Anderson - 2016 16 Alternatives to DCA:
• DCA occupies a unique place in metabolic therapies and cellular mechanisms. • The mechanisms of action are unique. • They are not exactly duplicated by any other drug
• Aside from two experimental drugs (3-BP and 2-DG) which have similar but not identical mechanisms there are no alternatives to DCA.
PS Anderson - 2016 17 Summary:
PS Anderson - 2016 18 Safety as a prescribed medication:
• Is extremely safe when ordered, monitored by and managed by a qualified physician or appropriate prescriber. • Inclusion in 503(a) would assure this is the case.
• Removal from 503(a) and reliance on application for 503(b), IND and or emergency IND status would unduly restrict access to the drug for metabolic therapies, salvage chemotherapy, research and other appropriate use.
PS Anderson - 2016 19 Personal use: Clinical and Research venues:
• I have personally ordered and managed over 10,000 doses (oral and parenteral) of DCA in clinical oncology care and research. My research colleagues have likewise managed a similar number of doses in addition to this number. • These have been under the NIH study protocols (BIORC) and the new Canada-US-Integrative Oncology Study (CUSIOS) auspices.
PS Anderson - 2016 20 Personal use: Clinical and Research venues:
• In our first NIH trial we developed a “salvage” therapy for patients with cancer failing all other therapies which used DCA as its core medication. In this case series we observed extension of life in over 70% of subjects. (* Case series to be published as the global data from the trial is published).
PS Anderson - 2016 21 Thank you.
PS Anderson - 2016 22 Melaleuca TEA TREE OIL alternifolia ORIGIN OF TEA TREE OIL
Essential oil obtained through steam distillation of the leaves and terminal branches of Melaleuca alternifolia Indigenous in New South Wales and Queensland, Australia
http://www.anniesremedy.com/images/oils /Koeh-teatree.jpg
http://avh.ala.org.au/occurrences/search?taxa=Melaleuca+alternifolia#tab_mapView
http://www.deelish.ie/wp-content/uploads/2012/03/melaleuca-alternifolia.jpg PHYSICAL CHARACTERISTICS
Height: Tall shrub to 7m high with papery bark.
Leaves: irregularly arranged, scattered to whorled, linear, 10-35mm long, 1mm wide
Fruit:
http://farm3.static.flickr.com/2013/ 2150180519_8a00eca13a.jpg Cup-shaped, 2-3mm in diameter, orifice 1.5-2.5mm in diameter http://plantnet.rbgsyd.nsw.gov.au/cgi- bin/NSWfl.pl?page=nswfl&photo=32&file=11/967/501849. jpg
http://plantnet.rbgsyd.nsw.gov.au/cgi- bin/NSWfl.pl?page=nswfl&photo=28&file=4/233/0 03257 jpg HOW ITS MADE: STEAM DISTILLATION PROCESS
1: Leaves and terminal branches of the 2 tea tree are loaded into the still 1 2: During the boiling process, steam + 3 essential oils are vaporized 3: Steam + essential oil vapor travel 4 down a condenser and reform into liquid 5 phase http://hgagarwood.com/wp-content/uploads/2015/06/tumblr_lod610RsYW1qbjz9oo1_1280.jpg 4: As water and oil build inside the container; oil floats to the top and separates from the water 5: Water is removed through bottom exit pipe and essential oils are siphoned from the top CHEMICAL COMPONENT OF TEA TREE OIL
International Standard of Oil of Melaleuca, terpinen-4-ol type (Tea Tree Oil)
Chemical Name Properties Range
anti-inflammatory, TERPINEN-4-OL 30%+ (Primary Constituent) antimicrobial, antifungal
γ-TERPINENE antioxidant 10-28%
1,8-CINEOL possible allergen 0-15%
α-TERPINENE antioxidant 5-13%
TERPINOLENe antioxidant 1.55% MECHANISM OF ACTION OF TEA TREE OIL
Cox, SD., et al. The mode of antimicrobial action of the essential oil of Melaleuca alternifolia from Journal of Applied Microbiology This study observed the results from exposing C. albicans, E. coli, and S. aureus to minimum inhibitory (MIC) and minimum bactericidal/fungicidal concentrations (MBC) . MIC of E. coli and S. aureus: 0.25% v/v . MBC of E. coli and S. aureus: 0.50% v/v . MIC of C. albicans: 0.125% v/v . MBC of C. albicans: 0.25% v/v Modes of Measurements . Assay of Cell Viability . Measurement of Respiration . Efflux of Potassium Ions . Propidium Iodide Uptake . Assay of Tea Tree Oil-induced carboxyfluorescein leakage MOA OF TEA TREE OIL CONT’D: CELL VIABILITY
(a) E. coli AG 100: (O) no tea tree oil () 0.50% v/v tea tree oil
(b) S. aureus NCTC 100: (O) no tea tree oil () 0.25% v/v tea tree oil () 0.50% v/v tea tree oil
(c) C. albicans KEM H6:100: (O) no tea tree oil () 0.125% v/v tea tree oil () 0.25% v/v tea tree oil ( )Fig 0.50% 1. Effect of v/v tea tree tea oil treeon viability oil of test organisms. MOA OF TEA TREE OIL CONT’D: EFFECT ON MICROBE RESPIRATION
Tea tree oil inhibited respiration all 3 studied microbes after 5 mins of of incubation (10 minutes for C. albicans) E. coli respiration (O) was completely inhibited at 0.5% v/v S. aureus respiration () inhibition began at 0.5% v/v C. albicans respiration () was inhibited at 0.125% v/v
Fig 2. Effect of tea tree oil concentration on O2 consumption rates in cell suspensions. MOA OF TEA TREE OIL CONT’D CELL WALL INTEGRITY
Fig 3. propidium iodide uptake Fig 4. K+ Leakage Fig 5. carboxyfluoresin leakage
() 0.25% v/v tea tree oil (O) E. coli in 0.25% v/v tea tree oil (O) Multilamellar lipid vesicles in () Control (no tea tree oil) () E. coli in control control () S. aureus in 0.25% v/v tea tree oil () Multilamellar lipid vesicle in () S. aureus in control 0.25% tea tree oil
Fig 3-5 shows tea tree oil causes an increase in cell wall permeability when compared to control solutions. FDA REVIEW OF EFFICACY EVIDENCE
Tab 5b; Section IIC: “Are there concerns about whether a substance is effective for a particular use?” Reviewers stated “A recent review considers most of these studies [regarding use in onychomyocosis, acne, tinea pedis, etc.] lacking in sufficient reliable evidence to rate TTO for effectiveness for these other uses (Natural Medicines database 2015). Please note that the Natural Medicines Database states that TTO is possibly effective for the following conditions: 1. Onychomycosis (Fungal Nail Infection) 2. Acne 3. Tinea Pedis (Athlete’s Foot) In addition, please note that the review only presented evidence on onychomycosis, when evidence is available for both acne and tinea pedis In the next couple slides, we have conducted our own review of the following evidence regarding the use of TTO in these conditions EFFICACY IN ONYCHOMYOSIS BUCK ET. AL (1994)
One of the study presented in the review was a randomized, double-blind, multicenter trial by Buck et al. (1994) The conclusion was made that this trial was insufficient due to “clotrimazole 1% solution, is not an approved treatment for onychomycosis” Please note that in 1994 there were no topical treatment of onychomyosis that were approved Approved topical treatment of onychomyosis with approval dates are shown below: . Penlac: Approved 1999 . Jublia: Approved 2014 . Kerydin: Approved 2014 EFFICACY OF OYCHOMYOSIS BUCK ET. AL (1994) CONT’D
It was mentioned that the study had exaggerated their mycological cure and clinical resolution and the following table was presented Clotrimazole 1% N=53 TTO 100% N=64 Mycologic Culture Negative 4 (11%) 7(18%) Partial or full clinical resolution 22(61%) 24(60%) “There were only five drop-out (four in clotrimazole and one in the TTO arm), but the percentages suggest that much lower numbers of subjects were used as denominators (i.e. clotrimazole N=36, and TTO N=40) in contrast to the number of patients enrolled.”
However, please note that authors stated that there was a 35% loss to culture follow up Therefore we present the following chart in the next slide EFFICACY OF ONYCHOMYOSIS BUCK ET AL. (1994)
117 patients Authors found no statistical difference in any groups enrolled
35% Loss to 76 patients Culture Follow- completed 6 up (41 patients) month therapy
Clotrimazole 1% TTO 100% N=36 N=40
Culture Negative Full or partial at End of resolution at end Therapy of therapy
Clotrimazole TTO Clotrimazole TTO 4 of 36 (11%) 7 of 40 (7%) 22 of 36 (61%) 24 of 40 (60%) EFFICACY IN ONYCHOMYOSIS BUCK ET AL. (1994)
Although this trial does not compare TTO with current approved topical therapies; please take into consideration that during this time there were no approved topical therapies for onychomyosis This study provides us information that TTO may help in relieving symptoms, improving nail appearance and possibly assisting with myocological cure Currently, nail lacquers represent an option for topical formulation vehicle used to deliver the drug, evaporates and leaves an occlusive film with a high concentration of the nail surface Compounding pharmacies give prescribers the option to include tea tree oil in prescriptions for topical lacquers EFFICACY IN ONYCHOMYCOSIS SYED ET AL. (1999)
Reviewers presented a second randomized, double-blind, placebo-controlled study that evaluated the efficacy of butenafine 2% with 5% TTO The aim of this study was to observe the clinical efficacy and tolerability of the combination product It was concluded that this trial was not adequate because it lacked the arm of monotherapy butenafine 2% to demostrate the contribution of 5% TTO Although this trial does lack that arm, it does provide us with information that a combination product containing butenafine 2% and TTO 5% provided a high cure rate when compared other topical agents. For this reason we present you our own review of this trial EFFICACY IN ONYCHOMYCOSIS SYED ET AL. 1999 CONT’D
Treatment Protocol . Apply three times daily with a fresh occlusive plastic 60 patients wrap provided began trial . Week 4-8; debridement of toenail with nail clipper if Week 4 ready 51 patients . All treatment discontinued at 8 weeks continued 9 patients treatment debrided Week 5 38 patients 13 patients continued debrided treatment Week 6 28 patients continued 10 patients treatment debrided
After week 6, remaining patients were not ready for debridement and treatment was discontinued due to treatment protocols. Total of 32 patients received debridement before the end of treatment Collection of specimen occurred at week 8, 24 and 36 to observe if mycological cure was achieved EFFICACY IN ONYCHOMYCOSIS SYED ET AL. 1999 CONT’D
40 patients were randomized into treatment group 20 patients were in placebo group All patients who received debridement were found to be in treatment group (32/40) compared to placebo (0/20); p- value <0.0001
When used adjunctively tea tree oil with butenafine resulted in better cure rate (80%), side effects (mild, 6.7%) and relapses (0) when compared to other antimycotic treatments used for onychomycosis EFFICACY IN ONYCHOMYOSIS CURRENT APPROVED TOPICAL TREATMENT MYCOLOGICAL CURE RATE
The following table was retrieved from Baran R. et al. Topical antifungal drugs or treatment of onychomyocosis: an overview of current strategies for monotherapy and combination therapy in European Academy of Dermatology and Venereology (2004) When comparing the mycological cure rate of the current approved drugs; the combination cream of butenafine 2% and TTO 5% had a superior mycological rate of 80% EFFICACY IN TINEA PEDIS (ATHLETE’S FOOT)
Satchell, A., et al. Treatment of interdigital Tinea pedis with 25% and 50% tea tree oil solution: A randomized, placebo- controlled, blinded study in Australasian Journal of Dermatology 158 Patients were randomized into 3 possible arms 1. Placebo (20% ethanol, 80% polyethylene solution) 2. Tea Tree Oil 25% in ethanol and polyethylene glycol solution 3. Tea Tree Oil 50% in ethanol and polyethylene glycol solution 4 week trial and measured the clinical response and mycological cure A previous study compared the use of 10% tea tree oil in sorbolene compared to 1% tolfanate and placebo. The sorbolene vehicle may have compromised the antifungal properties of tea tree oil and resulted in a decrease efficacy. EFFICACY IN TINEA PEDIS (ATHLETE’S FOOT) CONT’D
158 Patients Enrolled with positive microscopy
Placebo Group 25% TTO Solution 50% TTO Solution (55 patients) (54 patients) (51 patients)
Positive culture for Positive culture for Positive culture for dermatopytes (49) dermatophytes (43) dermatophytes (45)
Completed Study (38) Completed Study (46) Completed Study (36) 1 withdrew due to adverse 3 loss to follow up (2.19%) 7 loss to follow up (5.11%) reaction 6 loss to follow up (4.38%) EFFICACY IN TINEA PEDIS (ATHELETE’S FOOT) CONT’D
Higher Cure Rate in Tea Tree Oil Group (P-value: <0.01)
Higher Clinical Response in Tea Tree Oil Group (P-value: <0.005) EFFICACY IN TINEA PEDIS (ATHELETES FOOT CONT’D
Tablet 2: Patients within the tea tree oil group had a higher rate of cure when compared to placebo and was statistically significant with a p value of <0.01. Table 3: The clinical score consisted of an assessment of scaling and inflammation by the investigator and burning and itching by the patient which was rated as absent, mild, moderate, severe or very severe. Each category was given a corresponding score of 0-4 and added together to get the final clinical score. Clinical response at the end of the 4 week treatment and patients within the TTO group had significantly higher clinical response when compared to placebo. Marked clinical response was defined as reduction of three or more in clinical score to a final value of less than 3. These values were statistically significant with p value of <0.005 An effective cure was defined by the authors as patients who have marked clinical response in addition to obtaining mycological cure at 4 weeks. 16 out of 18 patients within 25% TTO arm and 18 out of 18 patients within 50% TTO arm who had mycological cure at 4 weeks achieved effective cure compared to 6 out of 14 patients within placebo arm who had mycological cure at 4 weeks achieved effective cure. EFFICACY IN ACNE
A current review by Hammer, KA. Treatment of acne with tea tree oil (melaleuca) products: A review of efficacy, tolerability and potential modes of action from the International Journal of Antimicrobial Agents (2015) reviewed: 7 studies regarding the use of tea tree oil in acne 5 of 7 studies showed products with ≥5% tea tree oil found that lesion numbers were reduced after 4-8 weeks of treatment The summary table of all the studies provided in the review is provided in the next slide Overall, the author suggested that tea tree oil applied twice daily for multiple weeks is likely to reduce the number of lesions EFFICACY IN ACNE SAFETY
Hammer KA. Review of the use of tea tree oil in Acne reported the following: 5 of 7 studies reported adverse effects 1 of 7 studies reported no serious adverse effects 1 of 7 studies did not provide details Rate of Adverse effects were higher with benzoyl peroxide when compared to tea tree oil (79% vs 44%) They concluded that tea tree oil was tolerated similarly to other topical facial acne medications The author also reviewed previous patch testing of TTO and concluded that irritant and allergenic potential of TTO rate is low SAFETY CONT’D
In a second review Carson CF. et al. Melaleuca alternifolia (Tea Tree) Oil: a Reviews of Antimicrobial and Other Medicinal Properties in Clinical Microbiology Reviews “Rationale for continued use of the oil rest largely on the apparently safe use of the oil for almost 80 years” The authors examined oral toxicity and concluded that incidences of oral poisoning in children and adults resulted in no human deaths and patients responded to supportive care and recovered without apparent sequelae In dermal toxicities the authors concluded that topically applied TTO rarely cause systemic effects FINAL WORDS
Tea Tree Oil (TTO) is readily accessible without a prescription TTO prescribed by physicians allows patients access to alternative methods that may help improve their medical condition TTO in compounded preparations allows physicians to provide patients who have failed standard topical therapy TTO provides physicians additional topical options before taking systemic therapies that may be associated with side effects not seen with TTO TTO products dispensed by compounding pharmacies allow pharmacist to educate patients on proper use and storage to help prevent incidental adverse side effects associated with OTC TTO products REFERENCES
1. Baron, R., Kaoukhov, A.Topical antifungal drugs for the treatment of onychomycosis: an overview of current strategies for monotherapy and combination therapy. Eur. Academy of Derm. And Venerology. 19:21-29 2. Buck, D. S., D. M. Nidorf, and J. G. Addino. 1994. Comparison of two topical preparations for the treatment of onychomycosis: Melaleuca alternifolia (tea tree) oil and clotrimazole. J. Fam. Pract. 38:601–605. 3. Hammer KA. 2015. Treatment of acne with tea tree oil (melaleuca) products: A review of efficacy, tolerability and potential modes of action. Int J Antimicrob Agents. 2015;45(2):106- 10. 4. Carson CF, Hammer KA and Riley TV. 2006. Melaleuca alternifolia (Tea Tree) oil: a review of antimicrobial and other medicinal properties. Clin Microbiol Rev. 2006;19:50–62. 5. Cox, S. D., J. E. Gustafson, C. M. Mann, J. L. Markham, Y. C. Liew, R. P. Hartland, H. C. Bell, J. R. Warmington, and S. G. Wyllie. 1998. Tea tree oil causes K+ leakage and inhibits respiration in Escherichia coli. Lett. Appl. Microbiol. 26:355–358. 6. Satchell AC, Saurajen A, Bell C, et al. 2002. Treatment of interdigital tinea pedis with 25% and 50% tea tree oil solution: a randomized, placebo-controlled, blinded study. Australas J Dermatol. 2002;43(3):175-8. 7. Syed, T. A., Z. A. Qureshi, S. M. Ali, S. Ahmad, and S. A. Ahmad. 1999. Treatment of toenail onychomycosis with 2% butenafine and 5% Melaleuca alternifolia (tea tree) oil in cream. Trop. Med. Int. Health 4:284–287. DMPS (Sodium 2,3-dimercapto-1- propanesulfonate):
Inclusion in the list of bulk drug substances that can be used in compounding under section 503A of the FD&C Act
Dr. Paul S. Anderson Seattle, WA Presented to the Food and Drug Administration June 2016 Efficacy:
PS Anderson - 2016 2 Arsenic Poisoning Cases:
On April 27, 2003, 16 people were poisoned with arsenic placed in coffee at the Gustaf Adolph Evangelical Lutheran Church in New Sweden, Maine • A disgruntled individual used arsenic, stored on his farm, to poison the church coffee • Sixteen persons were poisoned and transported to the emergency room at the 65-bed Cary Medical Center • Cary Medical Center contacted a poison index center for help and was told to use compounded DMPS
PS Anderson - 2016 3 Arsenic Poisoning Cases:
Dr. Karen Simone is the current President of the American Academy of Clinical Toxicology. She stated the following: 1. The sickest poisoned patients were transferred to Eastern Maine Medical Center [EMMC]. 2. These patients were initially treated with dimercaprol (BAL) for about 2 days…and…the BAL treatment was “failing”. 3. A medical resident contacted and consulted Dr. Karen Simone at the Poison Control Center in Portland, Maine. 4. Dr. Simone consulted other toxicologists, including Dr. Michael Kosnett. 5. Other toxicologists, including Dr. Michael Kosnett, recommended to start DMPS infusion.
PS Anderson - 2016 4 Arsenic Cases – Dr. Kosnett Comment
Thank you for bringing this to my attention. • The information contained in the FDA review brief is in several instances incorrect. • My colleagues and I in the medical toxicology community certainly value the antidotal quality of DMPS in several indications, where it is considered the drug of choice. • I would be pleased to recommend to FDA that the drug be available for compounding. Michael J. Kosnett, MD, MPH, FACMT
PS Anderson - 2016 5 Arsenic Poisoning Cases:
• A California compounding pharmacy was able to open its doors and provide compounded DMPS based on a office order from a physician at Cary Medical Center • Fifteen of the patients were treated with IV DMPS • One patient was not treated with DMPS and is the only person to die • There were no reports of adverse events • The Main Attorney General confirmed arsenic poison was used
PS Anderson - 2016 6 Poison Control Center Comment:
UCSF Poison Control Center & Vancouver Poison Control Center: every case is treated uniquely. It is best to have the treating physician contact the Center directly for consult. In short, DMPS is recommended first line agent when: i. The case is an acute, high level arsenic poison ii. Intravenous route of administration is preferred over intramuscular, e.g. dimercaprol [BAL] is an oily intramuscular injection, and absorption is slower. iii. DMPS has a better side effects profile than dimercaprol [BAL] iv. Intravenous route of administration is preferred over oral, e.g. Chemet /Succimer [DMSA], slower absorption and poisoned patient could be experiencing nausea, vomiting., diarrhea.
PS Anderson - 2016 7 Safety:
PS Anderson - 2016 8 Human Safety Summary:
• PubMed was used for clinical portion of this review • FDA Adverse Events Reporting System (FAERS) retrieved two cases • FDA’s Center for Food Safety and Nutrition (CAERS) reviewed for adverse events associated with DMPS and retrieved zero reports • FDA Adverse Event Reporting System (FAERS) • FAERS contains over nine million reports of adverse events and reflects data from 1969 to the present. • Only two cases reported
PS Anderson - 2016 9 The two cases:
Case one: • “…possibly dose-related; hypotension, when DMPS was given rapidly intravenously (reduced by slowing the infusion);…” Known adverse reaction with rapid IV infusion. • “56 year old patient received IV DMPS and EDTA and experienced low blood pressure (“around” 70/30). Patient received an epinephrine injection and recovered.” Case two: • “The 36-year-old male initially presented to an emergency department (ED) after injecting himself with elemental mercury and received diphenhydramine, and 10 days later re-presented to the ED.” • “He was found to have mercury deposits in his lungs and heart cavities, [this was prior to DMPS treatment] was hospitalized, received various therapies, including DMPS on day 12 after hospitalization and died on day 18 after admission.
PS Anderson - 2016 10 Human Safety:
•The following citations showing safety in human use of DMPS match the experience of the aforementioned toxicology experts as well as the presenters personal experience. •Appropriate dosing and administration is key to the safety of DMPS.
PS Anderson - 2016 11 Human Safety Data
• Cherkes AI, Braver-Chernobulskaya, BS; (Unithiol-ein Antidot gegen Kobalt); Farmakol. Toksikol. 21(3) 59-63 (1958) • Golota LG; (Therapeutic and antidotal properties of Unithiol); Farm. Zh. 1 18-22 (1980) • Clarkson TW, Magos L, Cox C, Greenwood MR, Amin-Zaki L, Majeed MA, Al- Damluji SF; Tests of efficacy of antidotes for removal of methylmercury in human poisoning during the Iraq outbreak; J. Pharmacol. Exp. Ther. 218(1) 74-83 (1981) • Chisolm JJ, Thomas DJ; Use of 2,3-dimercaptopropane-1-sulfonate in treatment of lead poisoning in children; J. Pharmacol. Exp. Ther. 235(3) 665-669 (1985)
PS Anderson - 2016 12 Safety Data – One Pharmacy Only:
Following information provided by one compounding pharmacy licensed in 49 states, state inspected, FDA inspected, National Association of Boards of Pharmacy (VPPS) inspected, Pharmacy Compounding Accreditation Board (PCAB) accredited, and ISO certified (ISO 9001-2008) • Physicians that have ordered DMPS since 1999 = 10,021 • Patients that have received DMPS since 1999 = 4,054 * Patient number is understated (office use orders) • DMPS sterile vials shipped since 1999 = 100,939 vials • Approximate DMPS doses = 67,292 • DMPS product complaints received since 1999 = zero • DMPS adverse events received since 1999 = zero
PS Anderson - 2016 13 Alternatives:
PS Anderson - 2016 14 Alternatives: DMPS in the treatment of arsenic and mercury poisoning.
• Calcium Disodium Versenate (CaEDTA) • Indication: • Edetate calcium disodium is indicated for the reduction of blood levels and depot stores of lead in lead poisoning (acute and chronic) and lead encephalopathy, in both pediatric populations and adults. • No indication for arsenic or mercury poisoning • Chemet (DMSA, Succimer) • Indications • Chemet is indicated for the treatment of lead poisoning in pediatric patients with blood lead levels above 45mcg/dL. • No indication for arsenic or mercury poisoning
PS Anderson - 2016 15 Alternatives: DMPS in the treatment of arsenic and mercury poisoning. • Bal in Oil (Dimercaprol) • Dimercaprol 100 mg / Benzyl Benzoate 200 mg / Peanut Oil 700 mg • BAL in Oil (Dimercaprol Injection USP) is indicated in the treatment of arsenic, gold and mercury poisoning. It is indicated in acute lead poisoning (used with EDTA) • Effective in acute poisoning by mercury salts if therapy is begun within one or two hours following ingestion. • Unstable in aqueous solution, therefore injection is formulated in peanut oil. Contraindicated in peanut allergy. • Penicillamine • No indication for arsenic or mercury poisoning • Syprine • No indication for arsenic or mercury poisoning
PS Anderson - 2016 16 Summary:
PS Anderson - 2016 17 Personal use: Clinical and Research venues:
• I have personally ordered and or administered in excess of 5,000 doses of DMPS • I have had no patient in that time experience a serious, life threatening or high grade adverse event. • I discontinued use of alternatives (BAL, Penicillamine) due to: • Higher incidence of adverse events • Pain • Injection site reaction • Allergic reaction • Occasional difficulty in sourcing drug
PS Anderson - 2016 18 Safety as a prescribed medication:
• DMPS is extremely safe when ordered, monitored and managed by a qualified physician or appropriate prescriber. • Inclusion in 503(a) would assure this limited access and use is the case.
• Removal from 503(a) and reliance on application for 503(b), IND and or emergency IND status would unduly restrict access and endanger patient safety. • Should another acute toxicity event occur the ordering toxicologist would have no avenue to obtain the drug.
PS Anderson - 2016 19 Thank you.
PS Anderson - 2016 20