US 2005O106267A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2005/0106267 A1 Frykman et al. (43) Pub. Date: May 19, 2005 (54) ZEOLITE MOLECULAR SIEVES FOR THE Related U.S. Application Data REMOVAL OF TOXINS (60) Provisional application No. 60/512,395, filed on Oct. (75) Inventors: Gregory K. Frykman, Washington, DC 20, 2003. (US); Glenn H. Gruett, New London, WI (US) Publication Classification Correspondence Address: (51) Int. Cl. ................................................ A61K 33/06 FOLEY AND LARDNER (52) U.S. Cl. .............................................................. 424/684 SUTE 500 3000 KSTREET NW WASHINGTON, DC 20007 (US) (57) ABSTRACT (73) Assignee: Framework Therapeutics, LLC Medical use of natural and Synthetic Zeolites for treatment, (21) Appl. No.: 10/965,799 prevention, and palliation in humans or animals of delete rious concentrations of ammonia, mercaptains, heavy metals (22) Filed: Oct. 18, 2004 and other toxins by oral administration. Particle Size Distribution, 12/30/03 s EPre-regeneration (%) s Post-regeneration (%) Patent Application Publication May 19, 2005 Sheet 1 of 3 US 2005/0106267 A1 I’0IH Patent Application Publication May 19, 2005 Sheet 2 of 3 US 2005/0106267 A1 'u'dd) Uoperabuo HN US 2005/0106267 A1 May 19, 2005 ZEOLITE MOLECULAR SEVES FOR THE Targeting Lead Paint Hazards; President’s Task Force on REMOVAL OF TOXINS Environmental Health Risks and Safety Risks to Children; Department of Health and Human Services and the Envi 0001. This application is based on U.S. Provisional ronmental Protection Agency; February, 2000) lead is most Patent Application No. 60/512,395, filed Oct. 20, 2003, the hazardous to the nation's 24 million children under six years entire contents of which are incorporated herein by refer old of which approximately 4.4% or 1 million have blood CCC. lead levels (BLL) >10 ug/dL. The spectrum and severity of 0002 The present invention relates to methods and com morbidity of lead poisoning increases as blood lead levels positions for treating, preventing, and palliating elevated increase: reduced IQ, decreased hearing, decreased growth levels of certain toxins in humans. and behavior problems in children can be observed at BLL as low as 10 ug/dL, impaired nerve function at 20 tug/dL, 0.003 Hepatic Encephalopathy Remains a Significant reduced Vitamin D metabolism at 30 lug/dL, damage to Health Problem hematopoiesis at 40 ug/dL, Severe Stomach cramps above 50 0004 Predominantly because of the large degree of alco tug/dL and Severe brain damage, kidney damage and Severe hol use in Society, chronic liver disease progressing to anemia between 50 and 100 tug/dL. Based on epidemiologi cirrhosis remains a burdensome health problem. While other cal models and estimates, a child is estimated to lose 2 IQ toxic liver insults are responsible to a lesser degree, the final (intelligence quotient) points for each 10 ug/dL increase in common pathway remains the Same: progressive hepatic blood lead level. fibrosis and decrease in the proportion of metabolically 0010 Current treatments include intravenous chelation active hepatocytes. These pathological changes result in therapy with EDTA (ethylenediamine tetraacetic acid) oral Systemic health effects related to poor detoxification of chelation therapy with drugs. Such as Succimer, penicillamine endogenously produced ammonia and exogenously admin and British anti-Lewisite (BAL). Chelation therapy with istered medications. Because of the cirrhotic liver's mark EDTA is indicated for severe lead poisoning and must be edly reduced ability to neutralize and remove ammonia, a administered-either three times daily or as a continuous natural waste product from the metabolism of proteins, its infusion-in combination with Succimer. Succimer, an oral blood level rises causing a decreased ability for affected drug, is administered on a Subchronic basis and is not patients to mentate, Sense and move normally. This decrease indicated for BLL <20 tug/dL. Penicillamine may also be in these functions when attributable to chronic liver disease used, but is known for a particularly troublesome side effect is known as hepatic encephalopathy. profile, which limits its chronic use. Additional details are 0005. It is estimated that the economic burden to society found below. related to just the costs of hospitalization for chronic liver disease is over S1 billion annually in the United States. A 0.011 EDTA (edetate, versenate; CAS 62-33-9) remains large portion of these costs is the daily charge for the difficult to administer despite its demonstrable lead-chelat hospital room; the average Stay is approximately 6 dayS. ing activity. It remains a component of Standard of care for Thus, if an intervention could be developed that would Severe cases of lead poisoning where rapid decrease in the decrease the average length of hospital stay and/or diminish BLL is desired and requires hospitalization. Key pharma the need for patients to be hospitalized, patients with chronic cological properties of EDTA include only intravenous administration and half-life of 20 to 60 minutes. Rapid liver disease would benefit and the economic burden to clearance results in only one-half the drug remaining one Society would decrease. hour following administration and only 5% of the adminis 0006 Current standard of care includes the use of Sup tered dose remains after 24 hours. The dose must be adjusted portive care (hydration, Vitamins, nutrition administered for decreased renal clearance. Substantial monitoring is parenterally, treatment of any gastrointestinal bleeding.) and required for cardiac changes, renal function and Serum the drug lactulose, a non-absorbed disaccharide that func electrolyte changes resulting in daily phlebotomy and tions to decrease the rate of absorption of and increase the attachment to a cardiac monitor. These precautions are rate of fecal elimination of ammonia. Lactulose, which is recommended because of potential decreases in Serum Zinc, Sold as a crystalline powder in a Single-dose plastic package, copper and iron, which are also chelated by EDTA. Because is inconvenient to use in the acute hospital Setting because EDTA may only be administered parenterally, local pain and of the need for Suspension/dissolution in a Sorbitol Solution. Swelling are a risk. Systemic adverse events include fever, Moreover, lactulose is only modestly effective and does not chills, malaise, nausea, Vomiting, anorexia, myalgias, appear to have been Subjected to randomized controlled arthralgias and a histamine-like reaction. Nephrotoxicity can trials prior to receiving marketing approval by the US Food manifest as acute tubular necrosis, microscopic hematuria, and Drug Administration. proteinuria and elevated blood urea nitrogen and Serum creatinine. The liver may be affected as evidenced by 0007 Lead Poisoning Remains a Significant Health transient mild elevations of the transaminases and the bone Problem marrow may also be affected as evidenced by the findings of 0008. Despite advances in the recognition and treatment anemia and thrombocytopenia. of clinical and Subclinical lead poisoning, a large number of 0012 Succimer (CHEMET, dimercaptosuccinic acid, children in the United States are considered lead poisoned. DMSA; CAS304-55-2) is a white crystalline powder with Effective therapy exists for lowering blood lead levels, an unpleasant odor and taste characteristic of mercaptains. It however the long-term adverse event risk of these treatments is administered orally in divided doses based on the size of limit their use, especially at the lower levels of blood lead. the patient thereby making administration easier and not 0009 AS taught in a recent government publication requiring hospitalization. It is indicated for blood lead levels (Eliminating Childhood Lead Poisoning: A Federal Strategy >45 lug/dL and is expressly not indicated for prophylaxis US 2005/0106267 A1 May 19, 2005 against lead poisoning in a lead laden environment. It is half-life is short Such that following intramuscular admin effective in reducing the blood lead level, although Several istration, dimercaprol is essentially all renally excreted features limit and complicate its use. It is recommended to within 4 hours. There are a number of pronounced and administer Succimer every 8 hours for the first 5 days dose-related Side effects which the amount or dimercaprol followed by twice daily for the next 14 days. A waiting that may be administered. Approximately 50% of patients period is recommended before a Second 19-day cycle should administered the 5 mg/kg dose will experience one of begin. Weekly monitoring of the blood counts is recom Several adverse events. Amongst the most common of the mended for proper management of the drug-induced neu Side effects is a rise in Systolic and diastolic blood preSSure tropenia. If the absolute neutrophil count decreases below by up to 50 mmHg. Nausea is commonly reported and to a 1200 ful, Succimer administration should stop until recov lesser degree Vomiting. Headache is reported less commonly ery to >1500 full. Drug-induced elevations of liver tran than nausea although further details about the headache are Saminases, which are mild and transient and Seen in up to not described in the references cited. A burning Sensation in 10% of patient, should be monitored for weekly. A particular the lips, mouth and throat accompanied with the feeling of toxicity in the form of recurrent mucocutaneous eruptions constriction is well known. Conjunctivitis,