WO2019005422A1 - Methods for maintaining and improving kidney function in patients with kidney disease and on standard of care therapy - Google Patents
Methods for maintaining and improving kidney function in patients with kidney disease and on standard of care therapy Download PDFInfo
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- WO2019005422A1 WO2019005422A1 PCT/US2018/035635 US2018035635W WO2019005422A1 WO 2019005422 A1 WO2019005422 A1 WO 2019005422A1 US 2018035635 W US2018035635 W US 2018035635W WO 2019005422 A1 WO2019005422 A1 WO 2019005422A1
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- 229960004034 sitagliptin Drugs 0.000 description 1
- 208000017520 skin disease Diseases 0.000 description 1
- 230000003997 social interaction Effects 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 230000000153 supplemental effect Effects 0.000 description 1
- 229920001059 synthetic polymer Polymers 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- UYPYRKYUKCHHIB-UHFFFAOYSA-N trimethylamine N-oxide Chemical compound C[N+](C)(C)[O-] UYPYRKYUKCHHIB-UHFFFAOYSA-N 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
- 208000009852 uremia Diseases 0.000 description 1
Classifications
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- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
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- A—HUMAN NECESSITIES
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- A23K10/10—Animal feeding-stuffs obtained by microbiological or biochemical processes
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- A—HUMAN NECESSITIES
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- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
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- A—HUMAN NECESSITIES
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- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
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- A—HUMAN NECESSITIES
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- A23V2400/113—Acidophilus
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
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- A23V2400/249—Thermophilus
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2400/00—Lactic or propionic acid bacteria
- A23V2400/51—Bifidobacterium
- A23V2400/533—Longum
Definitions
- Urea-specific sorbents such as synthetic polymers and modified polysaccharides have been evaluated for the removal of urea and other nitrogenous wastes via the gut.
- Other sorbents such as oxidized starch, activated charcoal, and carob flour have also been investigated for the in vivo elimination of uremic toxins with some success.
- Prakash & Chang ((1996) Nature Medicine 2:883-88) demonstrated that microencapsulated, genetically-engineered E. coli DH5 are effective in removing urea and ammonia in an in vitro system. The same researchers obtained similar results in oral administration of E. coli DH5 cells in a uremic rat animal model. Bliss et al. ((1996) Am. J. Clin.
- US 5,756,088 teaches a prescription diet for the prevention and treatment of dog and cat dermatosis comprising a composition containing a poly-unsaturated fatty acid such as ⁇ -linolenic acid, ⁇ -linolenic acid and docosahexaenoic acid, and/or biotin, and an antiflatulent such as a lactic acid bacterium, a Bifidobacterium, a Lactobacillus , a butyric acid bacterium or a Bacillus, and optionally an oligosaccharide.
- a poly-unsaturated fatty acid such as ⁇ -linolenic acid, ⁇ -linolenic acid and docosahexaenoic acid, and/or biotin
- an antiflatulent such as a lactic acid bacterium, a Bifidobacterium, a Lactobacillus , a butyric acid bacterium or a Bacillus, and
- US 7,993,903 teaches a composition for inhibiting cholesterol absorption in the intestinal tract, wherein the composition includes Bifidobacterium, and optionally a Lactobacillus bacterium and carbohydrate.
- US 2011/0171283 teaches a composition containing at least one nutrient, at least one disinfecting or decontaminating and/or at least one proteases inhibiting substance and/or complex of substances incorporated in an absorbent dressing for external care and/or treatment of wounds to a human or animal.
- the protease inhibiting substance includes non-pathogenic acid producing micro-organisms (e.g., bifidobacteria, lactococci, or lactobacilli ) and/or synbiotics (e.g., xylooligosaccharide) .
- US 2009/0252709 teaches a preventive or therapeutic agent for gastritis or ulcer, which includes as an active ingredient Bifidobacterium bifidum.
- Bifidobacterium bifidum includes as an active ingredient Bifidobacterium bifidum.
- This reference teaches that other microorganisms (e.g., Bifidobacterium or Lactobacillus bacteria) , as well as sugars such as xylooligosaccharide .
- WO 2007/140622 teaches a probiotic composition containing a mixture of a Propionibacterium r a Lactobacillus , a Bifidobacterium and a Streptococcus, wherein said composition can further include a prebiotic.
- U.S. Patent No. 6,706,263 and 6,706,287 disclose compositions and methods for alleviating symptoms of uremia comprising a mixture of sorbents and bacteria.
- U.S. Patent no. 7,998,470 teaches compositions and methods for improving renal function comprising a probiotic Streptococcus bacterium that is enterically coated.
- U.S. Patent No. 8,257,693 teaches compositions for improving renal function consisting of L. acidophilus , B. longum, and S. thermophilus .
- U.S. Patent no. 8,481,025 discloses compositions and methods for treating renal failure comprising L. acidophilus, B. longum, S. thermophilus and psyllium husks.
- the present invention provides methods for maintaining and improving kidney function and improving quality of life in patients suffering from a disease that results in reduced kidney function comprising administering to a patient suffering from a disease that results in reduced kidney function an effective amount of a composition consisting of a RENADYLTM in combination with a standard of care treatment for the disease.
- RENADYLTM is a mixture of three probiotic bacteria (S. thermophilus strain KB 19, L . acidophilus strain KB 27, and B . longum) with two prebiotic components (xylooligosaccharide and inulin) in capsules containing 45 billion colony-forming units (CFUs) .
- the method provides for maintenance or improvement of kidney function as well as improvement in the quality of life of the patients being treated.
- kidney function improvement includes at least a 2 mL/min increase in Glomerular Filtration Rate (GFR) .
- the present invention is a method for maintaining or improving kidney function in patients suffering from different forms of kidney disease that involves administering to the patients a composition that combines the properties of probiotic and prebiotic components into a synbiotic product or composition to maintain or improve kidney function and improve quality of life in patients when combined with treatment regimens that are considered standard of care for the particular disease or condition being treated.
- the probiotic component is about 20% to about 70% of the total composition weight. In particular embodiments, the probiotic component is about 50% of the total composition weight. Likewise, the prebiotic component of the composition is about 20% to about 70% of the total composition weight or more preferably about 50% of the total composition weight.
- the probiotic components of RENADYLTM consist of three different probiotic organisms: S. thermophilics strain KB 19, L . acidophilus strain KB 27, and B . longum. These three probiotic organisms have been shown to reduce nitrogenous wastes in blood of patients and to improve renal function (U.S. Patent No. 8,257,693) and to be effective in the treatment of renal insufficiency (U.S. Patent No . 8,481, 025) .
- the prebiotic component of RENADYLTM is a non- digestive food that beneficially affects the host by selectively stimulating the growth and/or activity of one or more non-pathogenic bacteria in the colon and/or the growth and/or activity of one or more of the bacteria of the present composition.
- Prebiotic components are considered to have anti-carcinogenic, anti-microbial, hypolipidemic and glucose modulatory activities. They can also improve mineral absorption and balance.
- bacteria belonging to the Bifidobacterium and Lactobacillus families are stimulated by the presence of the prebiotic component and proliferate. Pharmacokinetically, prebiotic components reach the colon largely intact.
- Prebiotic components of RENADYLTM consist of inulin and xylooligosaccharide .
- Xylooligosaccharide is included in RENADYLTM as it promotes the growth of Bifidobacterium and Lactobacillus bacteria. Similarly, inulin is included as it promotes the growth of bifidobacteria and also lowers the levels of p- cresol and p-cresyl sulphate in chronic kidney disease (CKD) patients (Salmean, et al. (2015) J. Ren. Nutr. 25(3) : 316-320) .
- CKD chronic kidney disease
- synbiotic refers to a mixture of at least one probiotic component and at least one prebiotic component to promote health enhancing effects (Gibson and Roberfroid (1995) J. Nutr. 125:1401-1412) .
- the ingestion of said synbiotic product reduces the blood concentration of nitrogenous waste products that accumulate in the circulating blood stream.
- RENADYLTM it has been observed that the composition composed of S. thermophilics , L. acidophilus and B . longum (45 billion total) can reduce urea levels by 60% in approximately 24 hours.
- These waste products can be of an endogenous origin such as normal or abnormal metabolic routes or bacterial putrefaction.
- waste products can be of an exogenous origin as in dietary intake of proteins and amino acids.
- repeated ingestion of RENADYLTM itself has a highly beneficial effect upon the intestinal microflora by localization and colonization in the large intestine of microbes known to promote a healthy intestinal microenvironment .
- the present invention is a method for maintaining or improving kidney function and improving guality of life in a patient with reduced renal function, in particular in subjects with elevated levels of nitrogen-containing waste products.
- the method involves combining RENADYLTM treatment with the standard of care treatment that is already being administered to a patient. That standard of care will vary depending on the disease being treated. Administration of RENADYLTM has the additional beneficial effect of decreasing or reducing the levels of nitrogenous waste products in the blood to a normal range.
- normal levels of creatinine in the blood are in the range of 0.6 to 1.2 mg/dL
- normal blood urea nitrogen (BUN) levels range from 7 to 18 mg/dL
- normal uric acid levels in males and females is in the range of 2.1 to 8.5 mg/dL and 2.0 to 7.0 mg/dL, respectively.
- a subject with elevated creatinine, BUN and/or uric acid levels has levels that are above the normal range.
- a BUN/creatinine ratio of 5 to 35 is indicative of normal levels of nitrogenous waste products in the blood.
- means for determining the levels of nitrogenous wastes are well-known to the skilled laboratory clinician .
- Diseases contemplated for combination treatment with RENADYLTM and the standard of care include but would not be limited to those with diabetic nephropathy, hypertensive nephrosclerosis, glomerulonephritis, interstitial nephritis, or polycystic kidney disease wherein nephron function is impaired thereby decreasing glomerular filtration rate.
- diabetic nephropathy hypertensive nephrosclerosis
- glomerulonephritis glomerulonephritis
- interstitial nephritis or polycystic kidney disease wherein nephron function is impaired thereby decreasing glomerular filtration rate.
- One of skill in the art would understand what standard of care treatments would be combined based on the diagnosis made in a patient.
- a standard of care may be insulin or other drugs used to stabilize blood sugar levels that would include but not be limited to metformin, pioglitazone , rosiglitazone, glipizide, sitagliptin, and dapagliflozin .
- drugs such as anti-hypertensive agents, anti-inflammatory agents, and antibacterial agents, depending on the symptoms and causes of their disease.
- Standard of care may also include hemodialysis and peritoneal dialysis.
- RENADYLTM can be added to standard of care drug treatment regimens and provide beneficial effects on kidney function and quality of life, regardless of the standard of care treatment being used.
- the method of the invention provides for an increase in GFR or a reduction in the GFR decline in the patient after treatment with RENADYLTM in combination with standard of care treatment as compared to before treatment with the combination therapy.
- the average estimated GFR is more than 90.
- GFR is below 60 for more than three months, a patient is typically diagnosed with moderate-to-severe chronic kidney disease.
- a GFR below 15 indicates kidney failure.
- GFR increased by at least 2 mL/min for an individual when the combination therapy was administered daily or (2) the decline in GFR observed in a patient with chronic kidney disease could be slowed or reduced by approximately 2-fold when the combination therapy was administered daily.
- the average increase in GFR for subjects receiving the combination treatment was at least 3.5 ml/min/1. 3m 2 per year, which corresponded to an approximate 10% improvement in GFR.
- the present method provides both a quantitative and qualitative improvement in patients with reduced renal function.
- Example 1 RENADYLTM in Combination with Standard of Care , a Case Study in Four Indian Patients
- Patient 1 was a 77 year old man (67 kg) who had been on RENADYLTM for 10 months.
- Patient 2 was a 72 year old man (45 kg) who had been on RENADYLTM for four years.
- Patient 3 was a 55 year old man (71 kg) who had been on RENADYLTM for 9 months.
- Patient 4 was a 73 year old man (70 kg) who had been on RENADYLTM for one year.
- these patients had been taking two capsules of RENADYLTM (90 Billion CFUs) per day.
- the disease conditions included CKD (Patients 1, 2 and 4) and thin basement membrane glomerular nephropathy (Patient 3) .
- Physical, mental, and laboratory parameters were measured during the patients' time taking RENADYLTM.
- the patients evaluated their quality of life compared to their baseline condition (before they began taking RENADYLTM) .
- Results were as follows. For Patient 1, GFR increased by 9 mL/min, while energy increased and allowed for increased exercising and social functioning. In Patient 2, GFR increased by 6 mL/min and the patient reported increased energy level. In Patient 3, GFR increased by 12 mL/min, and the patient reported to be actively working. In Patient 4, GFR increased by 6 mL/min and this patient also reported to be actively working.
- a written survey was distributed to customers asking the subject's age; gender; ethnicity; whether the subject was suffering from hypertension, heart disease, diabetes or other co-morbidities; when the subject began taking RENADYLTM; what the subject's GFR was when they began taking RENADYLTM; what the subject's present GFR was; whether RENADYLTM improved the subject's quality of life (less stress, more energy, greater productivity, higher activity level, better appetite, etc.).
- the survey also requested that the subject provide a brief and candid testimonial about their experience with RENADYLTM thus far. Similar surveys had been performed in 2013 and 2015, but in those surveys GFR data was not specifically requested as it was in the most recent survey described here.
- GFR was initially compared at two points in time, i.e., baseline and then at the time the survey was taken, via a paired student's t test. Since follow up time differed for each patient, average change in GFR per year was compared in a similar fashion.
- ⁇ mixed modeling procedure using PROC MIXED (SAS) was used to model GFR changes according to the various years of follow-up, and to discern whether there were differences in GFR over time. This procedure took into consideration the repeated measurements per patient and estimated whether GFR differed among the various years of follow-up.
- this procedure allows one to model a "correlation structure", commonly referred to as a covariance pattern. Moreover, this estimate allowed for improved estimates of the standard errors of measurement . It also allowed for estimates at all-time points since data can be assumed to be missing at random (MAR) .
- MAR random
- various covariance structures to choose from.
- Three of the more common covariance structures include compound symmetry (cs) , for correlations that are constant for any two points in time, auto- regressive order one (arl) , for correlations that are smaller for time points further apart, and unstructured (un) , which has no mathematical pattern within the covariance matrix.
- the compound symmetry (cs) structure provided the best fit.
- the potential role of other factors such as gender and/or hypertension in GRF changes over time also was examined using the mixed method procedure. Chi- square analysis was used to explore whether there was an association between gender and Quality of Life. Data were analyzed using SAS system software (SAS Institute Inc, Cary, NC) .
- the average GFR1 (baseline GFR) was 30.52 ml/min/1.73m 2 (ranging from 4-100 mL/min/1.73m 2 )
- the average GFR2 (most recent measured GFR) was 34.07 ml/min/1.73m 2 (ranging from 5-106 mL/min/1.73m z )
- the average change in GFR from the beginning of RENADYLTM use to the respondents most recent doctors visit was an increase of 3.55 ml/min/1.73m z .
- the increase in GFR observed was statistically significant (p ⁇ 0.0013).
- 140 contained complete information, including GFR.
- the average baseline GFR of a survey participant was 30 ml/min (Stage IV CKD) .
- the most recent GFR reported varied from 5 ml/min to 106 ml/min.
- the highest GFR impact was an increase of 65 ml/min, and the largest decrease in GFR was -40 ml/min.
- the average increase for responders was 3.5 ml/min/1.73 m 2 , dividing that by the average time of three years they took the product gives an average per year increase in GFR of 2.9 ml/min.
- the normal progression of CKD based on the 2017 study conducted by Tsai et al. (PLoS ONE 12) would lead to a decrease in GFR of 4.42 ml/min/1.73 m 2 per year. Using this as the normal progression, the NKF/FDA preferred guideline would reduce decline in GFR by 40%. Thus, the annual decrease in GFR would be 2.6 ml/min per year.
- the GFR of a CKD person using the product would be 32.4 ml/min, a person with normal progression would be at 21.2 ml/min, and a person using a therapy resulting in 40% slower progression would be 24.8 ml/min.
- a RENADYLTM user would have a GFR that was 11.2 ml/min better than someone who is experiencing normal progression of CKD, and a RENADYLTM user would have a GFR that was 7.8 ml/min better than someone using a theoretical therapy that met the 40% guideline .
- Example 3 Long-term RENADYLTM Use in a Patient with Juvenile Diabetes and Nephropathy
- RENADYLTM use in a male patient for 11 years has been reported.
- the patient had been diagnosed with juvenile diabetic nephropathy. Beginning June 17, 2006, the patient began treatment with RENADYLTM .
- the dosage was 90 billion CFUs per day for the 11 year period.
- the individual was diagnosed with Juvenile diabetes in 1961 (56 years ago) , and nephropathy was diagnosed in 1986.
- the patient is currently taking nine prescription medications and insulin (insulin pump) for other health issues, and diabetes (Type I) respectively.
- the patient's GFR fluctuated from 41.7 to 24 mL/min/1.73m 2 , during the 11 years of the case study. On average, the patient's GFR declined by 1.6 mL per year. The patient always reported improved quality of life such as: more vigor, improved appetite, higher cognitive function, and ability to work continuously throughout the 11 year study period. No drug-drug interactions were reported during this long-term study.
- Blood urea nitrogen (mg/dL) ⁇ 9-23 mg/dL is considered normal .
- Creatinine (mg/dL), -0.0-1.3 mg/dL is considered normal.
- 5Glucose (mg/dL), 70-105 mg/dL is considered normal.
- RENADYLTM is a dietary supplement consisting of both prebiotic and probiotic components that has demonstrated its potential to reduce serum uremic toxins.
- Three pilot scale clinical trials and three biennial surveys (2013, 2015, 2017) of customers taking RENADYLTM showed that the strains in RENADYLTM benefit the renal failure population by several distinct mechanisms. These include 1) removal of nitrogenous wastes by S. thermophilics.
- the organism metabolizes uremic toxins, i.e., urea, uric acid and creatinine, resulting in increased growth of beneficial bacteria and reduction in growth of pathogens; 2) all three probiotic RENADYLTM strains produce bacteriocins (antimicrobial molecules), which further inhibit the growth of pathogens; 3) L. acidophilus reduces levels of cardiovascular toxins TMA and TMAO; 4) B . longum reduces production of phenols, cresols and other toxins, which get bound to serum proteins and cannot be removed by routine dialysis; and 5) modulation of inflammation, where inflammatory biomarkers like C-reactive protein (CRP) decreased .
- CRP C-reactive protein
- enteric dialysis with RENDAYLTM was safe and well-tolerated. It is non-invasive and less expensive. Hemo/Peritoneal dialysis is unable to reduce protein bound uremic toxins like indoles, cresols and other middle molecules. These toxins are associated with poor quality of life. Imbalanced gut microflora leads to high levels of uremic toxins, protein bound toxins, and infections such as Hepatitis C. RENADYLTM removes these toxins, lowers chronic inflammation, and stabilizes the gut microbiome thus providing benefit to pre-dialysis and dialysis patients regardless of age, sex, ethnicity, and comorbid conditions. RENADYLTM also appeared to have a stabilizing effect on overall health status and improved quality of life in the patient populations.
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EP18822773.0A EP3644753A4 (en) | 2017-06-26 | 2018-06-01 | Methods for maintaining and improving kidney function in patients with kidney disease and on standard of care therapy |
KR1020207002608A KR20200023432A (en) | 2017-06-26 | 2018-06-01 | Methods of Maintaining and Improving Kidney Function in Patients with Kidney Disease and Standard Managed Treatment Methods |
US16/619,145 US10953049B2 (en) | 2017-06-26 | 2018-06-01 | Methods for maintaining and improving kidney function in patients with kidney disease and on standard of care therapy |
CN201880042158.1A CN111032064A (en) | 2017-06-26 | 2018-06-01 | Methods for maintaining and improving renal function in patients with renal disease and receiving standard of care therapy |
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WO2021152441A1 (en) * | 2020-01-27 | 2021-08-05 | Frimline Private Limited | Pharmaceutical composition for reducing protein bound uremic toxins |
WO2021205242A1 (en) * | 2020-04-09 | 2021-10-14 | Pandurangan Prabhakaran | A therapeutic composition |
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WO2021205242A1 (en) * | 2020-04-09 | 2021-10-14 | Pandurangan Prabhakaran | A therapeutic composition |
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CN111032064A (en) | 2020-04-17 |
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US10953049B2 (en) | 2021-03-23 |
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