Composition for the treatment of progressive renal diseases

Abstract

Described herein is an association of at least one phosphate binder, at least one uremic toxin binder, at least one vasoactive antihypertensive agent and at least one antifibrotic agent for the management of progressive renal diseases including chronic kidney diseases (CKD) in domestic carnivores. Specifically, the application describes veterinarian compositions comprising such an association and the use thereof for the treatment of CKD conditions.

Claims

1. A method of treating a domestic animal for high blood pressure and/or progressive renal disease, the method comprising administering an association comprising at least one phosphate binder, at least one uremic toxin binder, at least one vasoactive anti-hypertensive agent and at least one antifibrotic agent sufficient to induce a decrease in serum creatinine concentration in the domestic animal; wherein the association comprises a mixture of calcium carbonate and magnesium carbonate in the ratio of calcium carbonate to magnesium carbonate of between 3:1 and 4:1, and wherein the domestic animal is a cat.

2. The method of claim 1, wherein the association is administered to the domestic animal once or twice daily.

3. A method of treating chronic kidney disease (CKD), chronic renal failure (CRF), chronic renal disease, kidney insufficiency, kidney failure or azotemia in a domestic animal, the method comprising administering an association comprising at least one phosphate binder, at least one uremic toxin binder, at least one vasoactive anti-hypertensive agent and at least one antifibrotic agent sufficient to induce a decrease in serum creatinine concentration in the domestic animal; wherein the association comprises a mixture of calcium carbonate and magnesium carbonate in ratio of calcium carbonate to magnesium carbonate of between 3:1 and 4:1, and wherein the domestic animal is a cat.

4. The method of claim 3, wherein the association is administered to the domestic animal once or twice daily.

Description

FIGURES

(1) FIG. 1 is a graph representing mean blood urea nitrogen (BUN) concentrations in g/l (with standard error of the mean, SEM) in cats that received the tested composition (formulated as in example I) during 84 days. The concentration in g/l is represented in ordinate whereas the time is represented in days in abscissa.

(2) FIG. 2 is a graph representing mean creatinine serum in mg/l with SEM concentrations in cats that received the tested composition (formulated as in example I) during 84 days (*p<0.05 compared to the beginning of the study at day 0). The concentration in mg/l is represented in ordinate whereas the time is represented in days in abscissa.

(3) FIG. 3 is a graph representing mean inorganic phosphorus serum concentrations in mg/l with SEM in cats that received the tested composition (formulated as in example I) during 84 days (*p<0.05 compared to the beginning of the study at day 0). The concentration in mg/l is represented in ordinate whereas the time is represented in days in abscissa.

(4) FIG. 4 is a graph representing mean magnesium serum in mg/l with SEM concentrations in cats that received the tested composition (formulated as in example I) during 84 days. The concentration in mg/l is represented in ordinate whereas the time is represented in days in abscissa.

(5) FIG. 5 is a graph representing mean calcium serum in mg/l with SEM concentrations in cats that received the tested composition (formulated as in example I) during 84 days. The concentration in mg/l is represented in ordinate whereas the time is represented in days in abscissa.

(6) FIG. 6 is a graph (scatter plot) representing the correlation between serum creatinine levels (diff creatinine in abscissa) and urinary fractional excretion of phosphorus (diff phosphorus excretion in ordinate) in cats that received the tested composition (formulated as in example I) during 84 days. The 95% confidence ellipse is represented in dotted line. The Pearson coefficient of correlation is 0.8566 (close to 1) (number of observations 10, Prob>|r| 0.0015), so one can state that the serum creatinine levels and urinary fractional excretion of phosphorus in cats are correlated.

(7) FIG. 7 is a graph (scatter plot) representing no correlation between evolution of serum creatinine levels (evolution of creatinine level in ordinate) and weight in cats (evolution of weight in abscissa) that received the tested composition (formulated as an example I) at day 0 and at day 84. The 95% confidence ellipse is represented in dotted line. The Pearson coefficient of correlation is 0.1756 (number of observations 10, Prob>|r| 0.6276), so one can state that the evolution of the serum creatinine levels and weights of the cats are not correlated.

(8) It should be clearly understood that the following examples are given purely as illustrations of the subject of the invention, of which they do not in any way constitute a limitation.

EXAMPLES

I. Preparation of a Veterinarian Composition According to the Present Invention

(9) The following composition

(10) TABLE-US-00002 Quantity Content Substance: (% p/v) in 1 ml Function Active agents ACE oligopeptides 2 20 mg Vasoactive anti- hypertensive agent Polysaccharides 10 100 mg Antifibrotic agent extracted from Astragalus membranaceus Calcium carbonate 3.75 37.5 mg Phosphate binder Magnesium carbonate 1 10 mg Phosphate binder Chitosan 1 10 mg Uremic toxin binder Excipient(s) Hydrophilic colloidal 1 10 mg Gelifying agent silica BHT 0.02 0.2 mg Antioxidant Liver powder 10 100 mg Appetizing material Polyoxyethylene (20) 0.5 5 mg Non ionic sorbitan monooleate tensioactive agent Miglyol Qs 100 Qs 1 ml Oily vehicle
is prepared as described below: Equipment needed: a stainless steel tank and a system of rotor-stator dispersion. Operating protocol:
In a suitable vessel: introduce all Miglyol; introduce then sequentially BHT, Polyoxyethylene (20) sorbitan monooleate, hydrophilic colloidal silica, Calcium Carbonate, Magnesium Carbonate, the ACE oligopeptides, Chitosan, the extracts of Astragalus membranaceus (Astralagus Root) and the liver powder, disperse until obtaining a homogeneous product.

II. Assessment of the Effect of the Administration of the Veterinarian Composition of Example I

Materials and Methods

(11) Animal Selection

(12) Prior to the study 10 adult healthy cats, 5 males and 5 females were selected randomly. At the day 0 of the study animals were aged from 2 to 5 years. Animals were fed by industrial food only; no changes in nutrition were recorded past 12 months. Animals were located in specialised centre for animal experimentation.

(13) The composition of example I was administered orally during 12 weeks at normal dose 0.5 ml per 1 kg of body weight and per day; it was given in one single administration in the morning before the meal.

(14) Biological Analysis

(15) Blood and urinary sampling, as well as clinical examination, body weight measurement were performed in the morning before feeding. Biological analyses were performed at four check-points (t0, t0+7 days, t0+42 days, t0+84 days). Next variables were considered: Blood urea nitrogen (BUN), serum creatinine (SCr), serum inorganic phosphorus (P), serum magnesium (Mg), serum calcium (Ca), urinary protein to creatinine ratio (UPC), urinary fractional excretion of phosphorus (UP %), urinary specific gravity (Ud).

(16) Statistical Analysis

(17) Analysing of the data was performed using SAS 9.2 software.

(18) The biochemical parameters were compared between D0 and D84 using a paired t-test or a Wilcox on signed ranks tests at the 5% significance threshold. In order to test correlation between the parameters urea, creatinine, phosphorus and weight on D0, Pearson coefficients of correlation were computed and tested at the 5% significant threshold.

(19) Results

(20) Blood and urine samples were collected from all cats at T0, T0+7 days, T0+42 days and T0+84 days. FIGS. 1 to 6 represents results of blood analysis in cats.

(21) Safety Parameters of the Tested Composition:

(22) Over the period of the study, all Ca and Mg blood levels remained within normal ranges in all animals supplemented with the tested composition (FIGS. 4 and 5). In particular, due to a theoretical concern regarding the possible induction of hypocalcaemia, no statistically significant changes were recorded in calcium blood levels (p=0.19) when comparing day 0 to day 84.

(23) Efficacy Parameters of the Tested Composition:

(24) Over the study period (day 0 compared with the day 84) animals supplemented with the tested composition had statistically significant decrease of inorganic phosphorus with p value equal 0.002 (FIG. 3). During the same period of time animals had statistically significant decrease of creatinine, with p values equal 0.016 (FIG. 2). BUN serum levels also decreased over study period time. Fractional excretion of phosphorus was statistically lower at the end of the study than in the begging (p=0.02).

(25) Statistical Correlation:

(26) Significant correlation were found (p=0.002) between changes in creatinine blood values and the changes in values of urine fractional excretion of phosphorus between day 0 and day 84 (FIG. 6). The same conclusion was obtained with a nonparametric test. Changes in blood creatinine levels and urea blood nitrogen levels were also found to be statistically correlated between day 0 and day 84 (0.038 for the group of animals involved in the study. No statistical correlation was found between changes in other parameters, including changes in body weight and creatinine blood levels over study period of time (FIG. 7).

(27) Discussion

(28) This trial provided data on safety and efficacy of use in vivo new complementary feed according to the invention containing an association of combined phosphate binders with other natural active substances. The tested composition have been proven to be efficient in lowering serum phosphorus concentration as well as in lowering blood urea nitrogen. More importantly, and reported for the first time, is the lowering of serum creatinine levels, which are considered as an important prognostic factor of renal health. This outstanding result has furthermore been obtained without inducing pathological hypercalcemia or hypermagnesaemia in the animals.

(29) As an additional benefit this in-vivo trial provided data of safety of use calcium and magnesium phosphate binders in feline specie; over 12-week use of the supplement there was no statistically significant changes in magnesium and calcium blood levels. In the course of this study we did not establish the long-term effects of the use of a maintenance diet plus intestinal phosphorus binder on the preservation of renal structure and function in cats, however for the first time an in-vivo trial have shown that association of phosphate binders with other reno-protectant substances will not only generate a decrease in phosphataemia, but improve other important prognostic factors of chronic renal disease such as creatinaemia. Phosphate binders-only use has been previously proven to not change levels of serum creatinine. Thus a significant decrease in creatinine serum levels could not be attributed to phosphate binders, but really to their association with other natural reno-protectant substances.