Internet for Pharmaceutical and Biotech Communities
| Newsletter | Post Jobs | Advertising |
 
 
 

  

Pharm/Biotech
Resources

Outsourcing Guide

Cont. Education

Software/Reports

Training Courses

Web Seminars

Jobs

Buyer's Guide

Home Page

Pharm Patents /
Licensing

Pharm News

Federal Register

Pharm Stocks

FDA Links

FDA Warning Letters

FDA Doc/cGMP

Pharm/Biotech Events

Consultants

Advertiser Info

Newsletter Subscription

Web Links

Suggestions

Site Map
 

 
   



 

Title:  Oral bacteriotherapy compositions and methods
United States Patent: 
7,026,160
Issued: 
April 11, 2006
Inventors:
 Ranganathan; Nataragan (Broomall, PA)
Assignee:
 Kibow Biotech, Inc. (Philadelphia, PA)
Appl. No.: 
676622
Filed: 
September 30, 2003


 

Woodbury College's Master of Science in Law


Abstract

A composition for treatment of renal failure with selected bacteria which converts nitrogenous waste into non-toxic compounds in vivo is provided. Also provided is a method of inhibiting build up of toxins and metabolic wastes and overgrowth of undesirable bacteria in a subject by administering the composition to the subject.

SUMMARY OF THE INVENTION

An object of the present invention is to provide a composition for treatment of renal failure comprising a selected bacteria which converts nitrogenous waste into non-toxic compounds in vivo.

A further object of the present invention is to provide a method of inhibiting build up of toxins and metabolic wastes and overgrowth of undesirable bacteria in a subject comprising administering to a subject a composition comprising a selected bacteria which converts nitrogenous waste into non-toxic compounds in vivo.

DETAILED DESCRIPTION OF THE INVENTION

In kidney failure there is a decrease in the glomerular filtration rate and the kidneys are unable to maintain homeostasis of the blood. Homeostatic balance of water, sodium, potassium, calcium and other salts is no longer possible and nitrogenous wastes are not excreted. Retention of water causes edema and as the concentration of hydrogen ions increases, acidosis develops. Nitrogenous wastes accumulate and a condition referred to as uremia develops in the blood and tissue. Uremic toxins can be defined as solutes that: (I) are normally excreted by healthy kidneys, (ii) accumulate progressively during the development of renal failure so that their concentration increases, and (iii) inhibit various physiologic and biochemical functions; as a whole, they contribute to a complex set of clinical symptoms that comprise the Uremic Syndrome. Examples of uremic toxins include, but are not limited to, ammonia, urea, creatinine, phenols, indoles, and middle molecular weight molecules. More specifically, in uremia, the concentration of serum creatinine, blood urea nitrogen (BUN), uric acid, and guanidino compounds such as N-methyl guanidine (NMG) and guanidino succinic acid, (GSA) are significantly altered with accompanying abnormalities in acid-base equilibrium, electrolytes and water retention. In addition there are several known and unknown substances of low and middle molecular weight which have been identified as uremic toxins which also accumulate. If untreated the acidosis and uremia can cause coma and eventually death.

The introduction of renal dialysis has contributed to rapid progress in the clinical treatment of renal failure and elucidation of uremia. When a patient has mild kidney failure where the serum creatinine level is less than 400 μmol/L, the patient does not require renal replacement therapy such as dialysis or renal transplant. However, in general, when the serum creatinine level rises to 900 μmol/L, the patient needs routine dialysis or a kidney transplant to survive.

Dialysis can serve as a lifetime therapy for ESRD patients. Phosphate binders such as calcium acetate, calcium carbonate or aluminum hydroxide are generally prescribed for uremic patients receiving dialysis to reduce elevated phosphate levels. In general, however, dialysis is very expensive, inconvenient, time consuming and may occasionally produce one or more side effects. With a successful kidney transplant, a patient can live a more normal life with less long-term expense. However, there are also high costs associated with transplant surgery, the recovery period and the continuous need for anti-rejection medications. Further, there are often times a shortage of suitable donors. Accordingly there is a need for alternative strategies.

The present invention provides a composition comprising one or more selected bacteria which when instilled into the gastrointestinal tract of a subject converts nitrogenous wastes accumulated in the subject due to renal insufficiency into nontoxic compounds. The term subject is meant to include humans. In renal patients, nitrogenous solutes traverse intestinal capillaries into the bowel through diffusion. The composition of the present invention can be administered orally, or through any other appropriate manner so that the selected bacteria are instilled into the gastrointestinal tract of the subject and nitrogenous wastes are reduced.

The selected bacteria are live bacteria which consume excess urea, creatine, and "uremic" solutes. The selected bacteria are preferably Bacillus pasteurii or Lactobacillus sporogenes.

The present invention further provides an in vivo method of reducing nitrogenous wastes due to renal failure in a subject comprising instilling selected bacteria into the gastrointestinal tract of the subject so that nitrogenous wastes are converted into nontoxic compounds by the selected bacteria. The selected bacteria of the compositions of the present invention may be instilled via any suitable means including but not limited oral administration of the selected bacteria as a pharmaceutical composition or food stuff, injection, surgical implantation, or intranasal administration. It is preferred that the compositions of the present invention be administered to the animal on a routine basis such as one or more times daily over a period of time. Reduction of nitrogenous wastes is indicated via blood, urine or fecal sample testing wherein a reduction in BUN levels or serum creatine levels of the blood, urine or fecal samples as compared to initial or control levels indicates effective treatment. The compositions of the present invention are useful for treatment of renal failure.

The present invention further provides a method of inhibiting build up of toxins and metabolic wastes and overgrowth of undesirable bacteria in a subject comprising administering to a subject a composition comprising one or more selected bacteria which when instilled into the gastrointestinal tract of a subject converts nitrogenous wastes accumulated in the subject into nontoxic compounds. The composition can be administered to the subject to alleviate the symptoms of uremia caused by kidney disease or an inborn error of urea metabolism. The compositions of the present invention may be administered to treat renal insufficiency, liver insufficiency, inborn error of urea metabolism or gastrointestinal disorders and diseases.

For example, Sprague-Daly rats weighing 281.20=/-41.6 gm were subjected to ⅚th nephrectomy after measurement of baseline weight, BUN, serum creatinine, urine volume and fecal flora composition. The study group consisted of 36 nephrectomized rats and 6 controls. After a two-week post surgery stabilization, cohorts of six rats were fed standard rat chow plus one of the following regimens: 1) placebo, 2) B. pasteurii 3) L. sporogenes, 4) L. acidophilus, L. bulgaricus; Bifidus, S. thermophiles, L. casei, and L. reuteri, 5) L. acidophilus, L. bulgaricus, Bifidus, S. thermophilus and 6) S. boulardii. Subsequent blood, urine, and fecal measurements were obtained every 30 days for a total of 120 days.

The subtotally nephrectomized rats fed B. pasteurii and L. sporogenes had lower BUN levels (62.0+/-21, 63.0+/-26 mg/dl) compared with placebo (99.0+/-46 mg/dl) a reduction of (38 and 37%). Serum creatine levels were similarly reduced in rats fed with B. pasteurii and L. sporogenes (0.9+/-)0.25, 0.9+/-0.2 mg/dl) compared to placebo (1.5+/-0.56 mg/dl) a reduction of 40% in both groups. Rats fed with regimens comprising only L. acidophilus, L. bulgaricus; Bifidus, S. thermophiles, L. casei, L. reuteri, L. acidophilus, L. bulgaricus, Bifidus, S. thermophilus or S. boulardii did not show significant difference in BUN or serum creatine, compared to placebo. Feeding increased the fecal count for the appropriate group of bacteria in all groups at eight weeks. These results indicate that B. pasteurii and L. sporogenes administered orally as dietary supplements metabolize urea and creatine in vitro in subjects. Whether similar activity is discerned in uremic patients and large animals is the subject of derivative study. L. acidophilus (NCFM) fed dialysis patients reduced uremic toxins and showed improved nutritional status of about a ten percent increase in daily caloric intake and 1.6% increase in BMI (p<0.05) with no side effects. This study used a rat model of CRF (⅚ nephrectomy) to test 6 non-pathogenic microorganisms (MO) for possible use in a probiotic product. Sixty rats had ⅚ nephrectomies performed. Baseline creatine levels(Scr), BUN were measured and Cr clearance calculated. Rats (18 male and 18 female) with sufficient renal impairment (Scr=1.0=/-0.4) were distributed into 6 matched groups (GP), ANOVA showed no significant difference between groups (p=0.516) at baseline. Rats were individually caged and fed a special diet beginning at day 30 supplemented with a particular MO additive daily for up to 126 days. Periodic BW, Scr, BUN and CrCl were measured. A control group of non-nephrectomized rats(n=7, Scr=0.2+/-0.1) received the same food without any supplement. All of the rats survived (Scr at end=0.5=/-0.1). Days of survival was the primary endpoint variable. The study ended at day 156.

TABLE 1
 
Survival in Groups of Mice Receiving Oral Diet
Supplements Containing Non-Pathogenic Microorganism
        % Mean    
GP Organism ALIVE DEAD SURVIVE days SD Median
 
G S. boulardi 2 4 33.3 111 44 113
B Placebo 2 4 33.3 116 39 122
F H1001 2 4 33.3 116 36 110
E SF101 3 3 50 126 33 132
C B. pasteruii 4 2 66.7 148 14 156
D L. sporogenes 5 1 83.3 149 16 156
 

As shown in Table 1, diets D and C were more effective than G, B, and F (p<0.05). The study showed that a probiotic containing either or both B. pasteurii and L. sporogenes is capable of increasing survival in otherwise untreated uremic rats.

In another aspect, the present invention further provides compositions for treating uremia or renal disfunction in a subject, comprising a mixture of one or more selected bacteria which converts nitrogenous waste into non-toxic compounds in vivo along with one or more of the following: a prebiotic, ammoniaphilic bacteria with high urease activity, and/or sorbents with specific adsorption affinities for uremic toxins such as creatinine, uric acid, phenols, indoles, middle molecular weight molecules and inorganic phosphate along with a water sorbent, for use in the alleviation of uremia.

Compositions comprising selected bacteria which converts nitrogenous waste into non-toxic compounds in vivo may be enteric coated and/or microencapsulated. Enteric coating of the composition is specifically designed to deliver sorbents and/or the selected bacterial source at the ileal and colonic regions of the bowel where maximal resorption of uremic solutes and other molecules are found to occur. This is preferably achieved via a coating material that disintegrates and dissolves at a pH of 7.5 or higher. Examples of enteric coatings with these characteristics include, but are not limited to, Zein, polyglycolactic acid, polylactic acid, polylactide-co-glycolide and similar coating materials. Enteric coatings also enable delivery of the sorbents to their site of action in relatively native form without binding of various digestive materials to the sorbents prior to reaching the target region.

Compositions of the present invention may further comprise a phosphate binding agent such as aluminum hydroxide gel, calcium carbonate or calcium acetate, magnesium hydroxide gel and/or a water binding agent such as psyllium fibers, naturally occurring gums such as locust bean gum, guar gum or modified starches.

Compositions of the present invention are administered orally to subjects in need thereof to decrease the build-up of toxins and metabolic wastes and/or to inhibit or decrease the over growth of undesirable bacteria in the subject. In one embodiment, the composition is administered to a subject with uremia to alleviate the symptoms of uremia. By "alleviation of symptoms" of uremia, it is meant that the composition removes sufficient levels of uremic toxins such that a patient suffering from uremia either does not require dialysis, requires dialysis less frequently or for shorter durations, or does not require initiation of dialysis as soon as would be needed without treatment. Compositions of the present invention can also be administered to a subject in need thereof to treat not only renal insufficiency and inborn error of urea metabolism, but also liver insufficiency and gastrointestinal disorders and diseases.

In a preferred embodiment, oral delivery of the compositions is accomplished via an emulsion or paste mixed with an easy to eat food. The oral delivery of the compositions may be via ready to eat food or other nutritional product. The delivery of the compositions of the present invention may be via pharmaceutical compositions of liquid, capsule, pill or other suitable forms. The probiotic or selected bacteria of this invention can be administered along with a mixture of sorbents in the emulsion or paste or separately in an ingestible capsule.

 

Claim 1 of 1 Claim

1. A composition for treatment of renal failure comprising Bacillus pasteurii which converts nitrogenous waste into non-toxic compounds in vivo, wherein said Bacillus pasteurii is enterically coated.

____________________________________________
If you want to learn more about this patent, please go directly to the U.S. Patent and Trademark Office Web site to access the full patent.

 

 

     
[ Outsourcing Guide ] [ Cont. Education ] [ Software/Reports ] [ Training Courses ]
[ Web Seminars ] [ Jobs ] [ Consultants ] [ Buyer's Guide ] [ Advertiser Info ]

[ Home ] [ Pharm Patents / Licensing ] [ Pharm News ] [ Federal Register ]
[ Pharm Stocks ] [ FDA Links ] [ FDA Warning Letters ] [ FDA Doc/cGMP ]
[ Pharm/Biotech Events ] [ Newsletter Subscription ] [ Web Links ] [ Suggestions ]
[ Site Map ]