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Methods and compositions for reducing or preventing vascular calcification during peritoneal dialysis therapy

A technology of vascular calcification and peritoneal dialysis, applied in the field of medical treatment, can solve the problems of reduced applicability and patients' inability to excrete drugs, and achieve the effect of preventing vascular calcification and reducing the progress of vascular calcification

Inactive Publication Date: 2013-01-02
BAXTER INT INC +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although many of these analogs are currently used to treat osteoporosis, their use in end-stage renal disease is contraindicated because patients cannot excrete the drugs and, unlike pyrophosphates, they cannot be treated by ubiquitous Cyclic pyrophosphate degrading enzymes such as alkaline phosphatase break down
Their accumulation is thought to cause osteomalacia, which reduces their suitability

Method used

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  • Methods and compositions for reducing or preventing vascular calcification during peritoneal dialysis therapy
  • Methods and compositions for reducing or preventing vascular calcification during peritoneal dialysis therapy
  • Methods and compositions for reducing or preventing vascular calcification during peritoneal dialysis therapy

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0054] Pharmacokinetic / Bioavailability Studies

[0055]Fifty-four male Sprague Dawley rats, each approximately 250 g, were randomly divided into two groups, intravenous ("IV") administration and intraperitoneal ("IP") administration. Both groups received a pyrophosphate ("PPi") dose of 2.0 mg / kg. As a single bolus, Group 1 was administered pH-adjusted (7.4), 4 mL / kg via tail vein infusion, containing PPi 2.25 mM and P-32-labeled PPi (50 μCi, specific activity 84.5 Ci / mmol). saline solution, and then rinsed with 0.2 mL of saline. Group 2 was administered PPi and P-32-labeled PPi (50 μCi, specific activity 84.5 Ci / mmol) via a single intraperitoneal injection at 40 0.15mM solution in dialysis solution at a dose of 60mL / kg. Blood (IV) as well as blood (IP) and peritoneal fluid (IP) were collected at various time points up to 8 hours post-dose.

[0056] Plasma and peritoneal fluid were analyzed by two methods: a liquid scintillation method to analyze total radioactivity, and...

Embodiment 2

[0064] Establishing vascular calcification as a model of human disease in the dialysis population

[0065] The homozygous apolipoprotein E knockout (apoE - / - ) mice were housed in polycarbonate cages in a pathogen-free, temperature-controlled (25°C) room with a strict 12-h light / dark cycle, and had ad libitum access to laboratory chow and water. All procedures were in accordance with the National Institutes of Health ("NIH") Guidelines for the Care and Use of Laboratory Animals (NIH Publication No. 85-23).

[0066] In 8-week-old female apoE - / - Chronic renal failure ("CRF") was established in mice, which were then randomly assigned to 4 groups as follows:

[0067] 1) Non-CRF-EKO (ApoE knockout) animals (control group, 6 mice);

[0068] 2) CRF / EKO animals treated only with dialysis solution without PPi (CRF placebo group, 8 mice);

[0069] 3) CRF / EKO animals (CRF PPi low dose group, 8 mice) treated with low dose PPi (30 μM, about 0.21 mg PPi / kg body weight / day) in dialysi...

Embodiment 3

[0080] The maximum tolerated dose study was conducted according to the study design in Table 3. The administered solution consisted of dextrose concentrate or modified dextrose concentrate mixed with buffer concentrate or modified buffer concentrate in a 3:1 ratio (dextrose:buffer). The compositions of the concentrates are shown in Tables 4-7. PPi was contained in the buffers or modified buffer solutions shown in Tables 5 and 7. As a bolus injection, each test article or control article was intraperitoneally administered once daily in a volume of 40 mL / kg to each of five different female rats through a butterfly needle for 7 consecutive days. Necropsy was performed one day after the last dose.

[0081] Septal tissue samples from all rats were trimmed, processed, embedded in paraffin, and sectioned. Hematoxylin and eosin stained slides were prepared and examined by light microscopy. Microscopic observations were subjectively graded according to the relative severity of the ...

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Abstract

Methods and compositions for reducing, preventing or reducing the progression of calcification in peritoneal dialysis patients are provided. In an embodiment, the present disclosure provides a method comprising administering to a patient during peritoneal dialysis therapy a dialysis solution comprising a therapeutically effective amount of pyrophosphate ranging between about 30 [mu]M and about 400 [mu]M. Formulations of dialysis solutions according to the dose ranges claimed in the present disclosure allow therapeutic amounts of pyrophosphate to be delivered to peritoneal dialysis patients.

Description

technical field [0001] The present disclosure generally relates to medical treatment. More specifically, the present disclosure relates to methods and compositions for reducing, preventing, or reducing the progression of vascular calcification in a patient in conjunction with peritoneal dialysis treatment and replacement therapy for insufficient pyrophosphate levels. Background technique [0002] A person's kidney system can fail due to disease, injury, or other causes. In renal failure of any cause, there are several physiological disturbances. Water, mineral balance and excretion of the daily metabolic load are no longer possible in renal failure. During renal failure, toxic end products of nitrogen metabolism (eg, urea, creatinine, uric acid, etc.) can accumulate in the blood and tissues. [0003] Kidney failure and reduced kidney function have been treated with dialysis. Dialysis removes waste, toxins, and excess water from the body that would normally be removed by ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K33/42A61K9/08A61P9/10
CPCA61K9/0019A61K9/08A61M1/287A61K33/42A61P7/08A61P9/00A61P9/10
Inventor 布鲁斯·L·里瑟尔杰弗里·A·怀特克里斯托弗·R·达尔顿
Owner BAXTER INT INC
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