WO1998001135A1 - Phosphorus eliminants, serum parathormone level increase inhibit ors, and osteodystrophy inhibitors - Google Patents

Abstract

Phosphorus eliminants, serum parathormone level increase inhibitors, and bone dystrophy inhibitors, containing as the active ingredient(s) at least one compound selected from among nicotinic acid, its derivatives and metabolites of these derivatives. The nicotinic acid derivatives include nicotinamide, tocopherol nicotinate, nicomol, inositol hexanicotinate and pentaerythritol tetranicotinate, while metabolites thereof include pentaerythritol, pentaerythritol mononicotinate, pentaerythritol dinicotinate and pentaerythritol trinicotinate originating in the pentaerythritol tetranicotinate.

Description

 Description Phosphorus excretion promotion, suppression of serum parathyroid hormone concentration increase, and inhibitor of bone dystrophy

 The present invention promotes excretion of phosphorus into feces, suppresses serum thyroid hormone levels, and prevents the development of secondary hyperparathyroidism, and promotes the development of secondary hyperparathyroidism. The present invention relates to an agent for suppressing a bone dystrophy as a lesion. Background art

 Hyperphosphatemia is considered to be caused by impaired urinary excretion associated with renal impairment, cell destructive diseases (migration from cells due to tumors, diabetes, leukemia, etc.), endocrine diseases, excessive intake of phosphorus, etc. I have. Even if the serum phosphorus level slightly exceeds the normal range (2.4-4.8 mg / dl), it is preferable to keep it at most about 5.5 fflg / dl, and if it exceeds this level, parathyroid function It is said that osteoporosis increases and causes bone lesions, for example, renal osteodystrophy in patients with renal failure.

 For the treatment of hyperphosphatemia, aluminum hydroxide (USP 5,496,545), iron hydroxide (JP-A-5-155776), chitosan (JP-A-5 213762), ferrous citrate (JP-A-7-233963) ) Has been proposed, but its usefulness has not yet been evaluated.

For example, aluminum hydroxide has been used extensively in the past to control blood phosphorus levels, but it has not been used at present due to problems associated with aluminum poisoning. At present, the commonly used phosphorus adsorbent is precipitated calcium carbonate, but it is considered to have a lower phosphorus adsorption capacity than aluminum hydroxide, so it has to be administered in large amounts and naturally treated for hyperphosphatemia. Requires long-term administration, resulting in high calcium There is a problem that blood is easily caused. Especially in the treatment of hyperphosphatemia in dialysis patients, hypercalcemia often occurs due to excessive administration of calcium preparations and activated vitamin D. Furthermore, in dialysis patients, there are cases where calcium deposits on soft tissues (lungs, kidneys) and the inner walls of blood vessels, which cause calcification and lead to organ damage and arterial hardening.

 As described above, it is becoming difficult for dialysis patients to maintain serum phosphorous levels within an appropriate range in L, which does not cause hypertensive lucidemia, is highly effective, does not cause hypercalcemia, and has high anti-hypercalcemia. There is a desire for the appearance of phosphoric agents. Disclosure of the invention

 Meanwhile, nicotinic acid derivatives are conventionally known to be effective in treating stomatitis, glossitis, and arteriosclerosis. In particular, penicillin erythritol tetranicotine (hereinafter, simply referred to as “niseritrol”) Is an ameliorating agent for hyperlipidemia developed by the present applicant, and has a serum lipid-lowering effect, a serum lipoprotein metabolism-improving effect, a platelet aggregation inhibitory effect, and a blood flow increasing effect. However, it has a surprising effect on promoting phosphorus excretion, an effect on suppressing an increase in serum parathyroid hormone concentration (hereinafter sometimes simply referred to as “PTH”), and an effect on suppressing calcium deposition in the kidney. And obtained the starting point of the present invention. Thereafter, as a result of further studies, it was found that nicotinic acid, various nicotinic acid derivatives, and metabolites of niceritrol also had the same action, and the present invention was completed.

 Accordingly, the phosphorus excretion enhancer, serum thyroid hormone level increase inhibitor and bone dystrophy inhibitor according to the present invention comprise at least one compound selected from nicotinic acid, nicotinic acid derivatives and metabolites of the derivatives. It is characterized as an active ingredient.

Nicotinic acid derivatives include nicotinic acid amide, tocopherol nicotinate, Comol, inositol hexanicotinate and pentaerythritol tetranicotinate can be exemplified. The metabolites of nicotinic acid derivatives include those derived from pendus erythritol tetranicotinate, that is, pentaerythritol, pentaerythritol mononicotinate, pentaerythritol dinicotinate, and penduris erythritol trinicotinate.

 The agent according to the present invention is administered orally or parenterally, and the dosage varies depending on the patient's condition, age, sex, body weight, dosage form, and the like.For example, when administered orally to an adult, The amount of active ingredient is 1-6000mg / day.

BRIEF DESCRIPTION OF THE FIGURES

 Fig. 1 is a graph showing relative values of niceritrol for the test drug, and for the control group without drug as 100% for the content of inorganic phosphorus in feces excreted during 24 hours. Fig. 2 is the same as Fig. 1, except that the test drug is nicotinic acid, nicotinic acid amide, tocoprolol nicotinate, nicomol or inositol hexanicotinate, and Fig. 3 is a normal diet. The graphs show the results of examination of serum ^ -thyroid hormone (iPTH) in the untreated group, the control group on a high-phosphorus diet, and the test group on a high-phosphorus diet and given nicelitrol. Fig. 4 is a graph showing the results of examining the phosphorus content per lg of dry weight of the kidney after the test was completed, using niceritrol as the test drug.Fig. 5 shows the results. It is a graph which shows a calcium content similarly. BEST MODE FOR CARRYING OUT THE INVENTION

 The present invention will be described in more detail with reference to pharmacological test examples and drawings showing the results.

 Pharmacological test example 1

Study drug: Niceritrol, Dosage: 100 and 500mg / lg,

 Administration route: oral,

 Test animals: 7-week-old male SD rats,

 Test environment: AM 7:00-PM 7:00 ON, PM 7:00-AM 7:00 OFF 12 hour cycle, temperature 20-25 ° C, CRF-1 solid feed (Charles River Japan Co., Ltd.) , Phosphorus content; 0.87, Calcium content; 1.2%) and free access to well water

 Group composition: 10 animals per group, drug-free control group, niceritrol 100 mg / kg administration group and 500 mg / kg administration group,

 Test method: After the animals arrived, they were acclimated by rearing them in bracket cages for 4 days, and further acclimated by rearing them for 3 U using metabolic cages. Thereafter, the animals were reared for 3 periods as a control period, and feces and urine were collected every 24 hours. The 24-hour period was set from PM 5:00 to PM 5:00 the next day. After the control period, the test drug was orally administered at a rate of 5 ml / kg by gavage at non-fasting every HPM 5:00 and feces and urine were collected every 24 hours as in the control period. . This drug administration, feces collection and urine collection are repeated for 4 days. Measurement items: food consumption, phosphorus content in feces M and phosphorus content in urine,

 Results and discussion:

 Food consumption;

 No significant difference was observed between the test drug administration group and the control group.

 About phosphorus content in feces;

 Relative values in the control group without niceritrol were as shown in Fig. 1, when the content of inorganic phosphorus in feces excreted in 24 hours was 100% in the control group without the niceritrol. There was a significant difference in the risk factor ρ <0.05 for the 100 mg / kg group and the risk ratio p <0.01 for the 500 mg / kg group.

About phosphorus content in urine; When the phosphorus content in urine excreted during the 24-hour period was converted to lg of feed and compared with the average value during the control period of 3 days, niceritrol 100 mg / kg and 500 mg were used. An increasing tendency was observed in the / kg administration group.

 Pharmacological test example 2

 The same test as in Pharmacological Pharmacological Test Example 1 was conducted, except that nicotinic acid, nicotinic acid amide, tricofrol nicotinate, nicomol and inositol hexanicotine were used as test drugs instead of niceritrol. (All doses of the drug were 100 mg / kg). The drug was administered by measuring the phosphorus content in feces excreted in 24 hours during the control period of 3 days before drug administration and the test period of 4 days. Assuming that the amount of phosphorus excreted in feces in the control group was not taken as 100%, the results of the relative excretion of phosphorus in the drug-administered group were as shown in FIG.

As is evident from FIG. 2, there was a significant difference in the risk factor _ρ <0.05 in the nicotinic acid and nicotinic acid amide-administered groups, and phosphorus in feces was also observed in the other drug administration groups. Increased excretion was observed.

 Therefore, it was found that administration of these drugs promoted excretion of phosphorus into feces. Pharmacological test example 3

 When pentaerythritol, which is a metabolite of niceritrol, and mono-, di-, and triesters were used as the test drug instead of niceritrol, the same test as in Pharmacological Pharmacological Test Example 1 was performed. Turned out to be.

 Pharmacological test example 4

 Study drug: Niceritrol,

 Dosage: 500mg / kg,

 Administration route: oral,

 Test animals: 5-week-old male SD rats,

Test environment: AM 7:00-PM 19:00 ON, PM 19:00 AM 7:00 OFF for 12 hours Vehicle, temperature 20-25,

 Group composition: 8 animals per group, untreated group on normal diet, control group on high-phosphorus diet, test group on high-phosphorus diet and administered niceritrol at 500 mg / kg / day,

 Test method: After acclimatized breeding, a part of the left renal artery was ligated under ether anesthesia, and one week later, the right 摘 was removed under ether anesthesia to prepare a renal failure rat. From the third day after the renal insufficiency rat was prepared, a high phosphorus diet (manufactured by Oriental Yeast Kogyo Co., Ltd., phosphorus content: 1.5%, calcium content: 0.5%) was freely taken for three weeks. Blood was collected three weeks after the start of feeding, and this was used as a blood sample before drug administration. After that, the animals were divided into groups, and the control group and the test group were fed the above high-phosphorus diet for 10 days, and the food consumption was measured daily. For all groups, drinking water was freely available for drinking water. The test group was forcibly orally administered a drug once daily after grouping. Blood was collected on the 10th day from the start of the high-phosphorus diet, and this was used as the blood sample after drug administration.

 The untreated group was bred on a solid feed CRF-1 (manufactured by Nippon Chars Riva Co., Ltd., phosphorus content: 0.87, calcium content: 1.2%) after the acclimatization and during the test period. It refers to the group who did not undergo any surgical procedures.

 Measurement items: Cumulative food consumption (g) and serum parathyroid hormone concentration (iPTH, pg / ml) Results and discussion:

 About cumulative food consumption;

 The untreated group showed a significant increase in the risk factor P <0.001 compared to the control group. ^ There was no significant difference in cumulative food consumption between the control group and the test group. . About i PTH;

i PTH is as shown in Fig. 3, and when compared with the control group, there was no significant difference in the drug administration group at the time of grouping. At 0.05, a significant difference was observed. It has been found that the compound has an effect of suppressing an increase in parathyroid hormone concentration.

In addition, in the untreated group, a significant difference was found in the risk factor p 0.001 compared to the control group both before and after administration.

 Pharmacological test example 5

 Study drug: Niceritrol,

 Dosage: 500nig / kg,

 Administration route: oral,

 Test animals: 7-week-old male SD rats,

 Test environment: AM 7:00-PM 19:00 ON, PM 19:00 AM 7:00 OFF 12 hours cycle, temperature 20-25. C,

 Group composition: 10 animals per group, untreated group on normal diet, control group on high-phosphorus diet, and test group on high-phosphorus diet and administered niceritrol at 500 mg / kg / day,

 Test method: After acclimatization, rats were randomly placed in metabolic cages, and were treated with solid feed 5002 (manufactured by PMI Foods, phosphorus content 0.747%, calcium content; 0.845) for the untreated group. %), While the control group and the test group were allowed to freely ingest a diet enriched in phosphorus at 1.5% based on the above solid feed. In each group, purified water was freely available for drinking water. After acclimated breeding, they were bred for 14 days and food consumption was measured daily. For the test group, the drug was forcibly administered orally once a day after the end of acclimatization.

 All test animals were sacrificed on day 15 after acclimation and the kidneys were removed. One of the removed kidneys was subjected to biochemical evaluation and the other was subjected to pathological evaluation.

 Measurement items: Cumulative food consumption (g), wet weight of kidney (g), dry weight of kidney (g), water content in water (g), phosphorus and calcium content in kidney (mg / g dry weight of kidney) and Histopathological evaluation (calcification of kidney)

Results and discussion: No difference was observed in the cumulative food consumption between the untreated group fed the normal diet and the control group and the test group fed the high phosphorus diet.

 There were no significant differences in renal wet weight, renal dry weight, and renal water content among the untreated group, control group, and test group, but the control group showed an increasing trend. On the other hand, the renal phosphorus and calcium contents are as shown in Figs. 4 and 5, and when compared with the control group, the test group showed a significant difference in the p <0.05, It was found that biseritolol has an effect of significantly reducing the phosphorus and calcium contents in the kidney.

 According to the histopathological findings, no change was observed in the untreated group, while slight to moderate calcium deposition in the extramedullary zone of the kidney was observed in the control group on a high phosphorus diet. . This calcium deposition was observed in the proximal tubule, Hen-leloop, and distal tubule, but not in the inner medullary zone, and there was no change in the collecting duct. On the other hand, calcium deposition was also observed at the same site in the test group administered with niceritrol, but the degree of calcium deposition was extremely low and niceritrol had an effect of suppressing calcium deposition. There was found. Industrial applicability

 The currently widely used drug for hyperphosphatemia is precipitated calcium carbonate, especially in the treatment of hyperphosphatemia in dialysis patients, where calcium preparations as a phosphorus adsorbent are administered in excess and active vitamin D Is also likely to cause hypercalcemia as a side effect because it is also administered.However, the agent of the present invention has an effect of promoting phosphorus excretion, an effect of suppressing an increase in serum parathyroid hormone concentration and an effect of suppressing calcium deposition. Effective prevention and treatment of bone metabolism abnormalities during hyperparathyroidism, especially the development of renal osteodystrophy such as soft tissue (lung, kidney) and calcium deposits in the inner walls of blood vessels. Bring the means.

Claims

The scope of the claims 1. Accelerated phosphorus excretion and suppression of increase in serum parathyroid hormone concentration, characterized by containing at least one compound selected from nicotinic acid, a nicotinic acid derivative and a metabolite of the derivative as an active ingredient. And inhibitors of bone dystrophy.  2. The phosphorus excretion according to claim 1, wherein the nicotinic acid derivative is nicotinic acid amide, tocoprolol nicotinate, nicomol, inositol hexanicotine, and pentaerythritol tetranicotinate. Promotes, suppresses increase in serum parathyroid hormone level and suppresses osteodystrophy.  3. The excretion of phosphorus according to claim 1, wherein the metabolite is erythritol, pentaerythritol mononicotine, pentaerythritol dinicotine, and pentaerythritol trinicotinate. Acceleration, suppression of increase in serum parathyroid hormone levels and suppression of osteodystrophy.