CN1315174A - Composite medicine for treating renale failure - Google Patents
Composite medicine for treating renale failure Download PDFInfo
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Abstract
A composite medicine for treating renal failure, hyperphospheremia and metabolic acidosis is an iron-contained compound chosen from iron citrate, iron acetate and their combination. It is applied by oral application.
Description
The present invention relates to control, particularly relate to and a kind ofly be used for the treatment of renal failure and with the medicine of hyperphosphatemia to the phosphate retention.
Phosphate is mainly from renal excretion.So inevitably the phosphate retention will take place when renal failure.Degenerate and renal failure patient's soft tissue calcification has important function by renal function for alleviating for the phosphorus restriction hydrochlorate.In the diet height of phosphorus take in experimental renal failure, make renal function worsen (according to document: Haut, L.L., Kidney Int17:722-731 (1980); Karlinsky, D.et al., Kidney Int 17:293-302 (1980)), and low-phosphorous absorption can stop chronic kidney hypofunction further to worsen (according to document: Lumlertgul, D.et al., Kidney Int29:658-666 (1986)).Nearest studies have shown that, can raise blood plasma vitamin D (metabolite of strong vitamin D) and suppress secondary hyperparathyroidism of phosphorus restriction hydrochlorate (according to document: Portale, A.A.et al., J.Clin.Invest 73:1580-1589 (1989); Kilav, R.et al., J Clin.Invest 96:327-333 (1995); Lopez, H.et al., Am.J Physiol 259:F432-437 (1990)), perhaps directly suppress parathyroid cells proliferation (according to document: Naveh-Many, T.et al., Am.Soc.Nephrol 6:968 (1995)).Summary is got up, and keeping normal plasma concentration and phosphatic tissue content is the important means that prevents the soft tissue calcification in secondary hyperparathyroidism, kidney osteanabrosis and the renal failure.
Phosphate in the dietary restriction is not easy to accomplish, and inferior on every Wendesdays dialysis also is not enough to remove the phosphate of every day and absorbs.So phosphate binders is widely used in controlling renal failure patient's phosphate metabolism.In the past thirty years, the doctor of kidney section once with aluminium carbonate or aluminium hydroxide as phosphatic bonding agent.Consider the poisoning by aluminum in the renal failure, stopped the use of aluminum complex, alternate is calcium carbonate and calcium acetate.Yet calcium carbonate or other calcium preparation not only are not enough to remove the phosphate of taking in every day, and too many calcium are provided for the end stagerenaldisease patient.
In nineteen forty-three, once there was the people that two routine chronic kidney hypofunction patients are used the minor official sour ferrum ammonia of Chinese holly and reached the several months to reduce blood plasma phosphate, the side effect of being reported is a diarrhoea (Liu, S.H., et al., Medicine, Baltimore 22:1031-1061 (1943)).Yet the minor official sour ferrum ammonia of Chinese holly (4-12 gram/day) when using therapeutic dose is because of containing a large amount of ammonia, so may not be an ideal complex.The ammonia that this complex discharges can cause the complication of gastrointestinal irritation etc., moreover this complex is being unsafe when the renal failure patient suffers from hepatopathy, because it can cause hepatic coma.
Moreover animal experiment proves that aluminum and iron salt are when reducing blood plasma phosphate and phosphuresis, and they also make bone ash matter and bone phosphorus sharply reduce (document: Cox, G.et al., J.Biol.Chem 92:Xi-Xii (1931)).For example, give rat in the growth feed with iron salt can cause growth retardation, low serum p disease and on suitable degree, lose bone ash matter and the body of calcium, phosphorus in total content.In one month, rickets (document: Brock, J.et al., J.Pediat 4:442-453 (1934) have taken place in rat behind the strict phosphorus restriction hydrochlorate; Rehm, P.et al., J.Nutrition 19:213-222 (1940)).To just hatching one day chicken, iron salt has also caused serious rickets and hypophosphatemia (document: Deobald, H.et al., Am.J.Physiol111:118-123 (1935)).
So there is a common recognition in medical circle, Here it is need develop a kind of effective phosphate binders soon with the treatment renal failure.
Therefore, one object of the present invention just provides a kind of utilization and can control hyperphosphatemia and phosphate retention method in conjunction with phosphatic complex.Another object of the present invention provides a kind of method of correcting metabolic acidosis in the renal failure.A further object of the invention just provides a kind of compositions of peroral dosage form, in order to suppress in the food phosphatic absorption and/or to correct metabolic acidosis.
According to the present invention, comprise the ferruginous chemical compound of ferric citrate and iron acetate, be used as medicament and be used for limiting in the digestive tract taking in the absorption of phosphorus.This chemical compound also can be used as the medicament of correcting metabolic acidosis.According to this invention, this chemical compound can also peroral dosage form be combined in the phosphate taken in the intestinal also and then prevent its absorption.The minor official sour ferrum of Chinese holly and/or the iron acetate that it is believed that each gram dosage can be in conjunction with about 40 milligrams of phosphorus.
Therefore, the method for the present invention metabolic acidosis that can be used for reducing the phosphate retention and correct renal failure.Moreover, from iron containing compounds, absorbing ferrum and also help treating the renal failure patient, anemia and iron deficiency because renal failure has often occurred together are particularly when patient accepts epo treatment.
Be not subjected to theoretic constraint, it is believed that ferric citrate and iron acetate and phosphate reaction, the precipitate of generation is iron phosphate or ferrous phosphate, all is insoluble, can not absorb in intestinal.The somebody thinks absorbed citric acid, no matter from ferric citrate or from iron acetate (it is converted into citric acid), all be converted into heavy carbonate, it can correct metabolic acidosis.
It is more obvious that other characteristics of the present invention and advantage will become in the following description and claim.
The invention provides and merge hyperphosphatemia or have the patient that the hyperphosphatemia tendency takes place to control the method for serum paraoxonase hydrochlorate level and metabolic acidosis suffering from renal failure.By method of the present invention, comprise to patient and use a kind of iron complexes that contains that comprises ferric citrate, iron acetate and conjugate thereof that is selected from.Thereby prevent the absorption of intestinal with the phosphate of taking in conjunction with patient's intestinal for Orally administered this complex of patient, the method can obtain therapeutic effect.
By the preferred embodiments of the invention, this contains iron complexes and is made into a kind of therapeutic dosage forms for oral dispenser, suffers from hyperphosphatemia or the patient of developing this situation tendency is arranged with treatment.Can be mixed with aqueous or the suspensoid shape so this contains iron complexes, perhaps make single solid dosage forms, for example compressed tablet or capsule.The method and the excipient that prepare colloid and solid dosage forms are well-known in the art.Compositions of the present invention also can the acceptable form of some materia medicas be used, for example ester, salt or prodrug.
The preparation of this oral agents must contain q.s and contain iron complexes, in case after being taken in by patient, the phosphate that can be in intestinal suppresses to be taken in conjunction with the phosphate of being taken in of capacity is absorbed, thereby reduces the probability that hyperphosphatemia situation or complication take place.So, each oral agents that contains iron complexes can contain the 500-1000 milligram of having an appointment and contain iron complexes.Contain the degree that the application of the treatment effective dose of iron complexes will be serious according to patient, the character of patient's food and the binding ability that contains iron complexes in prescription decide.So-called " treatment-effective dose " be meant according to the present invention and can reach selected desired result, and the dosage opposite physiological role or side effect can not take place the time; This desired result is often referred to the minimizing of observable clinically absorption phosphate absorption and/or the correction of metabolic acidosis.According to the present invention, the using dosage of complex can change, if necessary, but required bonded phosphate level in the reference patient digestive tract.Daily dose is can be effectively between about 5-10 gram.
As what will go through in the infra joint, doing in the viviperception with rat, roughly 1 gram ferrum (Fe
+++) can be respectively in conjunction with 180 milligrams phosphorus in 130 milligrams and the renal failure Mus in the normal mice, perhaps 1 gram ferric citrate can be in conjunction with 30 milligrams of phosphorus in normal mice, can be in conjunction with 40 milligrams the renal failure rat.Each animal roughly consumes 24 gram foods every day, and wherein iron content is 220 milligrams.It is identical in conjunction with potentiality to it is believed that ferric citrate and iron acetate have in human body.Moreover rat is taken in and contains iron complexes for by per kilogram 4 grams, side effect can not take place.
Preferably consider the oral administration of this chemical compound although should be understood that the present invention, this does not also mean that the pattern that will limit dispensing, and oral and systemic approach dispensing all is desirable.Moreover the present invention has also considered combined treatment carefully, is appreciated that also employed complex can be used any materia medica acceptable carrier among the present invention when throwing in, preferably not only avirulence but also suitable concrete pattern of throwing in.
This chemical compound is in order to use the program prescription that can adopt the medicine technical maturity.Following example can be got in touch to help understanding in aforementioned and other aspect of the present invention, and it is in order to explain rather than to limit that these examples put forward.
Example 1
1, raw material and method
Ferric citrate in normal rat with phosphatic combination:
Male normal Spraque-Dawley rat (N=6) raise with routine contain 1.02% phosphorus and 0.95% calcium two weeks of rat feed meal (the biomedical company limited of ICN, Cleveland, Ohio).The content of phosphorus in feedstuff is examined.The powder application agent feedstuff is in order to prevent that being urinated excrement pollutes.Other 6 rat are fed with same food but are contained two weeks of 4% ferric citrate.All animals are all closed in metabolic cage separately.The body weight of each rat, urine, excrement discharge and food consumption all carry out inferior on every Thursdays, the monitoring in totally two weeks.Urine excrement weekly lumps together, and expresses with the average of every day in the week.Blood drawing is once had a blood test and is starched phosphorus, sarcosine glycosides weekly.And when experiment finishes, the have a blood test other parathyrine of first, activated vitamin D and concentration of iron.
Iron complexes was renderd a service phosphatic combination when rat had renal failure:
Iron complexes in conjunction with rendeing a service, caused renal failure with kidney time full excision to phosphatic when the research rat had renal failure.A nephrectomy 2/3rds, another kidney three days is after flank Lu Zuoquan excision.The renal function of these animals reduces to normal 50%.In the whole observation process of four treated animals, its renal function is all similar.Animal is divided into four groups, 7 every group.Matched group is fed with around the normal rat powder feedstuff, and it neutralizes aforementioned identical, contains 1.02% phosphorus, 0.95% calcium.The nursing of other the three treated animal Fe that contains the minor official sour ferrum ammonia of 5% Chinese holly respectively, contains 16.5-18.5%, 4.4%FeCl
36H
2O, molecular weight 270.2, or 4% ferric citrate FeC
6H
5O
7, and around the food of molecular weight (M.W.) 245.Each hectogram iron content 0.95 gram in the three kinds of foods in back.To the body weight of each animal, the urine excrement is discharged, and reaches food consumption and monitors weekly four days, around being total to.Day urine excrement is weekly discharged the per average daily amt that lumps together with weekly and is expressed.Weekly blood drawing have a blood test slurry phosphorus, inosine and in having a blood test in the experiment end parathyrine by the first, the concentration of activated vitamin D and ferrum.
2, analytical method
Excrement in muffle furnace with 800 ℃ temperature through ashing in 30 minutes, phosphorus is surveyed then with 10% perchloric acid extraction excrement phosphorus in the back of spending the night.The mensuration of phosphorus and inosine is by the method for formerly describing (document: Hsu.C., et al., Kidney Int 25:789-795 (1984)).The blood plasma activated vitamin D is pressed method replication (document: Reinhardt, T.A.et al., the J.Clin.Endocrinol Metab 58:91-98 (1984) of Reinhardt etc.; Hollis.Hollis, B.W.et al., Clin.Chem.32:2060-2063 (1986)).The test bay coefficient of variation be 7.0% when low matched group (20pg/ml, N=12), be 4.1% when high matched group (100pg/ml, N=12).The test within variance coefficient is that 5.4% (N=6) is 4.7% during at high matched group when low matched group.The recovery meansigma methods of activated vitamin D is 65%.Use the rat parathyroid gland to detect medicine box and measure parathyroid hormone with the immune radiating detection method.
Total data is expressed with mean ± SEM.Statistical analysis is finished with ANOVA and repeated measure, and adopts FISHER ' S PLSD test.P＜0.05 o'clock thinks that the significance meaning is arranged.
3, result
Ferric citrate is in conjunction with phosphatic effect in the normal rat.
Two treated animals are grown with same speed.Their body weight is approximate in two weeks before and after handling.Matched group 264 ± 2.9 grams before handling; Treatment group 269 ± 3.7 grams.Handle back matched group 313 ± 4.7 grams; Treatment group 319 ± 3.5 grams.All rat (N=12) consumes equivalent food, and be 24 grams average every day.The phosphorus that consume every day, matched group is 240.8 ± 6.1 milligrams/day, the treatment group is 240.2 ± 7.2 milligrams/day.Survey first day every day urine phosphorus output from experiment contains ferric citrate in the test group food, reduces at first weekend to surpass 50%, and matched group is 71.4 ± 2.5 milligrams/day, and the treatment group is 30.4 ± 2.6 milligrams/day, P＜0.01.Second weekend matched group be 75.7 ± 4.0 milligrams/day, the treatment group is 30.7 ± 1.5 milligrams/day, P＜0.01.The daily output of inosine is as broad as long between first all interior two treated animals: matched group is 8.72 ± 0.38 milligrams/day, and the treatment group is 8.95 ± 0.80 milligrams/day; In second week, matched group is 9.99 ± 0.43 milligrams/day, and the treatment group is 9.44 ± 0.64 milligrams/day.The phosphatic minimizing of minimizing reflection intestinal absorption of urine phosphate output because rat when eating the food that contains ferric citrate excrement phosphate output roughly increase to 30 milligrams/day.Average excrement phosphorus discharge every day matched group is 135 ± 4.1 milligrams/day of first weeks, and the treatment group is 164 ± 10.7 milligrams/day, P＜0.03.136 ± 5.2 milligrams/day of second all matched groups, the treatment group is 163 ± 1.7 milligrams/day, P＜0.007.Can estimate that from these data every gram ferric iron roughly can be in conjunction with 130 milligrams of phosphorus, or every gram ferric citrate can be in conjunction with 30 milligrams of phosphorus.Blood parathyroid hormone (PTH) is 16.2 ± 3.8pg/ml at matched group, the treatment group is 16.0 ± 3.5pg/ml, activated vitamin D is 83.5 ± 1.5pg/ml at matched group, in the treatment group is 82.2 ± 2.0pg/ml, ferrum is 1.76 ± 0.17ug/ml at matched group, and the treatment group is 1.73 ± 12ug/ml, and packed cell volume is 48.8 ± 0.5% at matched group, and the treatment group is 47.8 ± 0.7%.The value of phosphorus is as broad as long between two treated animals, and the blood plasma concentration of iron all is similar between all animals.Prompting is in the in-test of fortnight, and to normal rat, ferrum is not absorbed.
Have in the rat suffering from renal failure, iron complexes is in conjunction with phosphatic effectiveness:
Phosphatic effectiveness of these iron compounds bind and past are similar to the research of normal rat.Yet, (the 4th week) on the 22nd, two animals, one belongs to ferric citrate ammonia group, and another belongs to the ferric citrate group, because of respiratory tract infection is condemned to death.Raise with its rate of growth of animal of ferric citrate ammonia and ferric citrate all identically, see Table 1 with control animals.Yet raise the animal that contains the iron chloride feedstuff, it is slower to tend to grow than matched group, even consume the food and the phosphorus of isodose, sees Table 2, table 3.
Table 1
| Average weight (g) weekly | ||||
| Test | First week | Second week | The 3rd week | # around the |
| Matched group ferric ammonium citrate FeCl 3Ferric citrate | ?234.9±8.7 ?226.0±7.3 ?229.2±9.4 ?243.6±7.8 | ????268.0±13.5 ????260.2±10.0 ????250.6±10.4 ????266.6±5.9 | ????309.5±13.5 ????296.4±14.2 ????269.2±11.4 ????306.9±8.8 | ????336.1±14.6 ????333.3±14.4 ????296.3±12.5* ????345.7±8.1 |
* compare body weight with matched group and significantly descend, P≤0.05
FeNH
4Citron salt group: ferric ammonium citrate;
# was illustrated in for the 4th week to citron ferrum ammonia group and ferric citrate group, N=6.
Table 2
| One all per day food intake doses (g/ days) | ||||
| Test | First week | Second week | The 3rd week | # around the |
| Matched group ferric ammonium citrate FeCl 3Ferric citrate | ????18.8±1.3 ????20.3±1.1 ????18.1±0.5 ????21.3±0.9 | ????20.8±1.8 ????23.0±1.6 ????20.4±1.0 ????23.3±0.9 | ????22.6±1.1 ????23.5±1.7 ????21.3±0.7 ????24.3±0.9 | ????22.2±1.1 ????23.1±1.5 ????21.4±0.7 ????24.8±0.5 |
# was illustrated in for the 4th week to citron ferrum ammonia group and ferric citrate group, N=6.
Table 3
# was illustrated in for the 4th week to citron ferrum ammonia group and ferric citrate group, N=6.
| One all per day phosphorus intakes (mg/ days) | ||||
| Test | First week | Second week | The 3rd week | # around the |
| Matched group ferric ammonium citrate FeCl 3Ferric citrate | ?193.3±13.4 ?198.5±10.8 ?178.0±4.6 ?210.8±9.6 | ?214±18.8 ?224.8±15.4 ?201.0±10.3 ?230.6±9.0 | ???232.6±11.6 ???230.4±16.7 ???210.3±7.1 ???240.1±9.9 | ?228.0±11.3 ?205.0±25.1 ?210.5±7.1 ?245.6±5.9 |
The phosphate that urine is discharged descends contain the food of iron complexes in consumption after immediately.Urinate average day discharge sarcosine glycosides and comparing its discharge third and fourth week with matched group than low, zero difference in four treated animals except the iron chloride group.Run through whole experimental period numerical value all around and compare remarkable reduction with the collator, see Table 5.On the contrary, in entire test, raise the rat with the iron content feedstuff, its excrement phosphate daily output all increases, and sees Table 6.Discharge the result from excrement phosphate, can estimate that 1 gram, 3 valency ferrum roughly can be in conjunction with 180 milligrams of phosphorus in the renal failure rat, perhaps 1 gram ferric citrate is in conjunction with 40 milligrams of phosphorus.This show iron complexes in suffering from the animal intestinal of renal failure effectively in conjunction with intestinal in phosphate to reduce its absorption.Therefore, the iron complexes that contains of this test can be used for suffering from the crowd of renal failure to reduce the phosphatic absorption of enteral.
Table 4
# was illustrated in for the 4th week to citron ferrum ammonia group and ferric citrate group, N=6.* compare P≤0.05 with matched group
| Average weekly day sarcosine glycosides excretion (mg/ days) | ||||
| Test | First week | Second week | The 3rd week | # around the |
| Matched group ferric ammonium citrate FeCl 3Ferric citrate | ?8.63±0.70 ?8.96±0.60 ?8.39±0.37 ?9.69±1.26 | ?9.81±0.63 ?10.28±0.74 ?8.86±0.38 ?10.59±0.57 | ?11.62±0.81 ?11.38±0.83 ?9.27±0.51* ?12.08±0.61 | ????12.9±0.96 ????11.79±0.87 ????10.73±0.48* ????12.79±0.50 |
Table 5
* compare P≤0.05 with matched group.# was illustrated in for the 4th week to citron ferrum ammonia group and ferric citrate group, N=6.
| The average weekly day excretion (mg/ days) of phosphate in the urine | ||||
| Test | First week | Second week | The 3rd week | # around the |
| Matched group ferric ammonium citrate FeCl 3Ferric citrate | ????61.8±5.2 ????28.3±2.2* ????30.8±1.5* ????33.1±3.4* | ????60.4±5.9 ????24.8±2.8* ????25.0±1.7* ????25.7±2.2* | ????65.7±3.9 ????25.5±3.2* ????17.3±2.6* ????28.1±1.7* | ????67.8±3.6 ????23.9±2.1* ????23.1±1.8* ????30.7±1.6* |
Table 6
* compare all P≤0.05 with matched group.# was illustrated in for the 4th week to citron ferrum ammonia group and ferric citrate group, N=6.
| The average weekly day excretion (mg/ days) of phosphate in the excrement | ||||
| Test | First week | Second week | The 3rd week | # around the |
| Matched group ferric ammonium citrate FeCl 3Ferric citrate | ????89.3±9.9 ????128.9±6.6 ????112.1±3.3* ????133.5±6.5 | ?111.6±10.1 ?148.4±9.7 ?145.9±5.7* ?156.3±6.7 | ????137.8±9.1 ????167.2±10.5 ????157.3±6.0 ????166.8±4.7 | ????140.4±7.4 ????170.6±12.1 ????162.5±8.3 ????182.8±4.7 |
Serium inorganic phosphorus hydrochlorate concentration belongs to normal range in these animals, as previously mentioned, the renal failure of this degree can not improve the blood plasma phosphate concn, sees Table 7 (document: Hsu, C.H.et al., Kidney Int 37:44-50 (1990)).The other parathyrine concentration of the blood first of these four groups of renal failure animals is significantly higher than those intact animal.Moreover in these four groups of renal failure animals, the other parathyrine level of the control animal first of renal failure is all higher than other group, though owing to have huge variation to cause its numerical value not reach significance,statistical in the matched group, see Table 8.Blood plasma sarcosine glycosides concentration does not have difference in this four treated animal.Yet the activated vitamin D concentration of blood plasma descends to some extent in the animal of taking in iron chloride.
Table 7
# was illustrated in for the 4th week to citron ferrum ammonia group and ferric citrate group, N=6.
| Serum phosphate concn (mg/ liter) before and after ferrum is taken in | |||||
| Test | Before the treatment | First week | Second week | The 3rd week | # around the |
| Matched group ferric ammonium citrate FeCl 3Ferric citrate | ????6.68+0.19 ????6.04+0.5 ????6.85+0.22 ????6.30+0.15 | ????7.79+0.33 ????7.23+0.23 ????7.24+0.42 ????6.94+0.27 | ????6.56+0.18 ????6.72+0.33 ????6.52+.026 ????7.09+0.13 | ????6.72+0.25 ????5.85+0.22 ????6.32+0.20 ????6.22+0.13 | ????7.18+0.60 ????6.11+0.13 ????6.14+0.23 ????6.29+0.16 |
Table 8
* these numerical value are measured behind 4 all balance studieses.# was illustrated in for the 4th week to FeNH
4Citron salt group and ferric citrate group, N=6.
| Serum sarcosine glycosides, calcitriol and PTH concentration | |||
| Test | * serum sarcosine glycosides | * serum calcitriol | * PTH concentration pg/ml |
| Matched group ferric ammonium citrate # FeCl 3Ferric citrate # | ????0.89±0.10 ????0.81±0.05 ????0.76±0.05 ????0.80±0.06 | ????54.2±2.8 ????56.1±2.2 ????45.9±3.8 ????55.5±1.6 | ????112.9±57 ????31.2±8.1 ????22.4±3.3 ????28.0±4.1 |
Table 9 summed up four treated animals test the around measured blood plasma concentration of iron and hematocrit at weekend.The renal failure rat is raised when containing the feedstuff of the minor official sour ferrum of Chinese holly, and its blood plasma concentration of iron is significantly higher than the control animal that feeds conventional feed.All the other each groups are with containing the iron complexes domesticated animal, and its blood plasma concentration of iron has raising in various degree, though do not reach statistical significance.Yet its hematocrit value is significantly higher than the animal of feeding with conventional feed in raising with the animal that contains iron complexes.Significantly, the minor official sour ferrum of Xiao Liang these iron complexes, particularly Chinese holly can be absorbed in intestinal.
Table 9
Compare * P＜0.04, * * P＜0.02, * * * P＜0.01 with matched group.# was illustrated in for the 4th week to FeNH
4Citron salt group and ferric citrate group, N=6.
| The concentration of ferrum and hemocyte ratio in the serum | ||
| Test | Ferrum (μ g/ml) | The ratio % of hemocyte |
| Matched group ferric ammonium citrate # FeCl 3Ferric citrate # | ????1.26±0.09 ????1.57±0.21 ????1.70±0.09 ????2.10±0.29** | ????40.0±4.4 ????44.7±1.0*** ????44.8±0.6*** ????43.3±0.6* |
4, discuss
Kidney is the main path that phosphate is discharged, so renal failure patient's phosphate retention is a common problem.The phosphorus restriction hydrochlorate is difficult to prove effective in recipe.Depending merely on every Wendesdays, time dialysis can not remove the phosphate (document: Hou, S.H.et al., Am., J.Kidney Dis 18:217-224 (1991)) that absorb every day.So phosphate binders (for example calcium carbonate or other calcium preparation) once was used to control renal failure patient's phosphate metabolism always.Yet, use these preparations to increase excessive calcium (document: Ramirez, J.A.et al., Kidney Int 30:753-759 (1986)) as the end stagerenaldisease patient.Must be noted that these end stagerenaldisease patient is not owing to there is approach to discharge calcium, great majority all have positive calcium balance state.Table 10 for example, end stagerenaldisease patient, when analysing time as hemodialysis on every Wendesdays except the absorption of calcium in the food is external, use the calcic dialysis solution of 3.5mEq/L and 2.5mEq/l can expect calcium the positivity fluctuation on average with reach respectively+896mg/4hrs (+384mg/ day) and+150mg/4hrs (+64mg/ day) (document: Hou, S.H.et al., Am.J.Kidney Dis 18:217-224 (1991)).Similarly, abdominal dialysis liquid is with 3.5mEq/l and 1.5% dextran, and the just fluctuation that causes calcium the normal patient of calcium sees Table 11 (documents: Martis to average 14mg/ exchange or 56mg/ day roughly, L.et al., Perita Dial Int 9:325-328 (1989); Piraino, B.et al., Clin.Nephrol 37:48-51 (1992)).Suppose that the dietary calcium that the end stagerenaldisease patient consumes is 800 milligrams/day, the percentage rate of estimating calcium absorption is 19% (document: Ramirez, J.A.etal., Kidney Int 30:753-759 (1986)), then the calcium balance that calculates for the end stagerenaldisease patient will be above 114 milligrams of/day (documents: Matkovic and Heaney.Matkovic of normal person's calcium balance thresholding in 18-30 year, V et al., Am.J.Clin.Nutr.55:992-996 (1992)).Add calcium carbonate or other calcium preparation and will further increase the absorption and the retention of calcium with treatment Secondary cases hyperparathyroidism, particularly the patient who surpasses 30 years old as phosphatic bonding agent.(document: Ramirez, J.A.et al., Kidney Int 30:753-759 (1986)).
Table 10
* with reference to Hou, S.Heal., the inferior on every Wendesdays estimated value * * that analyzes the calcium that flows estimates food intake every day calcium * * * with reference to Cobum among the am.j.Kiidney Dis 18:217-224 (1991), the absorption estimated value of the part calcium that J.W.et al.kidney int 3:264-272 (1973) draws
| Calcium balance during estimation patient hemodialysis is analysed |
| Use calcium dialysis 3.5mEq/l calcium balance |
| The calcium phosphate of flow regime in the dialysis solution, approximately+896mg/4h or+the about 800mg/d** calcium of calcium that 2688mg/wk (384mg/d) * feed is taken in partially absorb the total calcium balance of about 152mg/d (19%) * * * approximately+536mg/d |
| Use calcium dialysis 2.5mEq/l calcium balance |
| The calcium phosphate of flow regime in the dialysis solution, approximately+150mg/4h or+the about 800mg/d** calcium of calcium that 450mg/wk (64mg/d) * diet is taken in partially absorb the total calcium balance of about 152mg/d (19%) * * * approximately+216mg/d |
Table 11
* with reference to Piraino, B.eal., the estimation * * of the mobile calcium of four times a day exchange estimates food intake every day calcium amount * * * with reference to Coburn among the clin.nephrol 37:48-51 (1992), J.W.et al., the absorption estimated value of the part calcium that Kidney int 3:264-272 (1973) draws
| Estimate that the calcium balance in the patients abdomen penetrating fluid uses day Ca of absorption dosage 3.5mEq/l and the calcium balance of 1.5% glucose amount |
| Mobile positive calcium ion approximately+the 14mg/ exchange or+the about 800mg/d** calcium of calcium that the 56mg/d* diet is taken in partially absorb the total calcium balance of about 152mg/d (19%) * * * approximately+208mg/d |
The 20-53 common adult in year, phosphatic balance was negative value slightly or reached balance (document: Lakshmanas, F.L.et al., Am.J.Clin.Nutr.1368-1379 (1984)) its every day.Similar to the discharge of calcium, kidney is the main thoroughfare that phosphate is discharged.The phosphatic concentration of blood plasma remains on usually and roughly is lower than 20 ml/min with interior until glomerular filtration rate normal range.Under the renal failure situation, blood plasma is phosphatic normally to be to cause the result that phosphate is discharged to be increased because the blood plasma parathyroid hormone improves.Yet blood plasma phosphate level may be not enough to correctly reflect the phosphatic content of whole body.(document: Lau, K.et al., Philadelphia:Saunders 505-571 (1990)).
Though being absorbed in only between chronic dialysis patient and the normal person of phosphorus is as broad as long, but the intestinal absorption of accepting activated vitamin D treatment (phosphatic absorption will increase by 60% to 86% in food) its phosphorus as dialysis patient will increase (document: Ramirez, JA.et al., Kidney Int 30:753-759 (1986)).When hemodialysis, phosphatic outflow be haply 1057 milligrams/every dialysis once, or 3171 milligrams/(document: Hou, S.H.et al., Am.J.Kidney Dis 18:217-224 (1991)) weekly.Therefore, hemodialysis be not enough to remove in food every day absorbed phosphatic (4200 milligrams/weekly, suppose that the percentage rate that is absorbed as 1000 milligrams/day and phosphate absorption in the food is 60%, see Table 12) (document: Ramirez, J.A.et al., Kidney Int 30:753-759 (1986)).According to estimates, the ferric citrates that each dialysis patient every day need about 4 to 5 grams, iron acetate or its are in conjunction with to reach normal phosphate metabolism.
Table 12
* with reference to Hou, S.H et al., Am.j.Kidney Dis 18:217-224 (1991) draw 3 dialysis/weeks and mobile phosphorus estimation * * dietary intake every day estimation * * * with reference to Ramirez, J.A.et.al., Kidney int 30:753-759 (1986), the amount of the partially absorbing estimation of P
| Phosphatic balance in the phosphatic balance penetrating fluid in the estimation hemodialysis patient |
| In the penetrating fluid mobile phosphorus anion approximately-1057mg/4h or 3171mg/ week (453) mg/d* diet take in partially absorbing of about 1000mg/d** P about 60% or the total P balance of 600mg/d*** approximately+147mg/d |
The insider can realize from above explanation, and the content that the present invention showed can be implemented through different modes.Therefore, through in conjunction with instantiation of the present invention and after being illustrated, in actual applications, need not be confined to scope involved in the present invention, because experienced clinician can easily understand other some changes after having learnt description and having followed requirement.All patents quoted in the literary composition and publication are all as a reference.
Claims (13)
1, the chemical compound that is selected from ferric citrate, iron acetate and conjugate thereof is used for controlling the purposes of suffering from hyperphosphatemia or the medicine of phosphate retention in the patient body of the hyperphosphatemia of developing into tendency being arranged in preparation.
2, the described purposes of claim 1, wherein this medicine is the medicinal preparation for oral administration that contains the chemical compound that is selected from ferric citrate, iron acetate and conjugate thereof for the treatment of effective dose.
3, the described purposes of claim 1, wherein said chemical compound is a ferric citrate.
4, the described purposes of claim 1, wherein said chemical compound is an iron acetate.
5, the described purposes of claim 2, the treatment effective dose of wherein said chemical compound are the about 500-1000 milligram of single dose.
6, a kind of therapeutic composition, be used for controlling the interior phosphate retention of patient body that needs reduce the picked-up of diet phosphate, said composition is a peroral dosage form, and every dosage comprises that about 500-1000 milligram is selected from the chemical compound and the acceptable excipient of materia medica of ferric citrate, iron acetate and conjugate thereof.
7, the described compositions of claim 6, wherein said chemical compound is a ferric citrate.
8, the described compositions of claim 6, wherein said chemical compound is an iron acetate.
9, the chemical compound that is selected from ferric citrate, iron acetate and conjugate thereof is used for controlling the purposes of the medicine of suffering from renal prostration disease human serum phosphate metabolism and metabolic acidosis in preparation.
10, the described purposes of claim 9, wherein this medicine is the medicinal preparation for oral administration that contains the chemical compound that is selected from ferric citrate, iron acetate and conjugate thereof for the treatment of effective dose.
11, the described purposes of claim 10, the treatment effective dose of wherein said chemical compound are the about 500-1000 milligram of single dose.
12, the described purposes of claim 9, wherein said chemical compound is a ferric citrate.
13, the described purposes of claim 9, wherein said chemical compound is an iron acetate.
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| CN 00103592 CN1315174A (en) | 2000-03-31 | 2000-03-31 | Composite medicine for treating renale failure |
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