The effectiveness of using the citrate mixture "Blemaren" for uric acid nephrolithiasis


Pharmacological properties

Pharmacodynamics.
When effervescent tablets of blemarene are dissolved in water, potassium-sodium hydrocitrate is formed and carbon dioxide is released. in this case, residual alkaline ions are formed, which are excreted by the kidneys. thus, the pH of urine increases (depending on the dose, it is neutralized or alkalized). this increases the degree of dissociation and at the same time the degree of dissolution of uric acid and cystine. confirmation of litholysis of uric acid stones is performed radiographically. When taking the drug, the excretion of citrates increases and the excretion of calcium in the urine decreases. Alkalinization of urine, increased excretion of citrates and decreased excretion of calcium lead to a decrease in the amount of calcium oxalate in the urine, since in a weak alkaline environment citrate forms stable complex compounds with calcium. In addition, the citrate ion should be considered an effective physiological inhibitor of crystal formation and accumulation of calcium oxalate and calcium phosphate.

Pharmacokinetics. After a one-day use of the drug Blemaren, effervescent tablets, the administered amount of sodium and potassium is excreted from the body by the kidneys for 24–48 hours. With prolonged use of the drug, the daily excretion of potassium and sodium corresponds to the daily intake. There are no significant changes in blood gases or electrolytes in the blood or plasma. This means that due to the renal regulation of alkalization, the acid-base balance in the body is maintained, and the accumulation of sodium and potassium does not occur with normal kidney function.

Indications for use of the drug Blemaren

Litholysis of urate stones in the urinary tract and prevention of their primary and re-formation; litholysis of mixed urate-oxalate stones; prevention of calcium oxalate stones (prevention of re-formation of stones and growth of residual fragments); alkalinization of urine during cytostatic therapy during the use of uricosuric drugs, during the treatment of patients with cystine stones, as well as in renal tubular acidosis with phosphate lithiasis; as an adjuvant in the treatment of hyperuricemia with xanthine oxidase inhibitors (for example, gout); as an adjuvant in combination symptomatic treatment of skin porphyria tarda.

Application

The average daily dose is determined individually; it is determined by determining the urine pH.

Effervescent tablets are taken after dissolving in liquid (water or fruit juice). The liquid may be slightly cloudy and have some undissolved particles on the surface.

The daily dose is divided into 3 equal parts, which are taken throughout the day (for example, at 8:00, 14:00, 21:00). If a daily dose of more than 3 tablets is required, it is recommended to take one tablet in the morning, one in the middle of the day, and the rest at night.

Monitoring the effectiveness of the drug is carried out by determining the pH of fresh urine 3 times a day before the next dose of the drug. To do this, use standard indicator strips included in each package. The indicator zone of the test strip should be briefly immersed in urine, then removed and after 2 minutes, compare the resulting color of the test strip with the color scale printed on the set of indicator strips, and record the determined pH values ​​​​in the control calendar. The dose of the drug is considered correctly selected if the pH values ​​determined 3 times a day are within the recommended limits for each pathology. Changes in color of unused test strips will not affect pH results.

To dissolve uric acid (urate) stones, the urine pH should be in the range of 7.0–7.2.

If the daily profile of pH values ​​is below 7.0, the dose should be increased, and if it is above 7.2, it should be reduced.

For maintenance treatment of patients with urolithiasis, which is accompanied by calcium stones, the pH level must be kept within 6.2–6.8.

If the daily profile of pH values ​​is below 6.2, the dose should be increased, and if it is above 6.8, it should be reduced.

To dissolve urate-oxalate mixed stones and metaphylactic the formation of calcium-oxalate stones, urine pH must be maintained at 6.8–7.4 for a certain time.

The drug Blemaren is used before remote nephrolithotripsy for mixed (X-ray heterogeneous) stones to enhance its effectiveness, reduce the structural density of the stone and reduce the number of repeat sessions. The duration of citrate therapy in preparation for extracorporeal lithotripsy should be at least 3 weeks.

To alkalinize urine in patients with cystine stones, urine pH should be in the range of 7.5–8.5. This requires a higher dose of the drug.

When carrying out cytostatic therapy, urine pH should not be lower than 7.0, and when treating late porphyria of the skin, 7.2–7.5.

Uricosuric therapy, like the treatment of urate stones, should be carried out at a urine pH of 7.0–7.2.

The pH value, which can be determined using standard test strips, is in the range of 5.4–7.4. If it is necessary to control urine pH in patients with cystine stones or with late porphyria of the skin, special indicator strips should be used to determine the pH in the range of 7.2–9.7.

To dissolve stones (depending on their size and composition), the duration of treatment ranges from 4 weeks to 6 months. To prevent relapses of nephrolithiasis, the drug should be prescribed in courses, the duration and frequency of which are determined individually for each patient.

The effectiveness of using the citrate mixture "Blemaren" for uric acid nephrolithiasis

I.A. Aboyan, V.A. Sknar, S.V. Pavlov Municipal budgetary healthcare institution “Clinical Diagnostic, Rostov-on-Don”, Russia

Urolithiasis (UCD) has a high medical and social significance, which is due to a fairly high incidence, reaching 10% in the world, its annual growth in many countries and the defeat of the most able-bodied part of the population [1].

In the Russian Federation in 2012, the incidence of urolithiasis was 550.5 people per 100 thousand population, and its increase over the period from 2002 to 2012 exceeded 25% [2]. The prevalence of uric acid stones worldwide varies from 5 to 40% and varies geographically, so in North America it ranges from 5 to 10%, and in Israel it is 40% [3-5].

In the structure of the incidence of urolithiasis, there is an increase in the frequency of uric acid nephrolithiasis to 20-30%, which may be due to an increase in people's life expectancy, physical inactivity leading to impaired purine metabolism, and increased consumption of protein foods and alcohol.

The ratio of uric acid stones according to the results of a study of the composition of uroliths in recent years was 11.9-30.5% [7-10].

Numerous studies indicate the high efficiency of litholysis of uric acid stones using citrate mixtures (Blémaren and others) [11-17].

According to the recommendations of the European Association of Urology, the method of choice for non-invasive surgical treatment of stones up to 2 cm can be external shock wave lithotripsy (ESW) [11,18].

Most authors indicate that the effectiveness of this procedure depends on the size and density of the stone [6,14,17,19], along with some negative assessments of such a correlation [21].

In recent years, increasing attention has been paid to the effect of citrate drugs on stone density and the results of a subsequent course of extracorporeal lithotripsy (ESLT). Most studies have noted an increase in efficiency and a reduction in the duration of a course of DLT as a result of the use of citrates [14,16,19, 21].

The purpose of the study is to study the effectiveness of litholysis and the dynamics of the density of uric acid and mixed stones during therapy using citrate mixtures.

MATERIALS AND METHODS

We conducted a study of a group of 30 patients (14 women and 16 men aged 27-64 years) with uric acid nephrolithiasis. The size of the stones ranged from 8 mm to 22 mm, there were no signs of obstructive uropathy. Multislice computed tomography (MSCT) of the kidneys was performed on Siemens Somatom Difinition AS 64 and AS 40 devices in all patients before the start of therapy, after 3 months and after the end of the 6-month course of treatment (if a stone was present after 3 months according to MSCT).

The diagnosis of uric acid (urate) nephrolithiasis was established if the patient had a low stone density (138-600 NU) on MSCT of the kidneys; X-ray negative stones on plain urography or when performing a topographic image before MSCT of the kidneys, the results of X-ray phase analysis (XRF) of urinary stones that had passed earlier or were obtained as a result of lithotripsy, lithoextraction or surgical treatment before the current course of treatment, the presence of hyperuricemia and/or hyperuricuria. All patients received the Blemaren citrate mixture 3 times a day, in an individual pH-dependent dose from 0.5 tablets to 1.5 - 2 tablets 3 times a day during the course of litholysis (3-6 months).

In the presence of hyperuricemia and/or hyperuricuria, allopurinol 100–200 mg per day was also prescribed during the course of litholysis, usually in one dose. Some patients were recommended to take allopurinol twice a day if they had complaints of discomfort in the stomach with a single dose of the drug. In this case, the daily dose of allopurinol depended on the degree of hyperuricemia and/or hyperuricuria and was the minimum necessary to normalize the level of uric acid in the blood and/or urine.

RESULTS AND DISCUSSION

Complete dissolution of stones occurred in 22 patients (73.3%). In 6 cases (20%) there was a decrease in the size of the stone (Table 1). Of these, in three patients the stones decreased in size and passed naturally. The three remaining patients with a decrease in stone size underwent EBRT of stones. We noted greater efficiency in dissolving calculi when their size is less than 1 cm.

Table 1. Results of litholysis of uric acid stones using Blemaren

Resultn%
Complete dissolution2273,3
Partial dissolution620
No dissolution26,7
Total30100

As for two cases of lack of effect from the course of litholysis, in one case DLT was successfully performed. The density of this stone after the course of litholysis decreased slightly (by 6 HU units). Analysis of stone fragments showed a combination of uric acid dihydrate and apatite in a ratio of 70% and 30%. The second patient underwent laser nephrolithotripsy. XRF of this calculus revealed the presence of uricite and insoluble sodium urate in a ratio of 60%:40%. The density of the stone in this case also decreased slightly - by 3 units. HU.

In the study group, we studied the relationship between the effectiveness of treatment, stone density before and after treatment and the degree of reduction in stone density depending on the composition of stones according to X-ray phase analysis. The density and composition of stones from patients who had complete stone dissolution after 3 months are presented in Table 2.

Table 2. Initial density and composition of stones in patients who had complete stone dissolution after 3 months.

patient no.Density of stonesComposition of stones (XRF)
11296
2237080–90% uricite (anhydrous uric acid) and 10–20% uric acid dihydrate
34382contains approximately equal amounts of uricite and uric acid dihydrate
46138
57218
61029060% uric acid dihydrate and 40% uricite
71239080% uricite and 20% uric acid dihydrate
813196
91838490% uricite and 10% uric acid dihydrate
1025210
1130282
Average stone density НU286,9

The initial composition of stones and the degree of reduction in the density of stones in patients who had complete stone dissolution after 6 months are presented in Table 3.

Table 3. Composition of stones and the degree of reduction in the density of stones in patients who had complete stone dissolution after 6 months.

No.patient no.Density of stonesStone density after treatmentDegree of stone density reductionComposition of stones (XRF)
13420300120uric acid dihydrate, about 90%, a little uricite, about 10%; uricite 90% and ammonium urate 10%, possible admixture of uric acid dihydrate
25484320164
39388240148uricite and some uric acid dihydrate, possible traces of calcium urate
41422613690uricite
515290150140
61632818014880% uricite and 20% uric acid dihydrate
721324220104
822388234154
923412303109
102834031030
112936030852
Average stone density НU360245,5
Average degree of stone density reduction114,5

The density, the degree of its reduction and the composition of the stones of patients in whom partial dissolution of the stones was noted are presented in Table 4.

Table 4. Density, degree of density reduction and composition of stones from patients with partial dissolution of stones

No.patient no.Density of stonesStone density after treatmentDegree of stone density reductionComposition of stones (XRF)
11151045060uric acid dihydrate 85-90% and 10-15% apatite
2175245186uric acid dihydrate 50% and apatite 50%
31953045080uricite and 5-10% wewellite (calcium oxalate monohydrate); after 800 °C – residue about 5–10%, calcium oxide
42058051070uricite and 10% wewellite (calcium oxalate monohydrate) + calcium urate 5%
5245805107085% uricite+and 15% wewellite (calcium oxalate monohydrate)
62653647759uric acid dihydrate 85% + veddelite 5% + apatite 10%
Average stone density НU543,3485,8
Average degree of stone density reduction52,5

The density, the degree of its reduction and the composition of the stones of patients in whom stone dissolution was not noted are presented in Table 5. These patients are characterized by a relatively high density of stones and a low degree of reduction in the density of stones.

Table 5. Density, degree of density reduction and composition of stones from patients in whom stone dissolution was not noted

No.patient no.Density of stonesStone density after treatmentDegree of stone density reductionComposition of stones (XRF)*
185245186uric acid dihydrate 50% and apatite 50%
227390387360% uricite and 40% sodium urate
Average stone density НU457452,5
Average degree of stone density reduction4,5

As can be seen from tables 2-5, the best results were observed with litholysis of monophasic uric acid stones. As the density of stones increases, the proportion of patients with successful litholysis decreases and the duration of the dissolution process lengthens.

Table 6 shows the dynamics of stone density during litholysis in patients receiving the Blemaren citrate mixture for 6 months (complete dissolution, partial dissolution and no dissolution).

Table 6. Dynamics of stone density during litholysis in patients receiving the citrate drug Blemaren for 6 months (complete dissolution, partial dissolution and no dissolution)

No.patient no.Stone density before treatment (HU)Density of stones after 6 months. treatment (HU) Degree of stone density reduction (HU)
13420300120
25484320164
3852451846
49388240148
51151045060
61422613690
715290150140
816328180148
9175245186
101953045080
112058051070
1221324220104
1322388234154
1423412303109
152458051070
162653647759
17273903873
182834031030
192936030852
Average stone density НU432343,2
Average degree of stone density reduction87 (31,6%)

As can be seen from the table, during the treatment the density of stones decreased significantly, by an average of 89 units. НU (31.6%).

During the study, we noted a decrease in the level of stone density during therapy with the citrate drug Blemaren in all patients, while the stone density according to MSCT in all patients with successful litholysis was less than 500 NU.

Figure 1 shows the relationship between the average density of stones and the results of litholysis (the degree and timing of stone dissolution).

Rice. 1. Relationship between the average density of stones and the results of litholysis

Our study also revealed a directly proportional relationship between the average degree of reduction in stone density during treatment and the results of litholysis, that is, the degree and timing of stone dissolution (Fig. 2).

Rice. 2. Average degree of reduction in the density of calculi during litholysis

CONCLUSIONS

Litholysis of uric acid stones using a citrate mixture (Blemaren) is a highly effective non-traumatic method of treating patients.

During treatment, a significant decrease in the density of uric acid and mixed stones was noted

The noted decrease in density turned out to be more pronounced when performing litholysis of monophasic (single-component) uric acid stones.

In addition, we noted that this type of treatment turned out to be highly effective when the stone density according to MSCT data is less than P 500 NU.

LITERATURE

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  2. Apolikhin O.I., Sivkov A.V., Moskaleva N.G., Solntseva T.V., Komarova V.A. Analysis of uronephrological morbidity and mortality in the Russian Federation for a ten-year period (2002-2012) according to official statistics. // Experimental and clinical urology. 2014; (2):2-12
  3. Gutman AB, Yu TF. Uric acid nephrolithiasis. Am J Med 1968; 45:756.
  4. Hesse A, Schneider HJ, Berg W, Hienzsch E. Uric acid dihydrate as urinary calculus component. Invest Urol 1975; 12:405.
  5. Scholz D, Schwille PO, Ulbrich D. et al. Composition of renal stones and their frequency in a stone clinic: relationship to parameters of mineral metabolism in serum and urine. Urol Res 1979; 7:161.
  6. Grenabo L, Hedelin H, Pettersson S. The severity of infection stones compared to other stones in the upper urinary tract. Scand J Urol Nephrol 1985; 19:285.
  7. Konstantinova O.V., Shaderkina V.A. Epidemiological assessment of urolithiasis in outpatient urological practice. Experimental and clinical urology. 2015;(1): 11-14
  8. Sknar V.A., Aboyan I.A., Shukaev I.L., Pavlov S.V., Zolotukhin D.A. Investigation of the composition of 2200 urinary stones using advanced X-ray diffraction analysis: our experience. Materials of the 1st scientific and practical conference of urologists of the North-Western Federal District of the Russian Federation “Current issues of urology”, St. Petersburg. 2015.s. 111
  9. SpivacowFR, Del Valle EE, Lores E. et al. Kidney stones: Composition, frequency and relation to metabolic diagnosis., Medicina 2016;76(6):343-346
  10. D'Alessandro M., Gennaro G., Tralongo P. et al. Fourier Transform Infrared Analysis of Urinary Calculi and Metabolic Studies in a Group of Sicilian Children, Iranian J Kid Dis. 2017;(3)209-216
  11. Pytel Yu. A. Zolotarev I. I. Urate nephrolithiasis, Moscow, Medicine, 1995. 90 p.
  12. S. H. Al-Shukri, M. N. Slesarevskaya, I. V. Kuzmin. Litholytic therapy of urate nephrolithiasis, Urology. 2016;(2): 23-27
  13. Slesarevskaya M. N., I. V. Kuzmin, Al-Shukri S. Kh. Litholytic therapy of urolithiasis. Urological Journal 2015;(1):112-11319.
  14. Rudenko V. I., Rapoport L. M., Kuzmicheva G. M. Modern aspects of citrate litholysis. Effective pharmacotherapy, 2017; 24, S. 10-12.
  15. Alyaev Yu. G., Kuzmicheva G. M., Rapoport L. M., Rudenko V. I. Modern aspects of citrate therapy in patients with urolithiasis. Medical class, 2004;4. S.. 20-24.
  16. Chistik T. Citrate therapy in outpatient practice of urolithiasis: focus on Blemaren®. Kidneys 2015; 4 (14): 71-74.
  17. Glybochko P. V., Blumberg B. I., Osnovin O. V., Soldatenko M. V., Rossolovsky A. N., Maksimova A. V., The influence of stone density and size on the effectiveness of external lithotripsy using Dornier Compact Delta and Sonolit devices . Saratov Scientific and Medical Journal, 2011;7,(S2):208.
  18. Neisius A, et al. Shock wave lithotripsy: the new phoenix? World J Urol 2015 Feb; 33 (2): 213-221.
  19. Alyaev Yu. G., Rapoport L. M., Rudenko V. I. Citrate therapy to prepare for extracorporeal lithotripsy. Urology and Nephrology 2002;(4):20-23
  20. Chekhonatskaya M. L., Rossolovsky A. N., Bobylev D. A. The relationship between the density and size of stones in patients with nephrolithiasis and the effectiveness of treatment using external shock wave lithotripsy, Saratov Journal of Medical Scientific Research, 2017;13(1):77 -81
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The article was published in the journal “Experimental and Clinical Urology” No. 2 2022, pp. 44-49

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Urolithiasis disease

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Journal "Experimental and Clinical Urology" Issue No. 2, 2018

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special instructions

In conditions that promote the formation of urinary stones (for example, parathyroid adenoma, uric acid stones associated with malignoma), etiotropic therapy measures should be taken.

When dissolving uric acid stones, one should not allow many days of excessive alkalization of urine (pH above 7.8), given the possible appearance of a precipitate of phosphate salts on the surface of the uric acid stone, which may prevent its further dissolution. In addition, a prolonged and pronounced alkaline state of metabolism is undesirable.

Before using the drug, it is necessary to determine the level of electrolytes in the blood plasma and check kidney function. If renal tubular acidosis is suspected, it is necessary to additionally monitor the acid-base balance.

During treatment, urine and blood test parameters should be checked regularly. Particular attention should be paid to the acid-base balance.

Patients with heart failure must take into account the effect of potassium on myocardial excitability: 1 tablet of Blemaren contains 380 mg of potassium ions or 9.7 mmol of potassium, which can affect the effect of cardiac glycosides (an increase in the extracellular concentration of potassium reduces the effectiveness of glycosides, and its decrease increases the arrhythmogenic effect ).

For patients with uric acid metabolism disorders, it is recommended to combine the drug with allopurinol.

Persons who follow a sodium-restricted diet should take into account the increased sodium content of this drug (1 tablet contains 220 mg of sodium ions or 9.7 mmol of sodium).

During drug therapy, it is recommended to adhere to a low-protein diet, that is, limit the consumption of foods rich in purines (for example, meat, sausages, animal entrails, sardines), and also limit salt intake. Every day you need to drink 2-3 liters of liquid in the form of tea, fruit juice or alkaline mineral water.

The drug does not contain carbohydrates and can be used to treat patients with diabetes.

Patients with severe hepatic impairment should only take Blemaren if closely monitored.

The drug should not be used in patients with hereditary galactose intolerance, Lapp lactase deficiency or impaired absorption of glucose-galactose.

Use during pregnancy or breastfeeding. When using the drug according to the instructions, no negative effects were noted during pregnancy and lactation.

The ability to influence reaction speed when driving vehicles or other mechanisms. Does not affect.

Children. The effectiveness and safety of the drug in children have not been sufficiently studied, so it is not recommended for use in patients of this age category.

The prevalence of nephrolithiasis in developed countries is up to 5%. Most urinary stones are composed of calcium oxalate (60%), calcium phosphate (20%), uric acid (10%), cystine (3%), tripelphosphate (7%). There are several reasons for the formation of stones. This is low diuresis, increased excretion of calcium in the urine - hypercalciuria. Hyperuricosuria, an elevated serum uric acid level, is found in approximately 10% of patients with calcium oxalate stones. The causes of hyperuricosuria may be gout, consumption of foods rich in purines, hemoblastosis, alcohol abuse, or taking uricosuric drugs. With hyperuricosuria, crystals or colloidal particles of uric acid form, promoting the formation of calcium stones.

Low urine pH is the cause of urate stones. In an acidic environment, uric acid is in an undissociated form and easily crystallizes, forming urate or mixed stones or promoting the formation of calcium stones. With renal distal tubular acidosis, secondary oxaluria, hypokalemia, heavy physical activity, increased consumption of animal protein and excess sodium, hypocitraturia is observed. Citrate forms soluble complexes with calcium, reducing the saturation of urine with calcium salts. Decreased urinary citrate excretion is another cause of stone formation in the urinary system. Hypocitraturia is the only disorder for 10% of patients with urolithiasis, and for 50% of patients it is combined with other causes of stone formation. When examining patients with nephrolithiasis, urine pH and its dynamics are clarified. At a pH of more than 7.2, tripel phosphate stones are formed, and at a pH of less than 5.5, urate stones are formed. An inverse relationship has been shown between high fluid intake and the formation of kidney stones. A general recommendation for patients who develop urinary stones may be to maintain a high urine output (at least 2 liters) by drinking significant volumes of fluids.

Adequate patient education regarding fluid intake and diet appears to be more important since treatment outcome will be largely determined by patient compliance. The ideal drug should prevent the formation of calcium stones, not cause side effects, and allow for simple dosage regimens. These aspects are especially important for achieving a sufficiently good degree of adherence to treatment. Low citrate excretion is one of the well-studied and common disorders in the calcium type of stone formation. Citrate plays an important role given the possibility of forming complexes with calcium. Moreover, citrate inhibits the growth and aggregation of these crystals. Administration of alkaline salt results in increased pH and increased citrate excretion. Taking drugs that create conditions for the dissolution of stones can be an effective first-line therapy [11]. This treatment method is used in addition to external shock wave lithotripsy (ESWL), percutaneous lithotripsy, urethrolithotripsy, or open surgery to facilitate removal of small residual fragments.

The clinical effectiveness of extracorporeal lithotripsy is related to the physicochemical characteristics of the stone [12, 14, 17, 18]. One of the significant prognostic factors is the structural density of the stone, determined by spiral X-ray computed tomography (CT density) [8, 13].

Research conducted at the Urology Clinic of the First Moscow State Medical University named after. THEM. Sechenov, in order to identify the dependence of the frequency of DLT on the structural density, showed that when the structural density is more than 800–1000 on the Hounsfield scale (HU), the frequency (2–3) of repeated DLT sessions increases and there is a need to use high-energy disintegration modes [13]. In view of this, preoperative drug preparation for DLT means the need to use drugs that change the structure, density and size (volume) of the stone [13]. Achieving this clinical result is possible with citrate therapy: potassium-sodium citrate preparations (Blemaren), potassium citrate and potassium-magnesium citrate.

The importance of citrate therapy is especially increasing after DLT of calyx stones, in particular, in patients with recurrent and residual stones of the lower calyx. According to a randomized study (110 patients), conducted in patients with complete passage of stones after radiotherapy and treatment with potassium citrate, after 12 months there were no recurrent stones, and in the control group the latter occurred in 28.1% of cases [9]. Similar results were observed in the group of patients with residual stones. When treated with potassium citrate, the period of remission was significantly higher compared to the group in which patients did not receive treatment (44.5 and 12.5%, respectively). According to the authors, potassium citrate therapy is important in the preventive treatment of calcium oxalate urolithiasis after radiotherapy of lower calyx stones.

The combined use of EBRT and chemolysis is the most minimally invasive method of treating patients with staghorn stones who are not candidates for percutaneous nephrolithotripsy. Crushing the stone leads to an increase in its surface, which increases the efficiency of chemolysis. Taking drugs intended for chemolysis is effective only for uric acid stones.

The high effectiveness of citrate therapy in the prevention of recurrent calcium oxalate stone formation has been noted by a number of authors [1, 2, 10, 15, 16]. Carrying out citrate therapy after radiotherapy helps to reduce the incidence of recurrent and residual calcium oxalate stone formation by 2 times [3]. The effectiveness of preventive citrate therapy (potassium-magnesium citrate) for calcium oxalate stones is 85% [5]. Prevention with citrate preparations is most effective for stones made of uric acid (100%), calcium oxalate (86.7%) [16], as well as for combined stones of calcium oxalate and phosphate (96.7%). The authors emphasize the relevance of preventing calcium oxalate stone formation using citrate in hypercalciuria with hyperuricosuria, in the presence of calcium oxalate dihydrate (veddelite) in the stone and the risk of recurrent stone formation in a single kidney.

The fundamental advantage of the drug Blemaren (Esparma GmbH, Germany) over other citrate drugs is the predominance of citric acid over its salt, while a significant part of the buffering function is performed by potassium hydrogen carbonate. The reduced sodium content in the drug promotes accelerated dissolution of uric acid in the renal tubules and prevents their further crystallization. The limited amount of potassium in the drug makes it possible to expand the indications for its use in cases where the potassium content in the body is of clinical significance [19, 20]. Oral administration of Blemaren provides a dose-dependent shift in urine pH from acidic to neutral or alkaline, without changing the acid-base balance of the blood; a daily dose of potassium-sodium citrate of 66–110 mmol has no effect on the level of potassium, sodium, oxygen, carbon dioxide and hydrogen carbonate in the blood. Citrate binds calcium ions along its entire path - from the gastrointestinal tract, where it reduces calcium absorption, to the urinary tract, where this effect is most active due to the highest concentration of citrate. In addition, by stabilizing solutions, citrate prevents crystallization processes in the urine. The complex effect of citrate on the physicochemical state of urine leads to an increase in the solubility of urates, calcifications and, first of all, oxalates, complex magnesium-ammonium phosphates and some other salts, helping to inhibit stone formation and dissolve already formed stones, thereby increasing the inhibitory activity of urine [1, 2, 4, 6, 7, 15]. The dose of Blemaren is set individually depending on the achieved urine acidity, which must be maintained at the optimal level for each type of stone. Urine pH is monitored using indicator paper before each dose of the drug. For urate, calcium-oxalate or mixed urate-oxalate stones, the pH should be maintained within 6.2–6.8 during the day. Average daily doses range from 6–18 g, evenly distributed throughout the day in 2–3 doses.

Treatment is based on alkalinization of urine by taking citrate mixtures or sodium bicarbonate. The destruction of calcium oxalate stones using potassium sodium citrate is based on the binding of the calcium citrate ion to the ion and its transition to a soluble compound. Based on the data obtained, we believe that the action of Blemaren in vitro leads to a decrease in the hardness of calcium oxalate stones (from 1400 to 900 Нu), possibly due to an increase in their “porosity”.

During dynamic monitoring of litholytic citrate therapy with Blemaren in vivo using spiral X-ray computed tomography with densitometry for 3–6 weeks, we also noted a decrease in the characteristics of mixed stones (size, volume, structure, density). Changes in stone characteristics during citrate therapy are presented on plain radiographs and densitometric histograms (Fig. 1). In this clinical observation, citrate therapy reduced the average structural density of a kidney stone by 254 HU, which made it possible to fragment the stone in one DLT session.

We analyzed the results of clinical use of the drug Blemaren in the form of a water-soluble effervescent tablet in 30 patients aged 33 to 62 years in 2000–2001. The distribution of stone density according to computed tomography data is presented in Fig. 2.

In 13 (43.3%) patients, the stone density before treatment was from 700 to 1000 HU, and in 17 (56.7%) the density was from 1001 to 1500 HU. The dynamics of stone density according to computed tomography data are presented in Fig. 3. After using Blemaren, 26 (86.7%) showed a decrease in stone density, and 4 (13.3%) had an increase. The change in stone size depending on the change in density is shown in Fig. 4. There was a significant predominance of the number of patients with a decrease in the size of the stone against the background of a decrease in its density (p = 0.176). Thus, litholytic citrate therapy reduced the average density in 26 (86.7%).

However, in 4 (13.3%) patients the average density increased. Moreover, in 2 (6.67%) patients, an increase in the density of the stone along with an increase in size was noted. The analysis showed that the reasons for the negative result (increase in stone volume and density) of citrate therapy in 4 (13.3%) patients are as follows:

  • Use of the drug when phases predominate in the composition of the stone (more than 50%) with a density of more than 800 HU.
  • Inability to stabilize urine pH within 6.2–6.8.

Thus, carrying out citrate therapy with Blemaren before extracorporeal lithotripsy allows:

  • reduce the structural density of the stone;
  • change the macro- and microstructure of the stone;
  • by stabilizing the pH of urine, change crystallization processes.

Clinical assessment of the results of citrate therapy allowed us to detail the indications for prescribing citrate drugs before extracorporeal lithotripsy:

  • mixed stones (X-ray heterogeneous, pH<6);
  • the average density according to computed tomography is more than 800–1000 НU;
  • the volume of structures (voxels) of stone with a density of up to 800 НU is more than 45–50%.

A prerequisite for citrate therapy in preparation for DLT should be complex anti-inflammatory and antibacterial therapy, because the effect of “bacterial hypocitraturia” is possible due to the ability of bacteria to metabolize urine citrate [1, 2]. Repeated DLT sessions were performed in 4 (13.3%) patients with an average stone density of more than 1100 Nu due to partial disintegration of the stone or the formation of an extended “stone path”.

Thus, carrying out citrate therapy with Blemaren for mixed (X-ray heterogeneous) stones before ELT increases the effectiveness of external nephrolithotripsy and reduces the frequency of repeat sessions. The duration of citrate therapy in preparation for radiotherapy should be at least three weeks. When planning chemolysis, the pH level should be adjusted to 7.0–7.2. For urinary tract obstruction due to uric acid stones, oral chemolysis is prescribed in combination with urinary tract drainage. The dosage of the drug is determined by the pH level of the urine. For the purpose of prevention, the optimal pH level is 6.2–6.8. When carrying out chemolysis – 7.0–7.2.

Interactions

Interaction studies were conducted in adults only. simultaneous use of drugs containing citrate and aluminum may cause an increase in aluminum resorption, so it is recommended to maintain a 2-hour pause between taking such drugs.

The drug enhances the therapeutic effect of allopurinol.

Some drugs intended to lower blood pressure (aldosterone antagonists and other low-potassium diuretics such as triamterenes, spironolactones and amilorides), ACE inhibitors, sartans, and pain relievers and anti-inflammatory drugs (NSAIDs and peripheral analgesics) may reduce potassium excretion , which should be taken into account when prescribing them simultaneously with Blemaren (the risk of hyperkalemia increases). An increase in extracellular potassium concentration reduces the severity of the action of cardiac glycosides, while its decrease increases the effect of arrhythmogenic cardiac glycosides.

With long-term use of Blemaren, accumulation of quinidine in the body is possible if it is taken simultaneously, as well as a decrease in the effectiveness of nitrofurantoin (alkaline reaction of the environment), salicylates and lithium preparations (accelerated elimination).

Overdose

With normal renal function, no undesirable effect of the drug on changes in physiological metabolic parameters was noted either at the usual recommended dose or at a higher one, since the release of excess alkalis by the kidneys is a natural mechanism for regulating the acid-base balance in the body.

The upper limit of the urine pH range indicated above should not be exceeded for several days, since due to the increase in pH (pH factor 7.8) there is an increased risk of phosphate crystallization; furthermore, an overtly alkaline metabolic status is not considered a long-term problem.

A possible overdose can be corrected by reducing the dose of the drug. If necessary, measures can be taken to treat metabolic alkalosis.

Note!

Description of the drug Blemaren table. thorn. No. 80 on this page is a simplified author’s version of the apteka911 website, created on the basis of the instructions for use.
Before purchasing or using the drug, you should consult your doctor and read the manufacturer's original instructions (attached to each package of the drug). Information about the drug is provided for informational purposes only and should not be used as a guide to self-medication. Only a doctor can decide to prescribe the drug, as well as determine the dose and methods of its use.

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