CA1214993A

CA1214993A - Means for medicinal treatment and metaphylaxis of urate and mixed urate lithiase

Info

Publication number: CA1214993A
Application number: CA000445373A
Authority: CA
Inventors: Maria I. Georgieva; Georgi M. Georgiev; Dragomir T. Tzonev; Evgeni H. Minkov; Svetlin T. Iliev; Miryana V. Poneva
Original assignee: Pharmachim TPO
Current assignee: Pharmachim TPO
Priority date: 1984-01-16
Filing date: 1984-01-16
Publication date: 1986-12-09

Abstract

ABSTRACT OF THE DISCLOSURE:

The present invention is concerned with a composi-tion for treatment and metaphylaxis of urate and mixed urate lithiase comprising, as active component, a non-ionogenic surfactant having a general formula RCOO(CH2CH2O)nH in which R represents a radical or linolic acid or linolenic acid or oleinic acid and n is a number from 18 to 40. This therapeutic composition is acting on the principle of forming complex water-soluble components with the uric acid present in the urate concrements, dissolving the latter and elimi-nating the uric acid through the urine. The action is achieved very fast without the occurence of secondary effects. The composition can be applied also in the case of infected forms of urate lithiase as well as in the mixed forms of the same. The pH of the urine is unchanged thus preventing the precipitation of phosphate. A very fast convalescense of the sick persons is attained.

Description

This invention relates to a pharmaceutical composi-tion for treatment and metaphylaxis of urate, urate-oxalate and urate-phosphate lithiase. Nephrolithiase is the most fre~uent urological disease. According to the chemical composltion of the concrements the lithiases are respec-tively oE the urate, oxalate, cystine and phosphate type.
The treatment of the disease is at present mainly by chirurgi-cal intervention. Furthermore there are some methods and means of medicinal treatment (litholyse) which however are not reliable and do not always attain the expected results.
It is known that for the treatment of urate and mixed urate lithiase, composi-tions are applied, based upon salt compounds such as citrates (sodium and potassium), bicarbonates and citric acid alike the medicinal composi-tions with the trademark ma~urlite and solurane. In thetreatment of the mentioned lithiases are used also composi-tions containing medicinal plant extracts. Such a means is the composition known under the trademark uralite. All these compositions are based upon the property of the salt compound to maintain the p~ of urine in the patients up to 7 in order to create conditions hampering the crystallization of uric acid (l, 2).
The drawbacks of the known compositions are the following: there is a possibility for the p~l of urine to pass the value of 7 so that some phosphate are precipitated and the infection in the kidney~ is maintained. Furthermore the action of these compounds is attained after a period of treatment of several months. Besides the mentioned composi-tions call forth secondary toxical phenomena, they are not suitable in the case of infectious forms of lithiase and are not effective in the mixed forms of urate lithiase.
The object of the invention is to provide a pharmaceutical composition for treatment and metaphylaxis of urate and mixed urate lithiase in order to achieve a reliable and fast dissolution (lithiase) of the concrements. This object is attained by a composition comprising a pharmaceu-tically accepttable carrier and, as active component, a non-ionogenic surface active substance (surfactant) having a general formula R-COO(CH2CH2O~nH in which R represents a radical o linolic, linolenic or oleinic acid and n is a number from 18 to 40.
The composition according to the invention is acting on the principle of forming complex water-soluble compounds with the uric acid as an active component oE the urate concrements whereby dissolving the latter and elimi-nating the uric acid through the urine. The advantage of the composition according to the invention is the following:
the therapeutic action is achieved very fast ~within a month without occurence of secondary effects; it can be applied also i the case of infectious forms of urate lithiase as well as in mixed forms of the same (urate-oxalate lithiase and urate-phosphate lithiase); it does not change the pH of urine and consequently there is no danger of precipitation;
besides there is achieved a fast re-establishment of the working capacity of ill persons. The essential features of the invention are elucidated by the following exemplary implementing of said medicinal means:
The composition is applied in an amount of 0,375 g for a single dose in the average - 3 to 4 times per day per os. The average period of treatment is from 1 to 1,5 month.
The composition can be applied as a syrup, drops or as gelatine capspules where~y the active component is treated with known subsidi.ary components in observing the effective amount of the composition as mentioned hereabove.
In order to prove the effect of the medinical composition in vitro on urate concrements, experiments were carried out at 37C under static conditions. Samples of urate, urate-oxalate and urate-phosphate concrements were ` ) ., ~ .

analysed to determine their mass and the uric acid content. Then the concrements were left to stay in a

2,5 % aqueous solution of the medicinal composition and sub-mitted to a new analyse of said parameters. On the other side the solutions of the proposed co~oosition were analysed to determine the dissolved uric acid. The average mass reduction of the concrements after a 48 h staying in the medicinal means amounts to 20 ~.
In order to prove the effectiveness of the composition with respect to the same concrements however in an urine medium tests were carried out indicating that the average mass reduction of the concrements for a 48 h staying amounts to 23 %.
In order to prove the effectiveness of the medicinal composition under dynamic conditions experiments were performed in an apparatus simulating the human eliminating system whereby the average mass reduction of concrements augmented to 44,7 %.
Furthermore there were carried out comparative tests with the composition solurane under as well as under dynamic conditions. The average reduction or urate con-crements mass under static condition as a result of the solurane action is 7,1 ~ while with the composition according to the invention it is 19,6 %. Under dynamic conditions the average reduction of the concrements mass due to the action of solurane amounts to 21,9 % while with the proposed composition it is 44,7%.
In order to explain the working mechanism of the described medicinal co~x)sition, ultra-violet spectra of its solutions were recorded prior to and after staying in them of urate concrements. It has been established that the composition according to the invention possesses a characteristic ultra-violet spectrum with maximums at 262 nm, 272 nm and 284 nm. Following the urate concrement staying in the solu-9 ~

tions of the medicinal composition, a maximum of uric acid is appeared at 2B6 nm. The latter in comparison with the ultra-violet spectrum of uric acid in distilled water indicates a shifting of its characteristic maximum from 5 290 nm to 286 nm. This shiftiny in direction of the shorter wave length shows that the uric acid is present in the solutions of the medicinal composition in the form of a complex compound and not as a free acid.
The investigations to determine the toxicity of the composition according to the invention ~ experimental animals under conditions of an acute test as well as of chronic tests show that DL50 when administering per os i5 3680 mg/kg weight. No irritating action on mucous mem-branes, hypodermic tissue and muscular tissue has been reported. There are no changes in the blood pressure, the number of erythrocites and the enzymes. There are no indications for changes occuring in the internal organs.
In order to prove the elimination of the medici-nal composition through the hum~l kidneys, tests were carried out on healthy persons that are not suffering from nephroli-thiase whereby were determined the following parameters of urine: pH, surface tension and amount of uric acid. These persons were given a single dose of the medicinal composition (0,375 g) in a spoonful of syrup (2,5 % with respect to the active component). After a period of time of 20 min to 1 h from its administration, the persons tested eliminate the medicinal means through the urine as proved by ultra-violet spectrum. The urine shows a reduction of surface tension in average by 6,5 dyn/cm while the pH is not changing and the uric acid content is maintained at a constant level however as bound in a complex compound.
A group of patients was tested with a urate or mixed urate lithiase suffering. They were submit-ted to a treatment with the medicinal composition in form of a spoonful ~!..J'~

of syrup three times per day an hour prior to eating.
The sickness was controlled by analyses of urine, blood, x-rays photographs and echographies. A litholyse (dissolution) of the concremen-ts occurred after a period of 20 days to 2 months depending on the concrements size.
The working capacity of the patients improved already during the first week of treatment.

Claims

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A pharmaceutical composition for treatment and metaphylaxis of urate and mixed urate lithiase characterized in that it comprises a pharmaceutically acceptable carrier and, as active component, a non-ionogenic surfactant having a general formula RCOO(CH2CH2O)nH in which R represents a radical of linolic acid or linolenic acid or oleinic acid and n is a number from 18 to 40.