SK283244B6 - Pharmaceutical composition - Google Patents

Abstract

The use of the composition characterised by general formula (I), wherein X is uni- or bivalent metal ion suitable as a therapeutic, n is 1 or 2, for production the pharmaceutical composition for treatment or prevention of embryonic retardation or discordance.

Description

Technical field

The present invention provides a pharmaceutical composition characterized by a compound that is used to treat or prevent embryonic retardation or discordance.

State of the art techniques

The use of a formulated formulation containing dobezilate calcium as an active ingredient has been known in several indication areas since the 1970s in human therapy.

The active ingredient is administered in several formulated forms, of which the most important preparations are preparations for oral use (tablets, capsules) and which are known by the widely registered name Doxium, which produces e.g. OB. Lab. (Switzerland).

The preparation of calcium dobezilate (2,5-dihydroxybenzenesulfonic acid calcium salt) is discussed in U.S. Pat. No. 3,509,207 and in Spanish Patent No. 335,945.

The main areas of indication and experience can be summarized as follows.

Investigations in 120 patients suffering from dilated veins (primary and secondary occurrence of varicose veins) were conducted by Pietrek, G. (Z. Allg. Med. 56 (1980), 1217-1222) over three months of oral administration of Doxium. According to his research, patients' difficulties have decreased (parachroma, edema, feeling of excessive weight).

Treatment of patients suffering from chronic venous insufficiency in bimasked studies is reported by Haachen, H. J. and Lorenz, P. (Angiology, 1982, July 33 (7), 480-488). As a result of treatment with Doxium, the patients' subjective complaints decreased significantly and their health improved also according to plethysmographic analysis.

Investigations of patients suffering from these diseases were performed by Balmer, A. (Schweiz. Rundschau für Med. Praxis, 67, (39), 1978, 1440 - 1443) before and after topical application of Doxivenil gel. This preparation contains 2% calcium dobezilate and 2% heparinoid (potassium hydrodextran sulfate). The patients tolerated the treatment very well and the health status of 80-87% of them improved greatly.

Three months of treatment of patients diagnosed with diabetic retinopathy with oral Doxium administration have been reported by Barras, J. P. and Graf, C. (VASA / 1980/9 (2), 161-164). According to three different analytical methods at the end of the experiment, the viscosity of both plasma and whole blood was reduced. The relative viscosity and hematocrit value remained unchanged.

The capillary permeability of diabetic patients has been investigated by Sevin, R. and Cuendet, J. F. (Ophtalmologica 162: 33-40 / 1971 / 33-40). Retinopathy patients were divided into the following four groups:

- exclusively micro-aneurism,

- mild retinal haemorrhage,

- significant retinal haemorrhage, - extraretinal haemorrhage.

According to the results of fluorescence angiographic analysis, oral administration of Doxium had an excellent effect on the pathological capillary permeability and capillary resistance values.

Treatment of intense haemorrhage with Dixoproct suppository (containing 250 mg calcium dobezilate and 40 mg of the active ingredient lidocaine) was published by Berson, I. (Schweizerischc Rundschau fur Med. Praxis (1975.03.11 / 64 (10) 299-301)). within two weeks, an improvement was noted in 87% of cases.

After summarizing the literature data, it can be concluded that the known indications for oral use of calcium dobezilate are as follows: micro-angiopathies, partial diabetic retinopathy, chronic venous insufficiency, primary varicose veins, pregnancy varicose veins, calf ulcers, calf night cramps, anemic edema. Based on currently available data, this medicinal product may be used as an excipient in the following cases: external thrombophlebitis, post-thrombotic syndrome, edema, denatosis stasis, haemorrhoid disorders.

According to literature data relating to mode of action, calcium dobezilate acts by regulating the pathological functions of the capillary walls (increasing permeability and decreasing resistance). It inhibits the breakdown of collagen fibers, reducing the hyperviscosity of both plasma and blood. It indirectly inhibits lymph flow and, as a result, reduces swelling. The maximum blood concentration can be reached six hours after oral administration of 500 mg calcium dobezilate, which is approximately 8 pg / ml. A platform can be reached between 3 and 10 hours. 24 hours after dosing, the blood concentration is 3 pg / ml. The mean plasma half-life is 5 hours. Calcium dobezilate is bound to the plasma peptide in the range of 20-25%. It cannot be passed through the brain-blood barrier and even through the placental barrier. It can be determined in small quantities in breast milk. In the first 24 hours, about 50% of the orally administered amount is excreted in the urine and a very similar value is excreted in the faeces. The bulk of the compound is eliminated without any transformation thereof.

Regardless of the treatment period, the tolerance of the compound is very good. Its toxicity is very low, the LD ₅ value _(I tested in mice is 700 mg / kg. According to literature data, there is no interaction with other drugs at present.

To our knowledge, the administration of calcium dobezilate during pregnancy - except for the treatment of varicose veins - is not used. This is probably because the Oral Product Information Leaflet (Doxium, manufacturer eg OM Lab, Switzerland) contains the following statement: “Not recommended during the first three months of pregnancy”. "The doctor should be informed of any pregnancy." "The drug does not cross the placental barrier."

A variety of clinical images may occur during pregnancy, including embryonic retardation. This means that the development within the uterus is retarded compared to the average rate of development at a given stage of pregnancy. Based on domestic and international statistics, the frequency of embryonic retardation is between 10 and 30%. The large dispersion is attributed to the fact that the requirements for the survey and instrumentation have been established only during the last 5 to 10 years. Newborns born with a birth weight of 2,500 grams currently do not belong to the group of retarded newborns, but to premature births, especially if the birth takes place before the 37th week of pregnancy. In the case of neonates born after this period and exceeding 2500 g of birth weight, the diagnosis and the fact of retardation shall only be made in institutions where a neonatal specialist is present at the time of childbirth, or if the newborn child needs intensive therapy. For this reason, statistics may be more favorable than the actual rate of occurrence.

Another problem is that the complications associated with the disease very often lead to intrauterine necrosis and, moreover, the extent of prenatal mortality and the extent of the occurrence of other injuries is very high.

According to data published so far in the literature, the development of the disease may result from certain predisposing factors of the mother, such as smoking, alcoholism, poor nutrition, metabolic and endocrine disorders, chronic kidney disease, liver, lung disease, pregnancy toxemia, preeclampsia. The placenta may also be a possible source, for example, uterine developmental disorders, placental placement difficulties, early age, or multiple pregnancy discordance (twins). But these factors have not been studied comprehensively, since normal pregnancy may even develop along with congenital uterine disorder and after retarded pregnancy.

These are two classic forms of intrauterine retardation:

- retardation existing from an early stage of pregnancy, referred to as 'primary retardation', or

- after initial normal development, in the second or third period of pregnancy, embryo development is delayed or stopped. This is “secondary retardation”.

The development of diagnostic methods was made possible by the expansion of modern ultrasonographic techniques.

Following the recommendation of the European (and Hungarian) Ultrasound Association for a decision on embryonic retardation, an examination of the following five parameters is necessary and sufficient:

- embryo temporal bone diameter,

- embryo skull circumference,

- embryo chest circumference,

- embryo chest diameter,

- the length of the femur of the embryo.

By using the Color Dappler ultrasonographic technique, certain circulating measurements can be performed to support diagnosis. As a result of these data, it has been shown in recent years that hematocrit values of retarded embryos are high and carbohydrate and lipid stores are consumed. In the placenta of retarded embryos, multifocal thrombotization was determined and early necroses that led to premature placental maturation were determined.

Efforts to treat embryonic retardation have been underway since the 1950s. Attempts have been made to increase the level of maternal carbohydrates, or in parallel with this administration of low doses of insulin. Administration of Diaphylline to increase maternal blood circulation, application of a vacuum chamber placed on the maternal abdominal wall to reduce atmospheric pressure, or administration of medicines containing salicylate to reduce maternal blood viscosity (or blood aggregation). Among recent researches, administration of doses of acetylsalicylate has been reviewed and published by Shen, J. et al. (Br. J. Clin. Pharmacol. 35, 1993, No. 6, 664-677) who administered the drug to pregnant women who feared pre-eclampsia and the development of retarded embryos. It was determined that in each case examined, acetylsalicylate entered the embryo and that there was no significant difference between maternal and embryo blood concentration. No effect on embryonic retardation was noted. Using the Doppler ultrasonographic method, he examined the uterine artery on clinical specimens with the stated prognosis by S. Campbell (The Sixth World Congress of Ultrasound in Obstetrics and Gynecology, Rotterdam, 27-31 October 1996, Book of Abstracts, p. 256, article 517) ). No results have been reported with respect to embryonic retardation in the case of prophylactic aspirin administration. This is consistent with the fact (known to those skilled in the art) that none of the above treatments resulted in the onset of weight gain of the retarded embryo, hence the use of none of them has been widespread.

In summary, it can be concluded that the predisposing factors of the disease are known, the prognosis is partially resolved, but the efficacy of the therapeutic methods is very poor.

By focusing on treatment during research work, our goal was to achieve a treatment that is appropriate for

- treatment of retarded embryo,

- prevention of retarded embryo prognosis,

- in the case of discordance (multiple pregnancies with different development rates), improvement of retarded embryo conditions.

During the experiments we unexpectedly found that calcium dobezilate is suitable for the above treatment although it does not cross the placental barrier and cannot be directly detected in the embryo. Unlike previous treatments, this is surprising as scientists are looking for products that are capable of influencing embryo status directly by their presence. This observation is even surprising when we consider other research directions where increasing the maternal "providing party" was considered to be of primary importance in implementing this concept of administering an additional amount of carbohydrate or glucose to a pregnant woman. But these efforts have not produced results.

SUMMARY OF THE INVENTION

Accordingly, the present invention provides a compound of formula (I),

OH

U U.) x

OH ^LJ n in which:

X represents a 1- or 2-valent metal ion, useful therapeutically, n represents 1 or 2, which is suitable for the manufacture, treatment or prevention of embryonic retardation and for the treatment or prevention of discordance. The chemical structure of the compound is shown in formula (I).

Another object of the invention is the use of calcium dobezilate for the treatment or prevention of embryonic retardation and for the treatment or prevention of discordance.

Accordingly, the active ingredient is suitable for the treatment of pre-existing embryonic retardation or for its prevention. Predisposing factors have been discussed earlier, and in the event of their earlier accumulation, the disease is more likely. If retardation has occurred in only one case in previous pregnancies, the assumption of further retardation is not justified. But after two or more retarded newborns, in the case of a further pregnancy, this clinical picture will in all likelihood re-develop.

According to the envisaged mechanism, under the influence of the active ingredient, the blood supply to the placenta at the maternal-embryo interface will increase, and consequently the oxygen and nutrient supply towards the embryo side will be intensified. In the area of the placental villi the blood flow and the formation of microthrombi cease. Although maternal and embryonic blood from the blood vessels are not mixed, the blood volume flow and blood pressure towards the embryo also intensify as mother blood volume and blood pressure increase.

In our experience, in the case of discordance, administration of the active ingredient has an excellent effect on the development of gemination-B or -C which have been retarded in previous development. Based on the foregoing mechanism, the positive effects are due to an improved supply of oxygen and nutrients in the placenta that promote the development of gemination-B or -C.

This mechanism is not linked to the mechanism of formal indications and cannot be inferred from them. This is also supported by the fact that after examining patients suffering from pre-eclampsia (which is associated with: maternal swelling, albuminuria and high blood pressure) the authors stated that calcium dobezilate did not reduce maternal albuminuria and hypertension, moreover, platelet transformation was excellent. In the clinical picture (see large number of studies), the change in retardation necessary in the current period has not been confirmed or considered (Lege Artis Medicine, April 07, 1994, pp. 902-910).

Advantages of the solution according to the present invention

- the application of the active ingredient is recommended for the new indication area, where human use has been tested for over 20 years;

- the formulated preparations have no or only very limited side effects;

the active ingredient is unable to cross the placenta, it does not burden the embryo organism;

- this provides favorable therapeutic outcomes in those areas where treatment has so far been of limited success;

- during the second and third periods of pregnancy, it is sufficient to start the administration of the medicament even as a precaution.

DETAILED DESCRIPTION OF THE INVENTION

To encourage use in the new indicated area, a calcium dobezilate test was conducted with pregnant women divided into three groups.

For patients who belonged to the first group, embryonic retardation was diagnosed by the ultrasound analysis method, such as the embryonic temporal bone diameter, embryo skull circumference, embryo thoracic circumference, embryo thoracic diameter, embryo femur length and cardiovascular examination, eg embryo .:

- analysis of the area "below the acoustic graph" of the arterial umbilical cord blood flow and addition of the resistance index of the same artery;

- measuring the flow conditions of the embryo aorta;

- analyzes of the area under the acoustic graph of the blood flow of the cerebri of the embryo medium and supplementation of the resistance index of the same artery these analyzes were applied from the 28th week of pregnancy).

Patients belonging to the second group had discordance at multiple pregnancy (twins) and the diagnosis was made in accordance with the described methods.

In patients belonging to the third group, embryonic retardation could be expected due to the increased incidence of predisposing factors. In this group, both normal and multiple pregnancies (twins) occurred.

Group 1 Diagnosed embryonic retardation

According to the diagnoses made on the basis of the described analyzes, 144 pregnant women belonged to this group. Patients received 3 x 1 Doxium capsules (500 mg calcium dobezilate per capsule) daily.

The minimum treatment time was 2 weeks, optimally 6 to 10 weeks.

Treatment was started in the second to third period of pregnancy. In addition to the described embryonic analysis and determination of cardiovascular conditions after the introduction of therapy, the amount of amniotic fluid was measured at a weekly frequency, and the degree of placental maturity was also determined. Based on these parameters, if the degree of embryonic development and weight values reached the characteristic value of the pregnancy period, we started maintenance treatment. The maintenance dose was 2 x 1 Doxium capsules daily.

According to our results, based on both embryo size and functional analysis (stress test, cardiovascular parameters), pregnancy tolerance was possible if, in addition to retardation of the functional state of the embryo, there was a reason to terminate pregnancy. The effect of Doxium was most specific in cases and resulted in a newborn's mature weight ranging from 10 to 90 percent, suitable for carrying a child or bringing it almost to the deadline if

- treatment started before the 32nd to 34th weeks of pregnancy, and

- embryo retardation was not associated with maternal disease and / or developmental retardation, and / or dry birth.

Group 2

Discordance in multiple embryonic pregnancy (twins)

In this group 23 pregnant women were examined. Diagnosis and control of patients was performed in the same manner as described for the first group.

The starting dose was 3x2 Doxium tablets (250 mg calcium dobezilate per capsule) daily. The maintenance dose was 2x2 Doxium tablets.

Our results were as favorable as described for Group 1. In both groups, newborns

- do not show haemoconcentration;

- an increase in platelet aggregation was not characteristic;

blood viscosity was normal;

oxygen saturation was physiological;

- carbohydrates; lipid and peptide metabolism did not require correction in cases where treatment lasted only 8 to 10 weeks.

Group 3

Prognostics of embryonic retardation

93 pregnant women were selected for this study and accumulated predisposition factors were found. Patient control was performed as described in the first group. The dose of Doxium (daily 2x2 Doxium tablets, as described for the maintenance dose) was started at week 14 of pregnancy and was given up to 2 weeks before childbirth.

Based on our experience, embryonic retardation was not detected in the investigated cycle.

As a summary of our results:

- calcium dobezilate can be effectively applied for the treatment or prevention of the following diseases:

- no contraindications of disease were found on the treatment group;

- there were no drug interactions in the treated patients.

If the dosing period is not more than 2 weeks, the recommended minimum daily dose of calcium dobezilate is 500 mg and a maximum of 3000 mg.

Claims (2)

PATENT CLAIMS Use of a compound of formula (I): OH OH n in which X represents a 1- or 2-valent metal ion, useful therapeutically, n represents 1 or 2, for the manufacture of a pharmaceutical composition for treating or preventing embryonic retardation. Use of a compound of formula (I), according to claim 1, in the manufacture of a pharmaceutical composition for the treatment or prevention of discordance.