Ethosuximide inducted changes in the gastro-intestinal tract

Zagorchev P, Sirakov V, Uchikov A, Sirakov N.
Folia Med (Plovdiv). 1998;40(3B Suppl 3):28-33.
     SUMMARY:
     The duplication of the stomach and in particular of the pylorus is very uncommon. There is no precise data about double pylorus appearance frequency. The combination of an anomaly complicated by an ulcer process increases the interest in such a finding. This research shows a patient with a double pylorus and an acute ulcer situated in the anomalous pylorus which are determined radiologically and endoscopically. In the study the utmost significance of the fibrogastroscopy as well as the radiology for the diagnosis are discussed.SUMMARY:
     Ethosuximide is an alternative medicament that is used for coupling of petit mal, especially at childhood. Some clinical observations show that it has secondary effects on the gastrointestinal tract (GIT). The present research tries to define the characteristics of the Ethosuximide - the inducted secondary effects on the GIT, and to explain some of the possible mechanisms that cause them. The changes that occur in the GIT of patientscured with Ethosuximide are registered roentgenologically. The main change is the atony of the stomach and intestines and the reduced peristaltic activity. The influence of Ethosuximide is examined on smooth muscular samples of human stomach, taken in vitro using stomach resection. The medicament authoritatively reduce the spontaneous bioelectrical activity of the smooth muscular tissue, inffluences mainly it's components that have Ca+ nature. Together with that is indicated relaxation of the smooth muscular samples. In that research is expressed the thesis that this Etosuximide reduction of the Ca+-influx in the smooth muscular cells and the related relaxation probably are one of the main reasons of the secondary effects on the GIT.

KEY WORDS: ethosuximide, gastro-intestinal tract
     Introduction:
     Ethosuximide is a drug used for the treatment of petit mals (1). It reduces the low-threshold Ca2+ current through the neuronal T-Ca2+ channels (2, 3). It is believed that this mechanism ensures the basic protective effect of the drug on absence seizures. Clinical studies indicate that the negative side effects of Ethosuximide on gastrointestinal tract /GIT/ are expressed in heaviness in the stomach, anorexia and vomiting (4, 5, 6). Clinical investigations and the lack of stereoselectivity in its body distribution (7) impose the hypothesis that the possible effect of Ethosuximide is related to its action on gastrointestinal smooth muscle cells /SMC/. These cells possess membrane T- and L- Ca2+ channels (8) with kinetic and membrane-potential dependence similar to those of neuronal cells (9). The aim of the present study is to examine the character of Ethosuximide-induced functional disturbances in GIT, as well as their causative factors.

     Materials and Methods:
     1. X-ray contrast stomach examination. The contrast medium (Barium sulphate) was administered per os in a patient on Ethosuximide treatment. The plain facial radiographs of the gastrointestinal tract were performed using a Progress 800ST (CGR) X-ray apparatus.
     2. Measurement of mechanical activity of smooth muscle tissue. Smooth muscle strips were isometrically fixed between immovable base and tensosensor in a 20 ml organ bath containing modified Krebs solution with the following concentration (mmol/l): 139 Na+; 5 K+; 2,5 Ca2+; 1,1 Mg2+; 144 Cl-; 13 PO3; 3 HPO3 and 11,5 glucose (pH 7.3 +/-0.25). The solutions used were constantly aerated with a gas mixture of O2/CO2 (19/1 v/v) and temperated to 370C. The contraction was detected by a tensometric transducer with tensosensors DY 111-6/30 (Germany) and a tensoamplifier K. Tesar-D486 (Germany). Recording was made by tensorecorder Linseis (Germany).
     3. Measurement of bioelectrical and mechanical activity of smooth muscle tissue. The bioelectrical activity of smooth muscle strips from human stomach was studied in vitro by the single sucrose gap method. Morphologically and functionally intact regions from the antrum of human gastric corpus were obtained following routine gastrectomies. Smooth muscle strips (0.8 x 28 mm) were excised from these zones. The two electrode sections were separated by a layer of high resistancy saccharose. One of them was flushed with isotonic solution of KCl and the other with modified Krebs solution having the following concentration (mmol/l): 139 Na+; 5 K+; 2,5 Ca2+; 1,1 Mg2+; 144 Cl-; 13 PO3; 3 HPO3 and 11,5 glucose (pH 7.3 +/-0.25). The solutions used were constantly aerated with a gas mixture of O2/CO2 (19/1 v/v) and temperated to 370C. The bioelectric activity was measured by an operating enhancer (type MAA356) with high entering resistance. The contraction was detected by a tensometric transducer with tensosensors DY 111-6/30 (Germany) and a tensoamplifier K. Tesar-D486 Germany). Recording of both parameters was made by tensorecorder Linseis (Germany).
     4. Drugs and chemicals. Ethosuximide-Suxinutin was from Parke-Davis. The following Merck chemicals were used : NaCl, KCl, CaCl2, MgCl2, K2PO4, NaHCO3 and Glucose.
     5. Statistical analysis. The values obtained were expressed as mean +/- SEM. The statistical significance was assessed by Student's t-test. A value of P < 0.05 was considered as a significant difference.

     Results:
     1. Ethosuximide-induced effects on GIT of a patient. A patient D.H.T., 13 years old, with a temporal form of petit mal was treated with Ethosuximide for 12 months. The plasma level of the drug was within the therapeutic range. The side effects were heaviness in the stomach, anorexia, vomiting and burning in the stomach. The radiological contrast examination of the stomach and intestines showed a hypotonic stomach with hypersecretory liquid, slow and ineffective peristalsis, diffusely rough gastric mucosa. The pylorus evacuates the contrast medium following a long period of pyloric spasm. The contract medium forms a characteristic level in bulbus duodeni which persists for a long time. In the duodenal arc zones of locally augmented tone are registered, as well as areas with enlarged, atonic lumen with mixed type of diskinetic changes (Fig. 1). Significant gas collections are recorded in the small bowels. The evacuation of the contrast medium from the large bowels on the 48-th h. is presented on Fig. 2.
Fig. 1. As is described above in the text
Fig. 2. As is described above in the text
     2. Effect of Ethosuximide on the spontaneous bioelectric and contractile activity of smooth muscle strips. Ethosuximide affects the spontaneous bioelectric and contractile activity when added to the solution washing the samples. It is well known that human antral gastric SMC generate a plateaux type action potential (Fig. 3). Five quantitative parameters are used in order to characterize the bioelectrical activity, the spontaneous potentials in particular and to register the eventual changes in this activity:
     1. Potential frequency /min-1/.
     2. Initial pick amplitude /mV/.
     3. Initial pick duration /sec/.
     4. Plateaux amplitude /mV/.
     5. Plateaux duration /sec/.
     Our experiments reveal that 10-5 Ethosuximide affects differently the parameters studied (Fig. 4). No changes in the frequency of spontaneous potentials and in initial pick amplitude and duration are recorded. No effect on the membrane potential characterized as continuous hyper- or depolarizarion are registered.
Fig. 3. Record of spontaneous bioelectrical activity (SBEA) of human gastric smooth muscle
2 - A-pick
3 - T-pick
4 - A-plateaux
5 - T-plateaux
Fig. 4. Diagram of 5 parameters of spontaneous bioelectrical activity (SBEA) of 2 groups of human gastric smooth muscle: first one - control probes, and second - probes treated with ethosuximide 10-5 mol/l. With * is shown statistical significant differences among groups. Level of statistical significant difference is p<0.05, N=4
     A reliable reduction in the plateaux duration of spontaneous action potentials, as well as a tendency to decrease its amplitude is noted (Fig. 5).
Fig. 5. Record of spontaneous bioelectrical activity (SBEA) of human gastric smooth muscle in normal conditions and its changes after 5 min application of ethosuximide 10-5 mol/l.
     Along with these effects, Ethosuximide inhibits the mechanic activity of smooth muscle samples. The process affects both the tonic and the phasic components of the smooth muscle's mechanics (Fig. 6). Tone reduction is 4,9 mN. The amplitude of spontaneous phasic contractions decreases from 2.24 to 0.81 mN. The effect is reversible. The enhancement of the dose thoroughs the described changes. Doses of Ethosuximide at about 10-4 and higher induce irreversible changes in mechanic activity.
Fig. 6. Mechanogram of isometric tension responses of human gastric smooth muscle to Ethosuximide 10-5 mol/l.
     Discussion:
     Although based on a single case, the radiological contrast examination reveals that Ethosuximide induces marked functional changes in patient's GIT. The stomach is enlarged, hypotonic, with hypersecretory liquid in it. The peristalsis is ineffective and superficial. In duodenal arc diskinetic changes of mixed type are recorded. The evacuation of the contrast medium is retarded as a whole. These changes could provide a reliable explanation of the side effects of the drug reported by many patients. Our experiments in vitro give us grounds to assume that a significant part of the radiological changes are a result of Ethosuximide's direct effect on gastrointestinal smooth muscles. We discovered that the basic Ethosuximide-induced changes in spontaneous potentials are the reduction in their amplitude and in the plateaux duration. It is known that these complicated potentials have two components - a sodium one, generating the initial pick and a potassium one, generating the plateaux (10). It is evident that reducing the plateaux, Ethosuximide inhibits the Ca2+-component of the potential. At this particular stage of our experimental work, we could not interpret in details the precise mechanism of the process. The reduction of the plateaux is related indeed to the decreased Ca2+-influx in SMC (10), a process which itself inhibits their spontaneous mechanical activity. When these processes are regarded not at the cellular level, but at that of the whole human body, different compensation mechanisms should be also considered. In spite of the complex interactions between them, our in vitro experiments demonstrate that the process observed is one of the basic Ethosuximide-induced changes in human GIT.

     Conclusions.
     1. Ethosuximide induces radiologically recorded functional disturbances in the GIT of Ethosuximide - treated patients.
     2. Ethosuximide reduces the duration of the amplitude and the plateaux of spontaneous potentials derived from smooth muscle strips of human stomach.
     3. Ethosuximide inhibits the spontaneous mechanical activity of from smooth muscle strips.

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  Correspondence and reprint request to:

  D-r N. Sirakov MD, Medical University, Plovdiv, Bulgaria
  Department of Radiology, 15a "Vassil Aprilov" Blvd., Plovdiv 4000, Bulgaria
  e-mail: nsirakov@abv.bg