Snezana V. Jankovic

Inverse correlation of valproic acid serum concentrations and quality of life in adolescents with epilepsy

BACKGROUND Correlation between steady-state serum concentrations of antiepileptic drugs and both seizure control and adverse drug reactions frequency (two major determinants of quality of life in patients with epilepsy) is still matter of controversy. OBJECTIVE The aim of our study was to investigate whether a correlation exists between steady-state serum concentration of valproic acid and quality of life in adolescent patients with epilepsy. METHOD Twenty-one adolescent patients with epilepsy, treated with valproic acid for more than 6 months entered the study. On two occasions, 3 months apart, both through and 2-h-after-the-dose serum concentrations of valproic acid were measured, as well as quality of life, using QOLIE-AD-48 for adolescents. Adverse drug reactions and seizure control were also recorded. RESULTS Significant inverse correlation between through serum concentrations of valproic acid and total QOLIE-AD-48 scores was observed, together with correlation between through serum concentrations and adverse drug reactions frequency. The scores of memory/concentration and physical functioning QOLIEAD-48 domains were significantly and inversely correlated with through serum concentrations. CONCLUSION Our study suggests that therapeutic monitoring of valproic acid serum concentrations could be useful predictor and marker of the most important epilepsy treatment outcome--quality of life.

Contractile effects of endothelins on isolated ampullar segment of human oviduct in luteal phase of menstrual cycle

Endothelin-1 induces contractions of human oviduct ampullar segment in follicular phase of menstrual cycle, acting on ET(A) receptors. The aim of our study was to investigate effects of endothelin-1, endothelin-2 and endothelin-3 on isolated ampullar segment of human oviducts, taken from the patients in luteal phase of menstrual cycle. Fallopian tubes were taken from 20 female patients (one tube from each patient) during abdominal hysterectomy with adnexectomy, due to extensive uterine fibroids. The oviduct ampulla was mounted in an organ bath longitudinally, and the tension of the isolated preparation was recorded with the isometric transducer. Endothelin-1 produced concentration-dependent tonic contraction of the isolated ampullar segment (EC(50)=6.80 +/- 1.2 x 10(-10)M), and concentration-dependent inhibition of its rhythmic contractions (EC(50)=7.86 +/- 2.3 x 10(-10)M). Endothelin-2 produced concentration-dependent tonic contraction of the isolated ampullar segment (EC(50)=4.56 +/- 0.3 x 10(-10)M), without affecting its rhythmic contractions. Endothelin-3 did not affect either tone or rhythmic contractions of the isolated preparations. Selective antagonist for ET(A) receptor subtype, BQ 123, produced inhibition of endothelin-1 effects on both tone (pA(2)=9.50) and spontaneous rhythmic contractions (pA(2)=10.73), while selective antagonist for ET(B) receptor subtype, BQ 788, produced only inhibition of endothelin-1 effects on tone (pA(2)=9.61), while the effect of endothelin-1 on spontaneous rhythmic contractions remained unaffected. The results of our study suggest that in the luteal phase both ET(A) and ET(B) receptors regulate tone, and only ET(A) receptors regulate rhythmic activity of human oviducts ampullar segment.

Effect of exogenous glutamate and N-Methyl-D-aspartic acid on spontaneous activity of isolated human ureter

Objectives:  While the neurotransmitter role of glutamate in the gastrointestinal tract has been shown, its effects on smooth muscle of the human ureter have not previously been investigated. In our study we have investigated the effects of exogenous glutamate on the spontaneous activity of isolated human ureter, taken from 14 adult patients after nephrectomy.

Inhibitory effects of selected antiepileptics on spontaneous motility of isolated human oviducts.

ObjectiveSpontaneous motility of the human oviduct is an important factor in the regulation of fertility that can be influenced by a variety of substances. In this study we examined the effects of several antiepileptic drugs on spontaneous contractions of isolated human oviducts.Methods The isolated ampullar and isthmic segments of Fallopian tubes, taken from 34 patients with extensive uterine fibroids, were exposed to carbamazepine, lamotrigine, valproic acid, phenobarbital, diazepam and lorazepam.ResultsCarbamazepine and lamotrigine produced concentration-dependent inhibition of spontaneous contractions of both ampullar and isthmic isolated preparations, while the other investigated substances did not exhibit any effect. The effective concentrations of carbamazepine and lamotrigine fall within the range of their therapeutic serum concentrations.ConclusionWhen choosing antiepileptics for women of reproductive age, the effects of the drug on motility of the Fallopian tubes should also be considered.

Antipsychotic Drug Prescription in a Serbian Long-Stay Psychiatric Care Facility

ObjectiveThis study evaluated the current use of antipsychotic drugs in a long-stay psychiatric care facility.Design and SettingThe study was a cross-sectional survey of drug therapy in a long-stay psychiatric care facility, performed in the Institute for Psychiatric Care of Adults (IPCA) in Male Pcelice, Serbia, FR Yugoslavia.PatientsThe drug therapy of 806 inpatients was surveyed.InterventionsThe survey was performed on a randomly chosen day. The following data were collected from patient files and drug charts: age, gender, diagnosis, age of onset of illness, age of first hospitalisation, and current dosage of psychotropic drugs.Main Outcome MeasuresThe main outcome measures were the spectrum of drugs used for a particular disorder, the number of drugs used per patient, the average dose of each drug, and the average length of therapy.ResultsThe majority of the inpatients had schizophrenia (396) or mental retardation (330). Fifteen percent of the patients did not take any psychotropic medication. Among 682 patients taking psychotropic medication, 547 (80.2%) were receiving antipsychotics. The median daily dose of antipsychotic s was 450mg of chlorpromazine (CPZ) equivalent. 133 patients (24% of those taking antipsychotics) with schizophrenia were maintained on depot antipsychotics. The dosage of antipsychotics in patients with schizophrenia was higher than that in patients with other diagnoses (median 500 vs 400mg of CPZ equivalent per day; U = 42467; p = 0.0005; significant difference). Of the patients taking antipsychotics, 237 (43.4%) were taking one, 254 (46.4%) were taking two, and 56 (10.2%) were taking three or more agents. 243 (44.4%) patients were taking an anticholinergic antiparkinsonian agent, trihexyphenidyl, in a median daily dose of 5mg. 351 (64.1%) patients were taking some other psychotropic drug. The patients receiving both antipsychotics and other psychotropic drugs were on slightly lower dosages of antipsychotics than the patients receiving antipsychotics only (median 400 vs 450mg of CPZ equivalent per day; U = 35239.8, p = 0.691; NS).ConclusionsSignificant irrationalities in psychotropic drug use were observed: maintenance dosages of antipsychotics were higher than those recommended by international guidelines; two or more antipsychotics were administered to an unacceptably high proportion of patients, and adjuvant psychotropic medication was overused. There is a need for translating international guidelines into Serbian to allow Serbian practitioners to prescribe psychotropic drugs in line with modern views.

Captopril May Influence Tone of Human Oviduct Ampulla

To the Editor: Although numerous effects of angiotensin-converting enzyme (ACE) inhibitors were documented in various tissues, their influence on human oviduct was not investigated. It was shown that angiotensin II receptors exist in epithelial cells of fallopian tubes, and when stimulated by an agonist, they induce movement of negatively charged ions from a basal to luminal side of the epithelial cells. In a functional study on isolated human oviduct, angiotensin II-stimulated movements of the epithelial cells’ cilia, suggesting indirect influence on fertilization process; however, angiotensin II did not affect fallopian tubes’ motility in the same study. Knowing that ACE exists in oviduct tissues, especially in the ampullary region, and that another substrate, bradykinin, triggers tonic contractions of both isthmus and ampulla, we decided to test whether ACE inhibitors influence motility of isolated human oviduct. The fallopian tubes were taken from 14 female patients (39.3 9.7 years) during abdominal hysterectomy with salpingo-oophorectomy (performed in 2011 and 2012) due to uterine fibroids causing prolonged and irregular uterine bleeding for at least 3 months. The study was approved by the ethics committee of the clinical center “Kragujevac,” and the patients signed informed consent forms. Two types of fallopian tube preparations were mounted in the isolated organ baths: isthmus and ampulla. The tension of the isolated preparations was recorded by isometric transducer (Palmer Bio Science, Los Angeles, CA) and registered on a personal computer using special interface and software (Majk Electronic, Mladenovac, Serbia). Both phasic and tonic contractions of the isolated preparations were measured as the area under the tension recordings (AUC). Captopril (Sigma-Aldrich, Buchs, Switzerland) and enalapril maleate (Sigma-Aldrich, St. Louis, MO) were separately added to the organ baths in a cumulative way, gradually increasing their concentration in the baths’ solution. Enalapril (2.7910 –3.9910 4 M) did not affect either phasic, spontaneous activity, or tone of both isolated isthmus and ampulla. On the other hand, captopril (6.1910 –2.7910 3 M) caused concentration-dependent tonic contraction of the isolated ampulla (EC50=0.27 2.1910 7 M; F=9.14, df1=7, df2=16, P<.01) (Figure 1), while tone of the isolated isthmus and spontaneous activity of both isthmus and ampulla were not affected by this substance. It is not surprising that captopril caused tonic contraction of ampullar segment, while enalapril did not, since captopril has much higher affinity for ACE than enalapril in various tissues. The affinity of captopril for ACE is more than 100 times higher than that of enalapril, which explains why enalapril in almost the same bath concentrations did not cause contraction of ampulla, while captopril did. Our finding draws attention to that possibility that ACE inhibitors may interfere with fertilization in female patients who take these drugs chronically for various reasons. Of course, this is just a hypothesis that needs to be confirmed by cohort or case-control studies in real life. But, if confirmed, it would profoundly influence prescribing of ACE inhibitors to women during their reproductive age.

Effects of Exogenous Glutamate and Kainate on Electric Field-stimulated Contractions of Isolated Human Ureter

OBJECTIVES A neurotransmitter role for glutamate in the autonomous nervous system was recently demonstrated in the gastrointestinal tract, and its stimulatory effect on spontaneous motility of human ureter was shown. The aim of our study was to investigate the effects of glutamate on the release of neurotransmitters from intramural nerves of the human ureter. METHODS The effects of exogenous glutamate were tested on electric field-stimulated contractions of isolated human ureter, taken from 16 adult patients after nephrectomy. The longitudinal tension and intraluminal pressure of the isolated ureter were recorded simultaneously. The electric field stimulation was done with square wave pulses (20 V through electrodes, 400 mA, duration 1 ms, frequency 16 Hz). The pulse trains lasted for 30 s, a with 30-s pause. RESULTS Glutamate (7.9 x 10(-6) M/L to 10.6 x 10(-3) M/L) and kainic acid (6.3 x 10(-8) M/L to 2.2 x 10(-5) M/L) produced a concentration-dependent decrease in the electric field-stimulated activity of the isolated preparations. However, N-methyl-D-aspartic acid (9.1 x 10(-8) M/L to 3.1 x 10(-5) M/L), (RS)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (7.2 x 10(-8) M/L to 3.2 x 10(-6) M/L) and (+/-)-1-Aminocyclopentane-trans-1,3-dicarboxylic acid (7.7 x 10(-8) M/L to 6.5 x 10(-5) M/L) were ineffective. The electric field-stimulated contractions of isolated ureter were also inhibited by lidocaine (3.70 x 10(-4)M/L) and atropine (1.00 x 10(-6)M/L). CONCLUSIONS The results of our study suggest that glutamate inhibits electric field-stimulated release of acetylcholine in the human ureter through activation of kainate ionotropic receptors, located on the intramural nerve fibers.