Uterine leiomyomata (ULM) are benign smooth muscle neoplasms that are hormonedependent. Menorrhagia and anemia are the most common symptoms associated with this disorder. As many as 200000 cases of ULM per year are registered in the USA, and hysterectomy remains the major therapeutic option for treatment. Because gonadal hormones induce or maintain leiomyoma growth, selective progesterone receptor modulators have been evaluated as suitable therapeutic agents. Ulipristal acetate (UPA) is a therapeutic agent used as an emergency contraceptive agent. The therapeutic spectrum of the agent has been expanded by a new indication at the end of 2012. Based on two large-scale international randomized trials (PEARL I and PEARL II), UPA (Esmya tab. 5 mg) received European approval for preoperative treatment of ULM in the spring of 2012. The drug is indicated for treatment of moderate to severe symptoms of uterine fibroids. The duration of the treatment with UPA is limited to no more than 3 months when it is used to reduce the size of the tumor, to stop or reduce bleeding and to increase the red blood count prior to surgery. A disadvantage of the cited studies is that the course of treatment is limited to 3 months. Therefore, more data are needed regarding the benefits and risks of long-term treatment with UPA.
The use of UPA in some forms of hypermenorrhoea is discussed as a future therapeutic option but the data are not yet conclusive.
Ilia D. Kostadinov, Delian P. Delev and Ivanka I. Kostadinova
INTRODUCTION: Tricyclic antidepressants are used in the treatment of various pain syndromes. The antidepressant clomipramine inhibits predominantly the reuptake of serotonin in the central nervous system. The mechanism of its analgesic effect is not fully understood.
The AIM of the present study was to find experimentally any dose-effect dependence in the analgesic effect of clomipramine and the involvement of the 5-НТ2 and 5-НТ3 receptors in the mechanism of this effect. Material and methods: Fifty male Wistar rats were used in the study allocated to five groups (10 animals each): a saline treated control group, one positive control group treated with metamizole and three experimental groups treated with intraperitoneally administered clomipramine in doses of 5, 10 and 20 mg/kg bw, respectively. To study the role of 5-НТ2 and 5-НТ3 receptors in this effect we used another five groups (10 animals each): control, positive control and three experimental groups treated with clomipramine only, clomipramine and granisetrone and clomipramine and cyproheptadine, respectively. Three nociceptive tests were used: the hot plate test, analgesimeter and the acetic acid-induced writhing test. To gauge the antinociceptive action we used the increased latency in the hot plate test expressed as maximum possible effect % (%MPE), the increase in paw pressure to withdraw the hind paw in analgesimeter and decrease in the number of spinal cord writhes in the acetic acid test.
RESULTS: Clomipramine in a dose of 20 mg/kg bw significantly increased the %MPE in hot plate test and the pressure to withdraw the hind paw in the analgesimeter when compared with the control. In the acetic acid test clomipramine decreased non-significantly the number of writhes compared with the controls. Granisetrone reduced non-significantly the antinociceptive effect of clomipramine in all tests. Cyproheptadine potentiated the analgesic effect of clomipramine in acetic acid test and decreased it significantly in the hot plate test. In analgesimeter cyproheptadine decreased significantly the paw pressure to withdraw the tested hind paw at 1 hour and non-significantly at 2 hours.
CONCLUSION: Clomipramine in the dose of 20 mg/kg bw has a pronounced antinociceptive affect towards thermal and mechanical pain stimulation. The 5-HT2 and 5-HT3 receptor subtypes are very likely involved in the mechanism of this effect.
Maria T. Georgieva-Kotetarova, Ivanka I. Kostadinova and Delian P. Delev
Statins are widely used for treatment of hyperlipidemia. They have been shown to possess pleiotropic effects apart from their lipid-lowering activity - anti-inflammatory, immunomodulatory, and neuroprotective. Most studies suggest that statins can protect the brain against damage but it is not clear whether they improve cognitive function in patients without neuropathy. The aim of the present study was to investigate the effect of 3-month treatment with atorvastatin and rosuvastatin on learning and memory processes in rats without brain damage. Wistar rats were treated orally for 90 days with atorvastatin and rosuvastatin at a dose of 10 mg/kg b. w. in parallel with the vehicle-treated group. After that period, learning ability and memory retention was evaluated using an active avoidance test - automatic reflex conditioner (shuttle box). The learning session was carried out on 5 consecutive days. Memory retention test was performed on day 12. The following behavioral reactions were investigated: conditioned responses (avoidance), unconditioned responses (escapes), and intertrial crossings. We found increased number of conditioned responses in groups, treated with atorvastatin 10 mg/kg b.w., and with rosuvastatin 10 mg/kg b.w. during the learning session and on the memory retention test, as compared to the same-day control group. The atorvastatin-treated group showed an increased number of unconditioned responses on days 1 and 2, as compared to the control group. In the group treated with Rosuvastatin there was an increased number of escapes on days 1,2 and 4, as compared to the vehicle-treated group. Atorvastatin and rosuvastatin at a dose of 10 mg/kg b.w. improved processes of learning and memory retention after the 3-month treatment.
Ilia D. Kostadinov, Delian P. Delev, Marianna A. Murdjeva and Ivanka I. Kostadinova
INTRODUCTION: Fluoxetine is an antidepressant that has anti-inflammatory and antihyperalgesic effects in experimental models of pain and inflammation. The AIM of the present study was to determine the role of 5-HT2 receptors in the mechanism of anti-inflammatory and antihyperalgesic action of fluoxetine after single and repeated administration of the drug. MATERIALS AND METHODS: 40 male Wistar rats were randomly divided in five groups (n = 8) treated for 14 days with saline (control), diclofenac (positive control), fluoxetine, cyproheptadine (5-HT2 antagonist), and fluoxetine + cyproheptadine, respectively. We used the experimental model of inflammation induced by intraplantar injection of carrageenan and nociceptive test with mechanical pressure on the inflamed hind paw. RESULTS: Single and repeated administration of fluoxetine showed that it had significant anti-inflammatory and antihyperalgesic effects when compared with the control (p < 0.05). Cyproheptadine did not change significantly the anti-inflammatory effect of fluoxetine in the first 4 hours, after a single administration. At 24 hours the combination did not differ statistically when compared with the control. Cyproheptadin did not change significantly the anti-inflammatory effect of fluoxetine after repeated administration. After prolonged treatment the group that received fluoxetine + cyproheptadine showed a statistically significant increase in paw pressure to withdraw the hind paw compared with that treated with fluoxetine alone (p < 0.05). CONCLUSIONS: Fluoxetine has anti-inflammatory and antihyperalgesic effects in the carrageenan model of inflammation. 5-HT2 receptor mediated its anti-inflammatory effect in single dose treated animals. Spinal 5-HT2 receptors are involved in the antihyperalgesic effect of fluoxetine after repeated administration
Anita S. Mihaylova, Ilia D. Kostadinov, Nina D. Doncheva, Hristina I. Zlatanova and Delian P. Delev
Background: Parkinson’s disease (PD) is the second most common neurode-generative disease, usually detected by its motor symptoms. The non-motor symptoms, including cognitive deficits, have been of great interest to researchers in the last few decades.
Aim: To assess the effect of pramipexole on learning and memory in naïve and haloperidol-challenged rats.
Materials and methods: Male Wistar rats divided into 9 groups (n=8): naïve - saline, pramipexole 0.5; 1 and 3 mg/kg bw; Haloperidol groups - saline, haloperidol, haloperidol + pramipexole 0.5; 1 and 3 mg/kg bw. Two-way active avoidance test (TWAA) and activity cage were performed. The studied parameters were: number of conditioned and unconditioned responses, vertical and horizontal movements. Statistical analysis was done using SPSS 19.
Results: The naïve experimental groups significantly increased the number of conditioned responses during the tests for short- and long-term memory, compared with the saline groups (p<0.05). During the short-memory test only the animals with the lowest dose of PMX significantly increased the number of unconditioned responses whereas during the long-term memory test all experimental groups increased the number of escapes in comparison with the saline groups (p<0.05). Challenge dose of haloperidol attenuates learning and memory in pramipexol treated rats. Only the highest dose of pramipexol showed significant increase in conditioned and unconditioned responses compared with the haloperidol group (p<0.05).
Conclusion: Pramipexole improves learning and memory in naïve rats by enhancing dopaminergic neurotransmission. This is probably not the only mechanism involved. This is confirmed by the decrease in learning and memory ability in rats with haloperidol-challenge.
Hristina I. Zlatanova, Ilin K. Kandilarov, Ilia D. Kostadinov, Delian P. Delev and Maria T. Georgieva-Kotetarova
Background: Antidepressants have been found to possess antinociceptive and analgesic properties and are prescribed in the treatment of chronic pain.
Aim: To evaluate the antinociceptive properties of escitalopram after a single administration.
Materials and methods: Forty Wistar rats were used in the study. They were divided into 5 groups (n=8) treated with saline solution (control group), metamizole (150 mg/kg b.w.), escitalopram (5, 10 and 20 mg/kg b.w.) intraperitoneally. The nociceptive tests we used employed thermal (hot plate and plantar test), mechanical (analgesimeter) and chemical (formalin test) stimuli. Criteria for analgesic effect were increased latency in hot plate, plantar test, analgesimeter and decreased paw licking time in formalin test.
Results: The reference analgesic metamizole showed significant analgesic effect in all tests excluding the first phase with formalin. Escitalopram in doses of 5 and 20 mg/kg b.w. increased paw withdrawal latency in analgesimeter at 2 hours compared to control. Escitalopram in a dose of 5 mg/kg b.w. increased the duration of the stay on the hot plate at 1 hour, while doses of 10 and 20 mg/kg b.w. significantly increased this indicator at 1 and 3 hours in comparison to the saline treated group. In the plantar test, escitalopram in all used doses significantly increased the nociceptive response latency compared to control. A dose of 5 mg/kg b.w. decreased hind paw licking time during phase 1 of the formalin test, whereas doses of 10 and 20 mg/kg b.w. decreased phase 2 licking time compared to the control group.
Conclusion: The antidepressant escitalopram has analgesic properties but they are not dose- or time-dependent.
Ivana Uhrikova, Milan Sepsi, Jana Hlozkova, Pavel Suchy, Marta Kasajova, Katerina Machackova, Delian P. Delev, Rachele Ciccocioppo, Peter Kruzliak and Peter Scheer
Objectives: The aim of this study was to evaluate changes in hematology and coagulation in rabbits with right-ventricle pacing without medication.
Animals and methods: Blood was collected from ten non-anesthetized male rabbits from the jugular vein before and one month after pacemaker placement. Total erythrocyte, leukocyte and platelet count, hemoglobin, hematocrit and differential leukocyte count were done on automatic veterinary flow cytometry hematologic analyzer. Prothrombin time, activated partial thromboplastin time, fibrinogen level, D-dimers and kaolin-activated thromboelastography was measured from citrated blood.
Results: We found an increase in red blood cell mass and decrease in platelet count, while coagulation tests did not diff er between samplings.
Conclusion: Right-ventricle pacing seems to have no influence on hemostasis in rabbits.