Effects of selective serotonin reuptake inhibitors on motility of isolated fallopian tube.

Selective serotonin reuptake inhibitors (SSRIs) affect the smooth muscle cells acting on voltage-dependent channels for Na+ , K+ and Ca2+ , but their action is tissue and species specific. The aim of our study was to investigate effects of selective serotonin reuptake inhibitors on motility of the isolated fallopian tubes. Isolated preparations of isthmus and ampoule were taken from fallopian tubes of 20 women during hysterectomy due to uterine fibroids and then tested for reactivity on increasing concentrations of selective serotonin reuptake inhibitors. Escitalopram (from 0.9 × 10-9  M/L to 1.4 × 10-6  M/L) produced concentration-dependent increase of spontaneous contractions of the isolated ampulla (EC50 = 1.20 ± 1.06 × 10-8  M/L, r = 0.580, P < 0.05) (F = 2.980, df1  = 6, df2  = 28, P < 0.05). Paroxetine (from 1.2 × 10-9  M/L to 5.1 × 10-5  M/L) produced concentration-dependent increase of spontaneous contractions of the isolated isthmus (EC50 = 7.01 ± 3.50 × 10-8  M/L, r = 0.500, P < 0.05) (F = 2.350, df1  = 9, df2  = 40, P < 0.05). The SSRIs differ among themselves in regard to their potential to affect motility of the fallopian tubes. Escitalopram and paroxetine have clear stimulating effect which may interfere with functioning of the fallopian tubes, and potentially impair fertility if taken by women in reproductive period of life. The other SSRIs tested in the study did not produce significant effect throughout the concentration range used in the experiments.

Calcitonin Gene-Related Peptide Receptor Blocker Inhibits Spontaneous Activity of Human Ureter.

Calcitonin gene-related peptide (CGRP) is present in nerve fibers that innervate the human ureter and may have important influence on the motility of this organ. The aim of our study was to investigate whether CGRP could affect the motility of an isolated human ureter. The tension and intraluminal pressure of the isolated ureteral segments were recorded and registered on a personal computer. Both phasic and tonic contractions of the isolated preparations were measured as area under the tension or pressure recordings. CGRP and CGRP fragment 8-37 were separately added to the organ baths in a cumulative way, thereby gradually increasing their concentration in the baths' solution. Alpha-CGRP did not affect either phasic, spontaneous activity or tone of isolated ureteral segments, as measured by both tension and intraluminal pressure. On the other hand, CGRP 8-37 caused concentration-dependent inhibition of spontaneous contractions of the isolated ureteral segments.

Costs differences among monoclonal antibodies-based first-line oncology cancer protocols for breast cancer, colorectal carcinoma and non-Hodgkin's lymphoma.

PURPOSE: To assess and compare the costs of first-line monoclonal antibodies (mAbs) treatment protocols in breast cancer, non-Hodgkin lymphoma and colorectal carcinoma in South-Eastern Europe. METHODS: A retrospective, bottom-up case series study design was implemented with one-year time horizon and payer's perspective. The study sample size was 265 patients (breast cancer, N=137; colorectal cancer, N=44; and non-Hodgkin lymphoma, N=84), while treatment protocols included adjuvant mAbs: trastuzumab (N=137), bevacizumab (N=28), rituximab (N=16) and cetuximab (N=84). ICD-10 related resources use included history of medical services utilization, chronology (time out of service provision) and unit consumption of examinations, drugs prescribed, imaging, radiotherapy and surgical procedures provided etc., direct medical and lost productivity costs (€) across treatment groups during 2010-2013. RESULTS: The average length of observation was 125+97 days per patient. Total mean direct and indirect costs of care were: trastuzumab for breast cancer group € 17,740 per patient; bevacizumab for colorectal carcinoma group €8,775 per patient; cetuximab for colorectal carcinoma group € 27,181 per patient; and rituximab for non-Hodgkin lymphoma group €19,431 per patient. An average mAbs-treated patient incurred €17,897 costs of medical care. The total combined budget of these 330 patients was €4,742,775. CONCLUSIONS: The use of mAbs strongly correlated with high costs in first-line cancer medical care and dominated other cost domains. Cetuximab-based treatment protocols in colorectal carcinoma patients was substantially more expensive compared to trastuzumab (C50), bevacizumab (C20), and rituximab (C80) alternatives. Extremely high costs of mAbs are the key-issue for Eastern European policy makers by crossing the upper limits of affordability in middle-income economies.

Risk factors for potential drug-drug interactions in patients with chronic obstructive pulmonary disease.

Potential drug-drug interactions (pDDIs) are especially frequent in patients with chronic obstructive pulmonary disease (COPD) who, if hospitalized, experience, on average 6.5 pDDIs on admission, and 7.2 on discharge. The aim of our study was to identify and analyze risk and/or protective factors for occurrence of pDDIs in hospitalized patients with COPD. Main outcome was occurrence of pDDIs in COPD patients ascertained by Medscape, Epocrates, and Micromedex interaction checkers. The most serious pDDIs (contraindicated/serious/major/use alternative) were found in 16 (22%), 8 (11%), and 35 (49%) patients, according to the Medscape, Epocrates, and Micromedex, respectively. The COPD patients who were prescribed more drugs (especially antiarrhythmic and anticoagulants), by several independent prescribers, and having more comorbidities, were more prone to experience a pDDI; the only protective factor against pDDIs was age of the patients. In conclusion, COPD patients with the abovementioned risk factors should have their therapy more intensely monitored for pDDIs.

Correlation of Clinicopathological Characteristics of Breast Carcinoma and Depression.

The prevalence of depression among women with breast cancer (BC) is extremely variable in research studies. The aim of this study was to determine the prevalence of depressive disorder in women suffering from BC as well as to examine its relationship with clinical-pathological and immunophenotypic characteristics of BC. The study included 194 patients with BC who were diagnosed with the disease between 2009 and 2015 in the Clinical Center Kragujevac, Serbia. Pathohistological and immunohistochemical analyses was used on the material obtained after the surgical removal of breast tumors, determining all significant clinical and morphological parameters. The level of depression among the examinees confirmed that the differences in the level of depression between the histological grades were statistically significant. According to the univariate binary logistic regression, the depression of a patient correlates with the category of molecular tumor subtype/Luminal A (p < 0.0005), PR expression (p = 0.050) and lymphatic invasion (p = 0.025). Multivariate binary logistic regression showed that the onset of depression associated with the present molecular subtype of the tumor of a worse prognostic character (p = 0.019). Depression is a common disorder in women with breast cancer. The level of depression is correlates with some of the clinicоmorphological and immunophenotypic characteristics of BC.

Angiotensin Receptor Blocker Losartan Inhibits Spontaneous Motility of Isolated Human Ureter.

BACKGROUND AND OBJECTIVES: Ureteral motility is essential for elimination of intraluminal stones, and it may be adversely affected by cardiovascular drugs that a patient is taking chronically. The aim of our study was to test whether ACE inhibitors and an angiotensin receptor blocker may influence spontaneous contractions of isolated human ureter. METHODS: Both phasic and tonic contractions of the isolated ureteral segments taken from 10 patients were measured as changes of the longitudinal tension or pressure recordings. Captopril, enalapril and losartan were separately added to the organ baths cumulatively. RESULTS: While enalapril (2.7 × 10-7-3.9 × 10-4 M) and captopril (6.1 × 10-7-2.7 × 10-3 M) did not affect either spontaneous activity or tone of isolated ureteral segments, losartan (2.9 × 10-7-4.2 × 10-4 M) caused concentration-dependent inhibition of spontaneous contractions of the segments (50 % effective concentration (EC50) = 13.46 ± 1.80 × 10-6 M; F = 10.72, r = 0.79, p < 0.001). CONCLUSIONS: Due to differences in molecular mechanism of action, angiotensin receptor blocker losartan does and ACE inhibitors captopril and enalapril do not inhibit spontaneous contractions of isolated human ureter.

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.

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. METHODS: The segment of ureter, excised 3 cm distal from the pyeloureteral junction, was isolated in an organ bath. Both longitudinal tension and intraluminal pressure of the segment were recorded simultaneously. RESULTS: Glutamate administered in the lumen of the isolated ureteral segments (7.8 x 10(-7) M/L-3.5 x 10(-2) M/L) was ineffective. When added to the isolated organ bath from the serous side of the ureteral segment, glutamate (7.9 x 10(-6) M/L-10.6 x 10(-3) M/L) and N-Methyl-D-aspartic acid (NMDA) (9.1 x 10(-8) M/L-3.1 x 10(-5) M/L) produced a concentration-dependent increase in spontaneous activity of the isolated preparations, while kainic acid (6.3 x 10(-8) M/L-10.5 x 10(-5) M/L) and (+/-)-trans-1-Aminocyclopentane-trans-1,3-dicarboxylic acid (ACPD) (7.7 x 10(-8) M/L -6.5 x 10(-5) M/L) were ineffective. CONCLUSIONS: The results of our study suggest that an excitatory neurotransmitter glutamate stimulates spontaneous activity of the human ureter through activation of NMDA ionotropic receptors, located on smooth muscle cells or intramural nerve fibers.