Potential drug-drug interactions in adults receiving oral anticoagulant and antiaggregant therapy.

BACKGROUND: Anticoagulant and antiaggregant drugs are drug groups with high mortality and the most common cause of malpractice. RESEARCH DESIGN AND METHODS: 18 and 65 years were scheduled for pharmacotherapy in the Family Health Center. 122 patients during their anticoagulant and/or antiaggregant treatment were evaluated in terms of drug-drug interactions. RESULTS: Drug-drug interactions were detected in 89.7% of the patients included in the study. A total of 212 drug-drug interactions were found in 122 patients. Of these, 12 (5.6%) were identified as A, 16 (7.5%) B, 146 (68.6%) C, 32 (15.2%) D and 6 (2.8%) X risk category. The number of DDI was found to be significantly higher in patients aged between 56 and 65 years. The most drug interactions are significantly higher in the C and D categories, respectively. The most predicted clinical outcomes of DDI's were increased in the therapeutic effect and adverse/toxic reactions. CONCLUSIONS: Contrary to expectations, it is seen that although polypharmacy is relatively less in patients aged 18-65 years compared to patients over 65 years of age, it is very important to detect drug interactions in this age group in terms of safety, efficacy and treatment benefit in terms of drug-drug interaction.

Elevated serum midkine levels in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infected patients.

BACKGROUND: The coronavirus disease-2019 (COVID-19) pandemic has caused important health, economic, social, and cultural problems worldwide. Recent findings demonstrate an excessive cytokine release during the disease development, especially in the seriously life-threatening form of COVID-19. Among other chemokines and cytokines that are released in high amounts at the infection site of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), midkine (MK), which is a potent pro-inflammatory growth factor/ cytokine, can be also overexpressed and contribute to the pathophysiological process in patients infected with SARS-CoV-2. MATERIALS AND METHOD: Serum was collected from 87 intensive care unit (ICU) patients that are COVID-19 positive and 50 healthy volunteers in the control group with a negative PCR test and without disease symptoms. Circulating MK concentration was measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: COVID-19 patients had a significantly higher serum MK concentration compared to non-COVID-19 control subjects (1892.8 ± 1615.8 pg/mL versus 680.7 ± 907.6 pg/mL, respectively; P < 0.001). The cut-off MK concentration was 716.7 pg/ mL, with the sensitivity and specificity of 75.9 % and 76.0 %, respectively. The area under the receiver operating characteristic (ROC) curve of MK was = 0.827. Our findings showed that circulating MK levels are significantly increased in SARS-CoV-2 infected patients. CONCLUSION: We suggest that MK is involved in the pathogenesis of COVID-19 and may be a part of hypercytokinaemia. Therefore, MK may serve as a supporting biomarker in the diagnosis of COVID-19, and blocking MK actions or its targets may attenuate the inflammatory process and the severity of the disease.

The Neurochemical Effects of Prazosin Treatment on Fear Circuitry in a Rat Traumatic Stress Model.

OBJECTIVE: The timing of administration of pharmacologic agents is crucial in traumatic stress since they can either potentiate the original fear memory or may cause fear extinction depending on the phase of fear conditioning. Brain noradrenergic system has a role in fear conditioning. Data regarding the role of prazosin in traumatic stress are controversial. METHODS: In this study, we examined the effects of prazosin and the noradrenergic system in fear conditioning in a predator stress rat model. We evaluated the direct or indirect effects of stress and prazosin on noradrenaline (NA), gamma-aminobuytyric acid (GABA), glutamate, glycine levels and choline esterase activity in the amygdaloid complex, the dorsal hippocampus, the prefrontal cortex and the rostral pons. RESULTS: Our results demonstrated that prazosin might alleviate defensive behaviors and traumatic stress symptoms when given during the traumatic cue presentation in the stressed rats. However prazosin administration resulted in higher anxiety levels in non stressed rats when the neutral cue was presented. CONCLUSION: Prazosin should be used in PTSD with caution because prazosin might exacerbate anxiety in non-traumatized subjects. However prazosin might as well alleviate stress responses very effectively. Stress induced changes included increased NA and GABA levels in the amygdaloid complex in our study, attributing noradrenaline a possible inhibitory role on fear acquisition. Acetylcholine also has a role in memory modulation in the brain. We also demonstrated increased choline esterase acitivity. Cholinergic modulation might be another target for indirect prazosin action which needs to be further studied.

Increased noradrenaline levels in the rostral pons can be reversed by M1 antagonist in a rat model of post-traumatic stress disorder.

The dysregulation of hypothalamic-pituitary-adrenal axis and noradrenergic, serotonergic and glutamatergic systems are thought to be involved in the pathophysiology of post-traumatic stress disorder. The effect of selective M1 muscarinic receptor antagonist, pirenzepine on anxiety indices was investigated by using elevated plus maze, following exposure to trauma reminder. Upon receiving the approval of ethics committee, Sprague-Dawley rats were exposed to dirty cat litter (trauma) for 10 min and 1 week later, the rats confronted to a trauma reminder (clean litter). The rats also received intraperitoneal pirenzepine (1 or 2 mg/kg/day) or saline for 8 days. Noradrenaline (NA) concentration in the rostral pons was analyzed by HPLC with electrochemical detection. The anxiety indices of the rats subjected to the trauma reminder were increased when compared to control rats (p < 0.05). Pirenzepine treatment in traumatized rats displayed similar anxiety indices of non-traumatized rats treated with physiological saline. Although freezing time was prolonged with pirenzepine in traumatized groups the change was not found statistically significant. The NA level was 1.5 ± 0.1 pg/mg in non-traumatized rats and increased to 2.4 ± 0.2 pg/mg in traumatized rats. Bonferroni post hoc test revealed that the NA content of the rostral pons of the traumatized rats treated with physiological saline was significantly higher than the content of other groups (p < 0.01). We conclude that NA content in the rostral pons increases in respect to confrontation to a trauma reminder which can be reversed by M1 antagonist pirenzepine indicating the roles of M1 receptors.

Topographical connections of the substantia nigra pars reticulata to higher-order thalamic nuclei in the rat.

The substantia nigra pars reticulata (SNR) is the ventral subdivision of the substantia nigra and contains mostly GABAergic neurons. The present study explores whether the SNR relates to all dorsal thalamic nuclei equally or just to a particular group of nuclei, such as first or higher-order nuclei. Injections of biotinylated dextran amine (BDA) were made into the SNR of 10 male adult rats. The distribution of anterogradely labelled axon terminals in the thalamic nuclei was documented. The projections of the SNR to the thalamic nuclei were exclusively to some motor higher-order, but not to first-order thalamic relays. There were bilateral projections to the ventromedial (VM), parafascicular (PF), centromedian (CM) and paracentral (PC) nuclei and unilateral projections to the centrolateral (CL), mediodorsal (MD) and thalamic reticular nucleus (Rt). Labelled axon terminals in the thalamic nuclei ranged from numerous to sparse in VM, PF, CM, CL, PC, MD and Rt. Further, injections into the SNR along its rostral-caudal axis showed specific topographical connections with the thalamic nuclei. The rostral SNR injections showed labelled axon terminals of VM, PF, CL, PC, CM, MD and Rt. Caudal SNR injections showed labelling of VM, PF, PC, CM and MD. All injections showed labelled axons and terminals in the zona incerta. The nigrothalamic GABAergic neurons can be regarded as an important system for the regulation of motor activities. The SNR is in a position to influence large areas of the neocortex by modulating some of the motor higher-order thalamic nuclei directly or indirectly via Rt.