Follow-up of Favipiravir-Induced Nail Fluorescence: Implications for Nail and Drugs.

INTRODUCTION: Favipiravir creates fluorescence on nails, which can be seen with Wood's light. OBJECTIVES: The objectives of this study are to examine the properties of fluorescence in the nail due to favipiravir and to observe whether other drugs also produce fluorescence in the nail. METHODS: The research is descriptive, prospective, and quantitative. This study recruited 30 healthcare workers who received favipiravir treatment and 30 volunteers who took or did not take any medication except favipiravir from March 2021 to December 2021. Fingernails of the patients and control groups were examined under Wood's light in the darkroom. If fluorescence was observed in the fingernails, we followed up once a month until the fluorescence disappeared. We calculated the nail growth rate by dividing the distance of nail fluorescence from the proximal nail fold by the number of days since favipiravir was started. RESULTS: We found nail fluorescence in all patients receiving a loading dose of favipiravir. The fluorescence in the nail decreased and disappeared in the 3rd month. The average nail growth rate at the first visit was 0.14 mm/day. The nail growth rate at the second visit was 0.10 mm/day. A statistically significant difference was found between the first and second visit nail growth rates (z: -2.576; p=0.010<0.05). We found that other drugs did not produce any fluorescence in the nail. CONCLUSIONS: Nail fluorescence induced by favipiravir is dose-dependent and decreases in intensity over time. Nail fluorescence due to favipiravir is likely due to the active ingredient of the drug.

Is Seizure an Adverse Effect of Salbutamol in the Pediatric Population?

Background: Although studies on epileptic seizures occurring during acute asthma attacks are limited, there is widespread belief among families and physicians that salbutamol causes seizures. Aims: To investigate whether salbutamol triggers seizures in patients with epilepsy and asthma. Study Design: A retrospective cohort study. Methods: Epilepsy and asthma in patients aged 2-18 years who were admitted to the pediatric emergency department because of asthma attacks between January 2016 and December 2016 in a university hospital were evaluated retrospectively. The inclusion criteria were age 2­18 years, previous diagnosis of epilepsy and asthma, and admission to the pediatric emergency department due to asthma attacks. Results: 276 medical records were evaluated. The seizure group had a longer period of diagnosis for epilepsy than the seizure absent group in the pediatric emergency department (5.4 years and 3.1, respectively). According to the logistic regression analysis, the duration of seizures in the emergency department, duration of asthma diagnosis, duration of epilepsy diagnosis, uncontrolled asthma, and severity of asthma attack in the pediatric emergency department have significantly increased the possibility of having a seizure during an asthma attack in our study population. Conclusion: This study shows that patients using salbutamol have a lower risk of epileptic seizures than those who do not use salbutamol. This result should be verified by studies containing a large number of patients.

Anti-proliferative effects of paroxetine alone or in combination with sorafenib in HepG2 cells

Abstract Hepatocellular carcinoma (HCC) is a common cause of cancer-related death. Sorafenib is the first approved drug for the treatment of advanced HCC. Depression is frequent in cancer patients. Moreover, sorafenib might exert depression as an adverse drug reaction and paroxetine, a selective serotonin reuptake inhibitor, is a recommended pharmacotherapy. This study aimed to investigate the potential synergistic effects of paroxetine and sorafenib on HepG2 cell proliferation and death. Paroxetine and sorafenib were administered to HepG2 cells as single-agents or in combination. Cell viability was determined with XTT cell viability assay. Cellular apoptosis and DNA content were assessed by flow cytometry. The expression of anti-apoptotic Bcl-2 was examined by immunofluorescence confocal microscopy. A lower dose of sorafenib was found to be required to inhibit cell proliferation when in combination with paroxetine. Similarly, the coadministration enhanced cellular apoptosis and resulted in cell cycle arrest. Confocal imaging revealed a remarkably lower cell density and increased expression of Bcl-2 following combined treatment of paroxetine with sorafenib. To our knowledge, this is the first study demonstrating the synergistic effect of paroxetine and sorafenib in HCC and might provide a potentially promising therapeutic strategy.

Can Cytokines be used as an Activation Marker in Rheumatoid Arthritis?

AIMS: The etiopathogenesis of Rheumatoid Arthritis (RA) is not clearly understood. However, the role of the cytokines play an important part in this mechanism. We aimed to bring a new approach to the concept of 'remission' in patients with RA. BACKGROUND: RA is a chronic, autoimmune, inflammatory disease that involves small joints in the form of symmetrical polyarthritis and progresses with exacerbations and remissions. Pain, swelling, tenderness and morning stiffness are typical of the joints involved. Although it is approached as primary joint disease, a wide variety of extra-articular involvements may also occur. It is an interesting pathophysiological process, the exact cause of which is still unknown, with many environmental, genetic and potentially undiscovered possible factors in a chaotic manner. OBJECTIVE: In this cross-sectional study, sedimentation rate (ESR), C- Reactive protein (CRP), Tumor necrosis factor (TNF)-α, soluble-TNF-α receptor (TNF-R), Interleukin (IL)-1B and IL-10 were measured in three groups which were healthy volunteers, patients with RA in the active period, and patients with RA in remission. Disease activity score-28 (DAS-28) was calculated in active RA and RA in remission. METHODS: This study included 20 healthy volunteers, 20 remission patients with RA and 20 active RA patients. Venous blood samples were collected from patients in both healthy and RA groups. RESULTS: RA group consisted 43 (71.6%) female and 17 (28.4%) male. Control group consisted 11 (55%) female and 9 (45%) male. TNF-R was significantly high only in the active group according to the healthy group (p=0.002). IL-10 was significantly high in active RA, according to RA in remission (p=0.03). DAS-28 was significantly high in active RA, according to RA in remission (p=0.001). In the active RA group, ESR and TNF-R had a positive correlation (r:0.442; p=0.048). In the active RA group, there was also a positive correlation between TNF-R and CRP (r:0.621; p=0,003). Both healthy and active RA group had significant positive correlation between ESR and CRP (r: 0.481; p=0.032 and r: 0,697; p=0,001 respectively). CONCLUSION: TNF-R can be the main pathophysiological factor and a marker showing activation. TNF-R can be very important in revealing the effect of TNF on the disease and the value of this effect in the treatment and ensuring the follow-up of the disease with CRP instead of ESR in activation.

Therapeutic Drug Monitoring Characteristics in a Tertiary University Hospital in 2019.

Introduction Therapeutic drug monitoring (TDM) is defined as measuring drug concentration in a biological sample to optimize pharmacotherapy. This study aims to evaluate TDM requests in a tertiary university hospital retrospectively. Materials and methods TDM requests were evaluated retrospectively for lithium, valproic acid, carbamazepine, and digoxin in 2019. The age and gender of the patient, requesting department, and measurement results were evaluated. Lower levels than the reference values were considered as subtherapeutic, while levels higher than the reference were considered as toxic. Results  A total of 415 drug level measurement records were found. The pediatric age sample ratio was 13.7%, and the elderly age sample ratio was 11.8%. When all samples were evaluated according to the relevant laboratory cut-off values, 72.8% of samples were within the therapeutic level range, 21.9% of samples were subtherapeutic, and 5.3% were toxic. The pediatric age group had a higher ratio of toxic levels for the four drugs studied (54.5%). Conclusions Tests for lithium, valproic acid, carbamazepine, and digoxin would not be considered sufficient for TDM. Multidisciplinary teamwork might be appropriate for further implementation and interpretation of TDM.

Superior Optic Vein Thrombosis Related to Orbital Cellulitis Secondary to Aquatic Injury.

A 52-year-old woman presented with orbital cellulitis and sixth cranial nerve palsy as a result of striking the tail of a stingray while swimming. Her ophthalmologic and neurologic examination showed injury of the conjunctiva, corneal abrasion without mention of foreign body, contusion of the eyelid, and isolated lateral gaze palsy and ptosis in the right eye. Orbital magnetic resonance (MR) imaging and MR venography showed orbital cellulitis, superior and lateral rectus edema, and thrombosis of the superior ophthalmic vein on the right eye. She was treated appropriately, and her physical examination showed significant improvement within three months.

Sertraline in combination with sorafenib: A promising pharmacotherapy to target both depressive disorders and hepatocellular cancer.

INTRODUCTION: Hepatocellular carcinoma (HCC) is found within the first five most common tumors worldwide. Sorafenib is an approved agent in HCC treatment. Sertraline is a selective serotonin reuptake inhibitor. The aim of the study is to investigate the combination of sertraline and sorafenib at hepatocellular cancer cell proliferation and death. METHODS: HepG2 cells were treated with drugs and viability test XTT was performed. Cells were stained with hematoxylin and eosin for histological examination or with anti-Bcl-2 antibody and Hoechst 33258 for immunofluorescence. RESULTS: Viability results supported dose-dependent antiproliferative effect for both sertraline and sorafenib. Microscopic evaluation of stained cells exerts morphological changes. DISCUSSION: This is the first study to show that sorafenib and sertraline have synergistic effect in hepatocellular cancer.

Rational drug use for acute bronchiolitis in emergency care.

Uysalol M, Haslak F, Özünal ZG, Vehid H, Uzel N. Rational drug use for acute bronchiolitis in emergency care. Turk J Pediatr 2017; 59: 155-161. Despite the large variety of inhaled treatment options of acute bronchiolitis, there is no generally agreed treatment regime. This study aimed to determine the most appropriate treatment option. This was a double-blind randomized prospective clinical trial and has been performed in emergency department. The mean age of the 378 infants included in the study was 7.63 ± 4.6 months, and 54.8% (207) were boys. Patients were randomized by using the lottery method for simple random sample into 5 different treatment options; 3% hypertonic saline, nebulized adrenaline, nebulized adrenaline mixed with 3% hypertonic saline, nebulized salbutamol, and as control group; normal saline (0.9% NaCl). From the first treatment time until discharge time; treatment durations, adverse events and readmission rates within the first fifteen days were recorded for each patient. Nebulized adrenaline mixed with 3% hypertonic saline, as compared with other options, were associated with a significantly higher discharge rate at 4th hours (p < 0.001) and shorter length of hospital stay (p=0.039). However, there was no significant difference between options with regard to adverse events, discharge rates at 24th hours, and readmission rates within the first fifteen days. The superiority of discharge rates at 4 hours of nebulized adrenaline mixed with 3% hypertonic saline, was evaluated as `better acute response` and can be helpful to reduce hospitalization needs. Additionally, this option seems to be more effective to reduce length of hospital stay.

Evaluating the relationship of blood pressure, plasma angiotensin peptides and aldosterone with cognitive functions in patients with hypertension.

Renin Angiotensin Aldosterone System (RAAS) plays an important role in the development of hypertension. On the other hand, hypertension is a well-known and independent risk factor for cognitive impairment. The aim of the present study was to evaluate the relationship of blood pressure control, plasma angiotensin peptides and aldosterone with cognitive functions. Forty-one patients who were under treatment with the same antihypertensive medications for at least three months were included in the study. Plasma angiotensin II, angiotensin 1-7, angiotensin IV, and aldosterone concentrations were analyzed using an enzyme-linked immunosorbent assay (ELISA). Standardized Mini Mental State Examination (SMMSE) was used to evaluate cognitive functions. When the participants were grouped according to their SMMSE scores (cut-off value: 26 points), we determined significant differences between systolic blood pressure (SBP) levels, diastolic blood pressure levels, plasma angiotensin II and angiotensin 1-7 concentrations of the groups. When the participants were stratified according to their SBP levels (cut-off value: 140 mm Hg), we found significant differences in SMMSE scores and plasma angiotensin IV concentrations of the groups. A negative correlation between SBP and SMMSE scores and strong linear correlations among angiotensin peptides levels were determined. The relationship found between SBP and SMMSE in the present study was compatible with the literature. Our 33 patients were using at least one angiotensin II receptor blocker (ARB). Regarding AT1 receptor blockage, the significant association between higher SMMSE scores and increased angiotensin peptides may support a finding that ARBs prevent dementia and improve cognitive function. Further larger studies are needed to confirm and prove the relation of RAAS biochemical parameters with cognitive function.

Antimuscarinic-induced convulsions in fasted mice after food intake: No evidence of spontaneous seizures, behavioral changes or neuronal damage.

Prolonged or repeated seizures have been shown to cause spontaneous recurrent seizures, increased anxiety­related behavior, locomotor hyperactivity, impaired functions of learning and memory, and neuronal damage in the hippocampus and other brain regions in animals. Mice and rats treated with antimuscarinic drugs after fasting for two days or less develop convulsions after being allowed to eat ad libitum. To address whether such behavioral and neuroanatomic changes occur following these convulsions, mice treated i.p. with saline (control) or 2.4 mg/kg atropine and given food after 24 h of fasting were grouped according to seizure scores for behavioral and histological analysis. Following convulsions, the occurrence of spontaneous recurrent seizures was observed for 30 days. Motor activity and grooming behavior were assessed in the open field, and memory was assessed using the novel object recognition test 4 and 7 days after onset of convulsions, respectively. Animals allocated for the histological analysis were decapitated 7 days after onset of convulsions and hippocampal slices were evaluated for the percentage of degenerating neurons stained with Fluoro­Jade C. Spontaneous recurrent seizures, locomotor alterations, anxiety­related behavior, memory impairment, and neuronal loss in the granular layer of the dentate gyrus were not detected in the animals with seizure score 1-2 or 3-5. These results are in accordance with those related to the absence of behavioral changes, cognitive deficits, and hippocampal neuronal damage after single brief seizures in animals and patients with epilepsy.

Effect of Breast Milk Calcium and Fluidity on Breast Cancer Cells: An In Vitro Cell Culture Study.

AIM: The aims of this study were to investigate the effects of calcium at the same concentration as that found in human milk on the viability, proliferation, and adhesion of MCF-7 human breast ductal carcinoma cells by exposing them to calcium at the same frequency as in breastfeeding. MATERIALS AND METHODS: High-concentration calcium was applied for 30 minutes every 4 hours for 24, 48, and 72 hours. Cell proliferation and viability were measured using a hemocytometer and the MTT cell viability assay. The effects of calcium treatment were evaluated by a comparison among a multiple-, single-dose calcium treatment, and a control group. RESULTS: We show that calcium at the same concentration as that in milk caused a decrease in the number of cells but did not affect cell viability. CONCLUSIONS: The results of this study suggest that calcium caused a lowering of the number of cells from the luminal surface of the breast by triggering proliferation under the condition of fluidity. Calcium and fluidity together serve to eliminate breast cancer stem cells during the lactation period. Effects of the other components of milk can be analyzed by the new method developed in this study.

Effect of metformin on the human T98G glioblastoma multiforme cell line.

Metformin is a guanidine derivative found in Galega officinalis that is commonly used to treat diabetes mellitus. The mechanism of action of metformin involves regulation of the adenosine monophosphate-activated protein kinase/mammalian target of rapamycin signaling pathway, which is implicated in the control of protein synthesis and cell proliferation. This led to the hypothesis that metformin reduces the risk of cancer and slows tumor growth. Thus, in the present study, the effectiveness of metformin as an antiglioma agent was evaluated using the human T98G glioblastoma multiforme cell line. The viability of the T98G cells was assessed using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Apoptosis was monitored by measuring caspase-3 levels, as well as by terminal deoxynucleotidyl transferase dUTP nick end labeling and staining with acridine orange and ethidium bromide. The results demonstrate that metformin reduced cell viability and caused apoptotic morphological changes in the T98G cells. Furthermore, the caspase-3 levels in the metformin-treated T98G cells were higher than those in the control cells. Metformin induced apoptosis in the T98G cell line in a concentration-dependent manner. Metformin may provide an important contribution to the treatment of glioblastoma multiforme.

Comparison of the effect of intravitreal bevacizumab and intravitreal fasudil on retinal VEGF, TNFα, and caspase 3 levels in an experimental diabetes model.

AIM: To evaluate the influence of an intravitreal injection of bevacizumab and fasudil on the retinal vascular endothelial growth factor (VEGF), tumor necrosis factor alpha (TNFα), and caspase 3 levels in a diabetic rabbit model. METHODS: The study included 6 healthy rabbits (Group 1), 6 rabbits with experimentally induced diabetes mellitus (DM) (Group 2), 7 rabbits with experimentally induced DM to which intravitreal bevacizumab was administered (Group 3), and 7 rabbits with experimentally induced DM to which intravitreal fasudil was administered (Group 4). An intravitreal injection of 1.25mg/50µL bevacizumab in the right eye of rabbits in Group 3 and an intravitreal injection of 0.0064mg/50µL fasudil in the right eye of rabbits in Group 4 were administered on day 21 after the induction of DM. The studied eyes of the rabbits were enucleated three days after the intravitreal injection. The TNFα, VEGF, and caspase 3 levels were determined using the ELISA method. RESULTS: There was a statistically significant difference in the VEGF and caspase 3 levels between groups (P=0.005 and P =0.013, respectively), but the TNFα level did not differ significantly between groups (P=0.792). It was found that VEGF levels were significantly lower in Group 1 and Group 3 than in Group 2 using the Mann-Whitney U test with the Bonferroni correction (P=0.004 for both comparison). There was no statistically significant difference between other groups with regard to VEGF levels (the P value ranged between 0.015 and 0.886). Although the P values of the caspase 3 levels were 0.015 for Group 1 and Group 4, 0.038 for Group 2 and Group 3, and 0.018 for Group 3 and Group 4, these P values remained above the threshold P value of 0.0083, which was the statistically significant level for post hoc tests. CONCLUSION: An intravitreal injection of bevacizumab decreased both the VEGF level, which plays a role in angiogenesis, and the caspase 3 level, which plays a role in apoptosis. Although not as effective as bevacizumab, fasudil had a beneficial effect on the VEGF levels but significantly increased the caspase 3 levels.

Renin inhibitors in diabetes and hypertension: an update.

The coexistence of hypertension and diabetes increases the incidence of cardiovascular events and long-term morbidity and mortality. Blood pressure should be controlled with the most appropriate drugs as well as tight blood glucose control in patients with diabetes and hypertension. RAAS (Renin Angiotensin Aldosterone System) blockers have an important role in the treatment of these patients, in this sense, ACEi and ARB remained the major treatment option in hypertension guidelines. The most recent RAAS blocker to be approved by the FDA was aliskiren in 2007, a renin inhibitor. Studies showed that aliskiren is as effective as other antihypertensive drugs and has a safety profile similar to placebo. The potent renin inhibitor aliskiren directly inhibits the RAAS system at its rate limiting step and differently from other RAAS blockers; it decreases plasma renin activity (PRA). Although the relationship of increased PRA levels and cardiovascular risk has been shown, it is unclear if the PRA decrease provided by aliskiren has an impact on clinical outcomes and cardiovascular endpoints. On the other hand, large trials like ASPIRE, AVANT-GARDE, ALTITUDE, ASTRONAUT, which investigated the combination of aliskiren with other RAAS blockers, failed to show the expected outcomes or resulted with an increased incidence of adverse effects, which raised more questions. As a result of the ALTITUDE trial, combination of aliskiren with an ACEi or ARB is not recommended in patients with hypertension and diabetes, or at least moderate renal dysfunction. Trials designed to prove aliskiren's efficacy in new indications like diabetes, may face similar problems related to dual RAAS blockade because in the majority of cases, the optimal treatment is achieved with an ACEi or ARB. In this conjuncture, the increase in adverse events seen with aliskiren might be related to dual RAAS blockade rather than aliskiren directly. For instance, it is unclear whether the adverse event incidence would be the same, less, or higher if ALTITUDE was designed to investigate ACEi and ARB combination without aliskiren. In fact, every new molecular entity and mechanism of action faces the same barriers. For the time being, differentiating points like PRA lowering effects as an add-on therapy to calcium channel blockers or hydrochlorothiazide, and the populations that might have additional benefit, should be carefully investigated.

Scopolamine-induced convulsions in fasted mice after food intake: the effect of duration of food deprivation.

It has been shown that mice and rats treated with antimuscarinic drugs, scopolamine or atropine, after fasting for 48 h develop convulsions soon after refeeding. The present study was performed to evaluate whether mice also develop convulsions after being deprived of food for 1-24 h. The effect of day-night fasting on the development of convulsions was also determined in 12-h deprived animals. Mice were deprived of food for periods of 1, 2, 3, 6, 9, 12, 18, 24, and 48 h. Animals fasted for 12 h during the day or night were deprived of food at 08:00 or 20:00 h, respectively. At the time of testing, animals were treated with intraperitoneal (i.p.) saline or 3 mg/kg scopolamine. Twenty minutes later, they were given food and allowed to eat ad lib. All animals were observed for 30 min for the incidence and onset of convulsions. Fasted animals treated with scopolamine developed clonic convulsions after food intake. Incidence of convulsions was significant in 2-, 3-, 12-, 18-, 24-, and 48-h deprived animals. Convulsions observed after deprivation of food for 12 h during the day or at night were almost similar in both regimens. Our results indicate that food deprivation itself, rather than its duration, seems to be the principal factor in the development of these convulsions.