Administration Of Theophylline Research Articles

Pre-mating administration of theophylline could prevent the transgenerational effects of maternal morphine dependence on offspring anxiety behavior: The role of dopamine receptors

Opioid addiction causes some molecular alterations in the brain reward pathway, such as changes in gene expression that may be transferred to the next generation via epigenetic mechanisms such as histone acetylation. This study aimed to evaluate the effect of theophylline as an HDAC (Histone deacetylases) activator on D1 and D2 dopamine receptor expression in the nucleus accumbens (NAc) and anxiety behavior in the offspring of morphine-dependent female rats. Female rats were exposed to escalating doses of morphine for six days and were then treated with theophylline (20 mg/kg) or saline for 10 days before mating with normal male rats. Male and female offspring were tested for anxiety behavior using an elevated plus maze apparatus. Besides, the expression of D1 and D2 dopamine receptors in the NAc was evaluated by real-time PCR (polymerase chain reaction). Results showed that offspring of morphine-dependent female rats had increased expression of both D1 and D2 receptors in the NAc, as well as decreased anxiety behavior, compared to control offspring. However, the mentioned effects were returned to normal levels in the offspring whose morphine-dependent mothers had received theophylline for 10 days before mating. It is concluded that theophylline may be therapeutically effective in minimizing the adverse consequences of maternal morphine dependence on offspring behavior by restoring normal dopamine receptor expression levels and modulating anxiety. To completely comprehend the underlying mechanisms of this phenomenon, more research is required.

Caffeine dosing regimens in preterm infants with or at risk for apnea of prematurity.

Caffeine dosing regimens in preterm infants with or at risk for apnea of prematurity.

Oral Ergotamine versus Theophylline as Treatment of Post-dural Puncture Headache (PDPH) in Cesarean Section: A Randomized Clinical Trial

Introduction: Post Dural Puncture Headache is (PDPH) a relatively common complication of spinal anesthesia. This study aimed to compare the effect of oral administration of ergotamine and theophylline on PDPH in patients undergoing a cesarean section. Materials and Methods: This clinical trial was performed on 60 parturients undergoing cesarean section with PDPH. A tablet of theophylline (100 mg) or methyl ergotamine C (1 mg plus 100 mg caffeine) every 8 hours for 24 hours was administered randomly to patients referred to the hospital with PDPH. Using a checklist, demographic information, history of previous PDPH, number of punctures and intensity, location, and onset time of headache were collected. Intensity and duration of PDPH in the first 24 hours after surgery were the primary outcomes and nausea, vomiting, and vertigo were considered secondary outcomes. The intensity of the headache was assessed using Visual Analog Scale (VAS) before and within the first 24 hours after drug administration. Results and Discussion: In both groups, the VAS of headache significantly decreased at 2, 8, and 24 hours after administration of theophylline and ergotamine compared to pre-intervention time (theophylline from 8.6 ± 1.1 to 0.2 ± 0.1 and ergotamine from 8.6 ± 1.5 to 0.4 ± 0.2). However, the intensity of headaches was not different between the two groups at 2, 8, and 24 hours after the intervention. Duration of headache was similar in both groups (15.7 ± 5.9 in the theophylline group versus 17.5 ± 14.2 ergotamine group). In terms of secondary outcomes of nausea, vomiting, and vertigo, both groups were comparable. Conclusion: Oral administration of theophylline and ergotamine are similarly effective in reducing PDPH in cesarean sections. Clinical Trial Registration Number: IRCT20120915010841N14.

Theophylline Attenuates BLM-Induced Pulmonary Fibrosis by Inhibiting Th17 Differentiation.

Idiopathic pulmonary fibrosis (IPF) is a chronic and refractory interstitial lung disease. Although there are two approved drugs for IPF, they were not able to completely cure the disease. Therefore, the development of new drugs is required for the effective treatment of IPF. In this study, we investigated the effect of theophylline, which has long been used for the treatment of asthma, on pulmonary fibrosis. The administration of theophylline attenuated the fibrotic changes of lung tissues and improved mechanical pulmonary functions in bleomycin (BLM)-induced pulmonary fibrosis. Theophylline treatment suppressed IL-17 production through inhibiting cytokines controlling Th17 differentiation; TGF-β, IL-6, IL-1β, and IL-23. The inhibition of IL-6 and IL-1β by theophylline is mediated by suppressing BLM-induced ROS production and NF-κB activation in epithelial cells. We further demonstrated that theophylline inhibited TGF-β-induced epithelial-to-mesenchymal transition in epithelial cells through suppressing the phosphorylation of Smad2/3 and AKT. The inhibitory effects of theophylline on the phosphorylation of Smad2/3 and AKT were recapitulated in BLM-treated lung tissues. Taken together, these results demonstrated that theophylline prevents pulmonary fibrosis by inhibiting Th17 differentiation and TGF-β signaling.

The use of near-infrared spectroscopy in the acute phase of hypoxic-ischemic encephalopathy in newborns

Detection of new markers of renal hypoperfusion in full-term infants during therapeutic cooling in moderate or severe hypoxic-ischemic encephalopathy to prevent the progression of acute kidney injury (AKI). Aim. To evaluate the significance of using continuous peripheral NIRS monitoring in full-term infants with hypoxic-ischemic encephalopathy for early detection of renal hypoperfusion against the background of prophylactic use of methylxanthines. Materials and methods. A prospective randomized controlled trial was conducted from 2019 to 2022 on the basis of the Neonatal Intensive Care Department of the Zaporizhzhia Regional Clinical Children’s Hospital. We included 50 full-term infants who underwent a program of total therapeutic hypothermia for moderate or severe hypoxic-ischemic encephalopathy. The infants were divided into 2 groups, each receiving methylxanthine to prevent the progression of AKI. Continuous NIRS monitoring of renal and brain tissues was performed throughout the cooling phase and until the end of the warming period. The relationship between NIRS and the development of AKI, which was determined according to the modified neonatal scale KDIGO (2012) by increasing serum creatinine and decreasing urine output during the first 5 days, was studied. Results. NIRS monitoring revealed that changes in cerebral CrSO2 were observed somewhat earlier than renal RrSO2, as the kidneys were less susceptible to autoregulation and perfusion changes than the brain. The level of CrSO2 was identical in 2 groups and did not change after the administration of caffeine citrate or theophylline. The average peripheral renal saturation rates were slightly higher than CrSO2 and tended to increase during the observation period due to the development of renal reperfusion after hypoxia. While the level of renal oxygen extraction decreased. The results obtained indicated that the warming period was characterized by normalization of perfusion, increase in regional renal saturation and decrease in renal oxygen excretion. In general, acute kidney injury in stage I developed in 4 (8.00 %) newborns, and stage II – in 1 (2.00 %), which was equivalent in both study groups (P = 0.8009; U = 299.00). Instead, the other children had stage 0 – 45 (90.00 %). None of the neonates had stage III according to KDIGO (2012) and required renal replacement therapy. Conclusions. The combined use of methylxanthines and the maintenance of optimal postnatal hemodynamics through NIRS diagnostics are vital for the prevention and treatment of acute kidney injury in neonates with moderate or severe hypoxic-ischemic encephalopathy.

Theophylline Use to Prevent Permanent Pacing in the Contemporary Era of Heart Transplantation: The Rotterdam Experience.

IntroductionSinus node dysfunction and atrioventricular conduction disorders occur increasingly after orthotopic heart transplantation (HTX) due to aging donors and may require permanent pacemaker (PM) implantation. Theophylline has been used in the past in selected cases as an alternative to PM implantation.PurposeThe aim of this study was to investigate the rate and success of oral theophylline administration after orthotopic heart transplantation preventing permanent PM implantation.MethodsWe included all patients treated with theophylline post HTX due to bradyarrhythmia's in our center from January 1985 to January 2020. Data was obtained retrospectively through electronic patient files. Re-transplants and patients who died within 1 month post HTX were excluded from the analysis.ResultsOf the total of 751 heart transplant recipients, 73 (9,7%) patients (mean age 46 ± 15.2 years; 73% male) were treated with theophylline for bradyarrhythmia's early post HTX. Of these patients, 14 (19%) patients needed a permanent PM during hospitalization and 10(14%) patients stopped using theophylline because of adequate heart rhythm. In the end, 49 (6.5% of the total) patients were discharged with a theophylline (mean maintenance doses of 354 ± 143 mg). At the outpatient clinics, additional 6 (12%) patients needed a PM within 7 months after discharge, with the rest stable sinus rhythm.ConclusionIn this retrospective data analyses oral theophylline remained a viable alternative to permanent PM implantations in patients post HTX with increased heart rates, facilitating the withdrawal of chronotropic support and avoiding the need of permanent PM implantation.

Theophylline Post Heart Transplantation to Prevent Permanent Pacing: The Rotterdam Experience

<h3>Purpose</h3> Sinus node dysfunction and atrioventricular conduction disorders occur increasingly after orthotopic heart transplantation (HTX) due to aging donors and may require permanent pacemaker (PM) implantation. Theophylline has been used in the past in selected cases as an alternative to PM implantation. The aim of this study was to investigate the rate and success of oral theophylline administration after orthotopic heart transplantation preventing permanent PM implantation. <h3>Methods</h3> We included all patients treated with theophylline post HTX due to bradyarrhythmia's in our center from January 1985 to January 2020. Data was obtained retrospectively through electronic patient files. Re-transplants and patients who died within one month post HTX were excluded from the analysis. <h3>Results</h3> Of the total of 751 heart transplant recipients, 73 (9,7%) patients (mean age 46+-15.2 years; 73% male) were treated with theophylline for bradyarrhythmia's early post HTX. Of these patients, 14 (19%) patients needed a permanent PM during hospitalization and 10(14%) patients stopped using theophylline because of adequate heart rhythm. In the end, 49 (6.5% of the total) patients were discharged with a theophylline (mean maintenance doses of 354+-143 mg). At the outpatient clinics, additional 6 (12%) patients needed a PM within 7 months after discharge, with the rest stable sinus rhythm. <h3>Conclusion</h3> In this retrospective data analyses oral theophylline remained a viable alternative to permanent PM implantations in patients post HTX with increased heart rates, facilitating the withdrawal of chronotropic support and avoiding the need of permanent PM implantation.

Therapeutic diminution of Interleukin-10 with intranasal theophylline administration in hyposmic patients

ObjectiveTo determine changes in nasal mucus Interleukin-10 (IL-10) before and after intranasal theophylline treatment in hyposmic patients, and the relationship of these changes to orally administered theophylline treatment. DesignIL-10 was measured in nasal mucus samples of 17 normal subjects and 39 patients with hyposmia of multiple etiologies by use of a sensitive spectrophotometric ELISA assay. Hyposmia is defined clinically by standardized evaluation of impaired olfactometry, as well as subjectively self reported by the patient. ResultsPrior to treatment, IL-10 levels in nasal mucus were increased in hyposmic patients compared to controls. Following intranasal theophylline administration, over half of treated patients experienced a decrease of nasal mucus IL-10 toward control levels, correlated with a significant improvement in taste and smell function. Patients who increased with intranasal administration, similar to previously reported oral administration, showed no significant improvement in taste or smell function. ConclusionsNasal mucus IL-10 decreased in patients treated with intranasal theophylline. Mechanisms of action include phosphodiesterase and nuclear factor kappa-B inhibition, correlated with an improvement in both olfaction and gustation. IL-10 is induced by therapeutic and systemic administration of theophylline as with oral dosage, but reduced by lower and localized treatment.

Regadenoson stress CMR: safety, feasibility and hemodynamic response

Abstract Background and objectives The use of regadenoson for stress cardiac magnetic resonance (CMR) has potential advantages over other vasodilators. We sought to evaluate the safety, feasibility and hemodynamic response (heart rate and blood pressure) of regadenoson in an unselected population undergoing stress CMR for clinical work-up. Methods A total of 603 regadenoson stress CMR clinical examinations performed between May 2017 and May 2020 in our institution were retrospectively reviewed. Studies were performed using a conventional stress/rest CMR protocol with a 1.5T MRI scanner. A fixed dose of 5 ml of regadenoson was employed as stressor. As part of the protocol, 200 mg of theophylline was administered between stress and rest acquisitions to reverse the vasodilator effect of regadenoson. Adverse events, clinical symptoms, and hemodynamic response were assessed. Results In our cohort, no severe adverse events requiring hospitalization were observed, and only 5 adverse events were reported (0.83%). Only two patients (0.3%) did not complete the test due to adverse events or symptoms related to regadenoson administration (one case presented severe hypotension; the other presented unbearable chest pain). There were no cases of bronchospasm, stress-induced arrhythmia or death. Over half of patients reported mild symptoms after drug administration (52%, n=314), more frequently dyspnea (19%, n=112), chest pain (18%, n=106) and flushing (6%, n=34). All symptoms resolved after theophylline administration. Overall, an increase in heart rate (mean increase and (standard deviation) = 24 (12.6) bpm and a mild decrease in systolic (−8.2 (17.1) mmHg) and diastolic (−4.9 (10.2) mmHg) blood pressure were observed as response to regadenoson. A blunted heart rate response was observed in elderly (p&amp;lt;0.01), diabetic (p&amp;lt;0.01) and obese (p=0.01) patients. Only 46 patients (7.8%) did not show tachycardization response. Conclusions The use of regadenoson in stress CMR proved to be safe and feasible in the vast majority of patients. Adverse events were not frequent with regadenoson and symptoms were transient and well tolerated, while premature ending of the test related to drug administration was very rare. Funding Acknowledgement Type of funding sources: None. Hemodynamic response

The risk of development of acute kidney injury in full-term infants with administration of methylxanthines

Exploring new possibilities for the use of methylxanthines to prevent the development of acute kidney injury (AKI) in full-term infants with perinatal asphyxia. Aim: to evaluate the efficacy and safety of methylxanthines in full-term infants for the prevention and conservative treatment of acute kidney injury. Materials and methods. To test the effectiveness of the proposed method of AKI treatment, 38 infants were chosen and divided into 2 groups by random selection. Nursing and intensive care were according to current legislation (Order of the Ministry of Health of Ukraine No. 225 of March 28, 2014). The main group (n = 20) received therapy with caffeine citrate, the comparison group (n = 18) – theophylline. Both of these drugs were used to prevent the development of acute kidney injury – stage II and III according to KDIGO. Results. A significant difference in serum creatinine was found in the main group - the level of serum creatinine was higher than in the comparison group, but did not exceed the physiological norm. GFR on the 3rd day of life was higher with administration of theophylline, but in the group of caffeine did not exceed the reference values of the norm. No differences between urea levels and diuresis rates were found in the groups. The initial results indicate the lack of statistical significance when using various drugs of the methylxanthine group, namely theophylline and caffeine citrate. This is explained by the fact that in the main group 65.00 % (n = 13) of patients had AKI stage 0 according to KDIGO, and 35.00 % (n = 7) had stage I. In the comparison group, 55.56 % (n = 10) and 44.44 % (n = 8), respectively. Stages II and III in both groups of the study did not develop, the obtained data are equivalent – U = 163,00; P = 0,6296. However, the use of caffeine citrate may become a priority due to a better safety profile compared to theophylline. Caffeine is less likely to cause adverse effects in the form of non-pathological bile vomiting and has significantly lower relative risk of non-pathological bile vomiting in infants (RR 0.26 (95 % CI 0.10; 0.66)). Conclusions. Conservative methylxanthine therapy in full-term infants with perinatal asphyxia prevents the development of stages II and III of AKI according to KDIGO. However, it is necessary to continue the collection of material to increase the statistical significance, as well as to study the early and long-term consequences of this therapy.

Therapeutic Induction of Interleukin-10 by Theophylline Administration for the Treatment of Hyposmia

Therapeutic Induction of Interleukin-10 by Theophylline Administration for the Treatment of Hyposmia

Antinociceptive effect of the hydroethanolic leaf extract of Calotropis procera (Ait) R. Br. (Apocynaceae): Possible involvement of glutamatergic, cytokines, opioidergic and adenosinergic pathways

Ethnopharmacological relevancePain remains real and still a major problem in clinical medicine which requires new agents with improved efficacy for more therapeutic benefits. Plant sources can serve as a basis for the search for some novel drugs hence the analgesic effects of the hydroethanolic extract of Calotropis procera (CPE) which is widespread in Ghana and other tropical areas and used in folkloric medicine for painful and inflammatory conditions was evaluated. Materials and methodsThe analgesic properties of orally administered CPE at doses of 30, 100, and 300 mg/kg were evaluated in thermal (tail immersion), chemical (acetic acid-writhing, formalin-induced paw licking, glutamate-induced nociception) and mechanical (Randall-Selitto) tests for analgesia. The involvement of tumour necrosis factor-alpha (TNF-α), interleukin 1β (IL 1β), bradykinin, and prostaglandin E2 (PGE2) on the analgesic effects of CPE were also evaluated in hypernociception assays measuring mechanical pain thresholds. ResultsThe latency of tail withdrawal in the tail immersion test was significantly increased (p = 0.0001) while writhing induced by acetic acid was significantly reduced (p < 0.0001) on treatment with CPE (30–300 mg/kg). The extract also significantly inhibited both phase 1 and phase 2 nociceptive states induced by formalin comparable to morphine (p < 0.0001). Furthermore, the extract significantly attenuated hyper-nociception induced by TNF-α (p < 0.0001), interleukin 1β (p = 0.0102), bradykinin (p < 0.0001), and prostaglandin E2 (p < 0.0001). Additionally, glutamate-induced paw licking was reduced significantly (p < 0.05). The antinociceptive effects exhibited by CPE (100 mg/kg) in the formalin test was reversed by systemic administration of naloxone (2 mg/kg) and theophylline (5 mg/kg) but not glibenclamide (8 mg/kg), granisetron (2 mg/kg), atropine (3 mg/kg), yohimbine (3 mg/kg, p.o.) nor nifedipine (10 mg/kg). ConclusionOverall, the hydroethanolic leaf extract of Calotropis procera possesses analgesic properties that is mediated possibly through the glutaminergic, opioidergic, and adenosinergic pathways.

The Effect of Perioperative and Postoperative Theophylline Administration on Inflammation in Patients Undergoing Pediatric Open-Heart Surgery

Introduction: The aim of this study was to evaluate the effects of intraoperative and postoperative theophyl- line infusion on inflammation in children who underwent open heart surgery with cardiopulmonary bypass (CPB) for congenital heart diseases. Patients and Methods: This randomized controlled study was carried out with 140 children who underwent open heart surgery with CPB in a tertiary hospital. The patients were randomly enrolled into two groups (the- ophylline group= 70, control group= 70). Following the induction of anesthesia, theophylline infusion was applied to theophylline recipients from the beginning of the operation to the end of the 24th hour after surgery via a central venous catheter (CVC). The patients in the control group were infused with 0.9% NaCl solution at the same volume and duration via CVC. Results: Postoperative red blood cell distribution width was significantly higher than preoperative values in the theophylline group (p= 0.003), but no significant difference was found in the control group (p= 0.188). In both groups, postoperative vasoactive-inotropic scores, and lymphocyte and platelet counts were lower than preoperative measurements (p&lt; 0.001 for each in both groups). While preoperative white blood cell counts were similar, postoperative values were found to be lower in the theophylline group (p= 0.022). Conclusion: In pediatric patients undergoing open heart surgery with CPB, the use of intraoperative and post- operative theophylline may be effective in reducing postoperative inflammation, as demonstrated by lower white blood cell counts; but it does not significantly affect other clinical features.

Trapping Acrolein by Theophylline/Caffeine and Their Metabolites from Green Tea and Coffee in Mice and Humans.

Acrolein (ACR) is found exogenously as a widespread environmental pollutant and endogenously, where it is thought to be involved as a pathogenic factor in the progression of many pathological conditions. Eliminating ACR by dietary-active substances has been found to be one potential strategy to prevent ACR-associated chronic diseases. This study first compared the scavenging ACR efficacy of four purine alkaloids, theophylline (TP), paraxanthine (PXT), theobromine (TB), and caffeine (CAF), and then, TP, CAF, and their metabolites were investigated for their ability to trap ACR in vivo. Our results indicated that TP, which possesses an -NH moiety at the N-7 position, exhibits the best ACR-trapping capacity in vitro, while CAF has a slight ability to trap ACR due to the substitutions by -CH3 at the N-1, N-3, and N-7 positions. After oral administration of TP or CAF, the ACR adducts of TP and the metabolites of TP or CAF (e.g., mono- and di-ACR-TP, mono-ACR-1,3-DMU, and mono-ACR-1-MU) were detected in urinary samples obtained from both TP- and CAF-treated mouse groups by using ultra-performance liquid chromatography-tandem mass spectrometry. The quantification studies demonstrated that TP and its metabolites significantly trapped ACR in a dose-dependent manner in vivo. Furthermore, we also detected those ACR adducts of TP and TP/CAF's metabolites in human urine after four cups of green tea (2 g tea leaf/cup) or two cups of coffee (4 g coffee/cup) were consumed per day. Those results indicated that dietary TP or CAF has the potential capacity to scavenge ACR in vivo.

Anti-nociceptive Effect of Euphorbia hirta Leaf Extract: Involvement of Adenosine, Cholinergic, and Opioid Receptors.

The study was designed to investigate the anti-nociceptive activity of Euphorbia hirta leaf and its possible mechanism of action. The extract of Euphorbia hirta obtained from the leaf was prepared as per standard procedures and evaluated at the three doses (300, 600, and 1200 mg/kg, i.p). The extract was screened for anti-nociceptive activity using heat-induced (tail-flick) and chemical-induced (acetic acid-induced writhing and formalin-induced paw lick) nociception models in mice. The possible mechanism of action of the extract was evaluated using antagonists of notable nociceptive pathways. Intraperitoneal administration of Euphorbia hirta extract at the doses of 600 and 1200 mg/kg significantly (p<0.05) reduced the formalin-induced paw licking in both neurogenic and inflammatory phases of the test. While administration of the extract at the dose of 300 mg/kg significantly inhibited the pain due to formalin in the inflammatory phase but not in the neurogenic phase. The anti-nociceptive effect of Euphorbia hirta extract increased the reaction time to thermal stimulus, also inhibited the acetic acid-induced writhing dose-dependently. The antinociceptive effect exhibited by Euphorbia hirta extract in the formalin test was reversed by the administration of naloxone, theophylline, and atropine. Glibenclamide, nifedipine, and yohimbine, however, did not significantly block the anti-nociceptive effect of the extract. Meanwhile, methylene blue administration enhanced the anti-nociceptive effect of the extract. The results indicated that Euphorbia hirta extract produces a dose-related antinociceptive effect in several models of chemical and thermal pain, through mechanisms that might involve interaction with adenosine, cholinergic, and opioid receptors.

Theophylline as an Add-On to Thrombolytic Therapy in Acute Ischemic Stroke: A Randomized Placebo-Controlled Trial.

Delayed recanalization increases the risk of infarct growth and poor clinical outcome in acute ischemic stroke. The vasoactive agent theophylline has shown neuroprotective effects in animal stroke models but inconclusive results in case series and randomized clinical trials. The primary objective of this study was to evaluate whether theophylline, as an add-on to thrombolytic therapy, is safe and effective in acute ischemic stroke patients. The TEA-Stroke trial (The Theophylline in Acute Ischemic Stroke) was an investigator-initiated 2-center, proof-of-concept, phase II clinical study with a randomized, double-blinded, placebo-controlled design. The main inclusion criteria were magnetic resonance imaging-verified acute ischemic stroke, moderate to severe neurological deficit (National Institutes of Health Stroke Scale score of ≥4), and treatment with thrombolysis within 4.5 hours of onset. Participants were randomly assigned in the ratio 1:1 to either 220 mg of intravenous theophylline or placebo. The co-primary outcomes were early clinical improvement on the National Institutes of Health Stroke Scale score and infarct growth on magnetic resonance imaging at 24-hour follow-up. Theophylline as an add-on to thrombolytic therapy improved the National Institutes of Health Stroke Scale score at 24 hours by mean 4.7 points (SD, 5.6) compared with an improvement of 1.3 points (SD, 7.5) in the control group (P=0.044). Mean infarct growth was 141.6% (SD, 126.5) and 104.1% (SD, 62.5) in the theophylline and control groups, respectively (P=0.146). Functional independence at 90 days was 61% in the theophylline group and 58% in the control group (P=0.802). This proof-of-concept trial investigated theophylline administration as an add-on to thrombolytic therapy in acute ischemic stroke. The co-primary end points early clinical improvement and infarct growth at 24-hour follow-up were not significantly different after post hoc correction for multiplicity (Bonferroni technique). The small study size precludes a conclusion as to whether theophylline has a neuroprotective effect but provides a promising clinical signal that may support a future clinical trial. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: EudraCT number 2013-001989-42.

Safety of regadenoson with theophylline reversal during dynamic computed tomography perfusion and magnetic resonance imaging in patients with coronary artery disease.

The use of regadenoson in dynamic computed tomography perfusion (CTP) and magnetic resonance myocardial perfusion imaging (MR MPI) is off‑label. The study aimed to assess the safety of regadenoson with theophylline reversal during CTP and MR MPI in patients with coronary artery disease (CAD). In this prospective study, patients with 1 or more intermediate coronary artery stenoses on computed tomography angiography underwent CTP and MR MPI with 0.4 mg of regadenoson. After examinations, 200 mg of theophylline was given intravenously in 100 ml of saline. Changes in blood pressure (BP) and heart rate (HR) were repeatedly assessed. All side effects and adverse events were recorded. Out of 106 examinations in 53 patients (25 females, 63.5 [8.5] years), all were diagnostic. There were no deaths, myocardial infarctions, severe arrhythmias, high‑grade atrioventricular blocks, or bronchospasms. The most common symptoms were palpitations (17%), hot flushing (8%), chest discomfort (4%), and mild dyspnea (3%). There were no differences between baseline and peak BP. There was an increase in median (interquartile range) peak HR after regadenoson as compared with baseline (MR MPI, 63 [59-75] bpm vs 93 [86-102] bpm; P <0.001; and CTP, 65 [60-70] bpm vs 95 [86-107] bpm; P <0.001). The hemodynamic response to regadenoson and its side effects were completely reversible by theophylline. Regadenoson may be a safe vasodilator for CTP and MR MPI in patients with CAD. The administration of theophylline after perfusion is safe and reverses side effects of regadenoson.

Potentially Inappropriate Prescriptions in Ambulatory Elderly Patients Living in Rural Areas of Romania Using STOPP/START (Version 2) Criteria.

BackgroundRational use of medications and monitoring of prescriptions in elderly patients is important to decrease the number and duration of hospitalizations, emergency medical consultations, mortality, as well as medical costs.PurposeTo identify potentially inappropriate medications (PIMs) and potential prescription omissions (PPOs), and determine their prevalence based on the Screening Tool of Older Persons’ potentially inappropriate Prescriptions (STOPP) v2 criteria and Screening Tool to Alert doctors to Right Treatment (START) v2 criteria for patients aged >65 years.MethodsThis cross-sectional study was conducted in two rural counties in Romania based on electronic prescriptions for chronic conditions (EPCCs) issued from 30 days to 90 days by a specialist or general practitioner. Collected EPCCs were evaluated by an interdisciplinary team of specialists based on 26 STOPP v2 criteria and 10 START v2 criteria.ResultsPIM prevalence was 25.80% and PPO prevalence was 41.72% for 646 EPCCs. The mean age of patients was 75 years and the mean number of drugs per EPCC was four. The most frequently identified PIMs were treatment duration (6.65%), theophylline administration (5.72%), drug indication (4.64%), cyclo-oxygenase-2 non-steroidal anti-inflammatory drugs (1.39%), and zopiclone prescription (0.77%). Statins (24.76%), beta-blockers (8.04%), and beta-2 agonist/antimuscarinic bronchodilators (5.88%) were the most frequently identified PPOs.ConclusionPPOs were more prevalent than PIMs for elderly populations living in the two rural counties in Romania we studied. Health practitioners (family physicians, specialists, and pharmacists) should focus on prophylactic and curative considerations when prescribing agents to decrease the morbidity and mortality of elderly rural Romanian patients.

Development of an RNA Virus-Based Episomal Vector Capable of Switching Transgene Expression.

Viral vectors are efficient gene delivery systems, although most of these vectors still present limitations to their practical use, such as achieving only transient transgene expression and a risk of insertional mutations. We have recently developed an RNA virus-based episomal vector (REVec), based on nuclear-replicating Borna disease virus (BoDV). REVec can transduce transgenes into various types of cells and stably express transgenes; however, an obstacle to the practical use of REVec is the lack of a mechanism to turn off transgene expression once REVec is transduced. Here, we developed a novel REVec system, REVec-L2b9, in which transgene expression can be switched on and off by using a theophylline-dependent self-cleaving riboswitch. Transgene expression from REVec-L2b9 was suppressed in the absence of theophylline and induced by theophylline administration. Conversely, transgene expression from REVec-L2b9 was switched off by removing theophylline. To our knowledge, REVec-L2b9 is the first nuclear-replicating RNA virus vector capable of switching transgene expression on and off as needed, which will expand the potential for gene therapies by increasing safety and usability.

Preparasi Teofilin dalam Pembawa Vesikular Etosom untuk Penggunaan Transdermal

Theophylline is a methyl xanthine of alkaloid derivative compound has been used as a bronchodilator in the treatment of chronic lung disorders, especially asthma. Oral administration of theophylline causes inconvenient for patients including bitter taste, narrow therapeutic range, and indigestion due to increased of gastric acid secretion. Therefore, other administration of theophylline has been developed as transdermal delivery system. This study disscused about preparation of theophylline in ethosome as vesicular carrier. Preparation of ethosome was used hot method (40oC) and cool method (30oC). Characterization of ethosomes includes observation of shape and size of vesicles by microscopic method and the vesicles were fractionated by centrifugation then entrapment efficiency (% EE) were measured by spectrophotometric method. Then optimazed theophylline that entrapped in ethosome. Based on the results, ethosomes preparation by hot method were produced Small Unilamellar Vesicle (SUV), the size were 0,0522-0,100 µm, and the highest value of % EE was 98.95%, while ethosomes preparation by cold method were produced Small Unilamellar Vesicle (SUV), the size were 0.0522-0.100 μm, and the highest value of % EE was 99.80%. The optimum concentration of theophylline was entrapped in etosom was 0.1%. It was concluded that cold method was the appropriate method for preparation of theophylline in ethosome as vesicular carrier.Keywords: Etosome, theophylline, vesicular, transdermal