Efficacy Of Theophylline Research Articles

FRI596 Randomized Clinical Trial Of Theophylline For Treatment Of Pseudohypoparathyroidism Type 1a

Abstract Disclosure: A.H. Shoemaker: None. J. Tamaroff: None. H. Jueppner: None. Background: Pseudohypoparathyroidism type 1A (PHP1A) is a rare, genetic disorder caused by heterozygous inactivating mutations involving the maternal GNAS allele, the gene that encodes the stimulatory G protein (Gsα). Due to tissue specific reduced paternal Gsα expression, several tissues, particularly proximal renal tubules and thyroid, show decreased Gsα-coupled receptor function. Resultant hormone resistances can be treated, but other aspects of PHP1A such as early-onset obesity and short stature are without effective treatment options. Gsα-coupled receptor signaling cascade begins with agonist-stimulated increase in cAMP, the second messenger which is rapidly degraded by phosphodiesterase (PDE). Given that PHP1A patients have reduced, but not completely absent, cAMP production, this clinical trial will test the hypothesis that the non-selective PDE inhibitor theophylline will improve Gsα-coupled receptor signaling. We describe the study design and baseline characteristics of PHP1A patients enrolled in a double-blind, randomized, placebo-controlled clinical trial of theophylline. Methods: A single center will enroll 34 patients. Inclusion criteria: age >=2 years old, diagnosis of PHP1A and obesity. Exclusion criteria include seizure disorder, uncontrolled hormone resistance, pregnancy, and other significant medical problems. Enrollment starts with the oldest age group (>=13 years) and safety/efficacy is reviewed by the DSMB after each block of 6 patients before opening to the next age block (7-12 and 2-6 years). Patients are randomized to theophylline vs. placebo using a permuted-block randomization (2:1) stratified by age and gender. Theophylline levels guide dosing with a goal level of 10-19 mcg/mL. Unblinded study staff review theophylline levels and the dosing protocol includes sham placebo dose adjustments. The primary outcome is change in BMI, expressed as % of the 95th %ile (BMI95), to account for age and gender. Secondary endpoints include changes in glucose tolerance and insulin secretion (insulinogenic index), rate of epiphyseal closure and hormone replacement doses. Results: To date we have screened 27 and enrolled 24 patients. Enrollment in the youngest age block (2-6 years) opened in December 2022. Enrolled patients range from 4 to 55 years old (mean 16.0 ± 10.4 years, 18 pediatric patients), 92% are female, 100% are white and 13% are Hispanic. All patients were obese with a mean BMI95 130.8 ± 23.8%. Three adult patients withdrew due to headaches, nausea/difficulty swallowing pills or travel difficulties. The most common adverse event related to study drug was transient nausea/vomiting. Conclusion: This randomized clinical trial designed to test safety and efficacy of theophylline for PHP1A is ongoing. Thus far the study drug and procedures have been safe and well tolerated. Presentation: Friday, June 16, 2023

Efficacy of theophylline in patients with syncope without prodromes with normal heart and normal ECG

BackgroundPatients affected by syncope without or with very short (≤5 s) prodrome with normal heart and normal ECG have been seen to present low plasma adenosine levels. We investigated whether chronic treatment of these patients with theophylline, a non-selective adenosine receptor antagonist, results in clinical benefit. MethodsIn a consecutive case-series of 16 patients (mean age 47 ± 25 years, 9 females) who had ECG documentation of asystolic syncope, we compared the incidence of syncopal recurrence during a period without and a period with tailored theophylline therapy. ResultsDuring a median of 60 months before ECG documentation of the index episode, the patients had a median of 2 syncopes per year. During the 6 months of the study phase without therapy, the patients had a median of 2.6 syncopes per year, p = 0.63. During the 23 months of the study phase with theophylline, the patients had a median of 0.4 syncopes per year, p = 0.005 vs history and p = 0.005 vs no therapy. In the 13 patients who had an implantable loop recorder during both study phases, the incidence of asystolic episodes > 3 s decreased from 9.6 per year to 1.1 per year, p = 0.0007. During theophylline treatment, syncope recurred in 1/5 (20%) patients who had an idiopathic atrioventricular block as the index event versus 9/11 (81%) patients who had a sinus arrest, p = 0.005. ConclusionTheophylline is effective in reducing syncopal burden in patients with syncope without prodromes with normal heart and normal ECG. Its efficacy is greater in those with idiopathic atrioventricular block.

Novel Therapeutic Options in the Management of Reflex Syncope.

Syncope is a symptom associated with a wide range of pathological conditions, ranging from benign to life threatening. The most frequent is the reflex syncope that may be challenging to treat because of the complex and partially unknown pathophysiological mechanism that has to be addressed by the chosen therapy. Head-up tilt testing is so far the only clinical test able to reproduce reflex syncope, but its diagnostic yield has been recently redefined. A new mechanism such as adenosine-sensitive syncope and idiopathic atrioventricular block have been recently described, and the appropriate therapy is not yet established. There is uncertainty on the efficacy of theophylline and on the use of cardiac pacing in these patients. Clinical trial published data and position paper from the main expert groups on fludrocortisone, midodrine, etilefrine, beta-blockers, and cardiac pacing as useful therapies for patients affected by reflex syncope. Theophylline proved in observational trials to be efficient in preventing reflex syncope recurrences in patients with documented spontaneous paroxysmal conduction disorders comparable to cardiac pacing in a subgroup of patients. Reboxetine and sibutramine may elicit a significant pressor and tachycardic effect able to delay the onset of symptoms during head-up tilt testing. Droxidopa has short-term effects on improving the symptoms because of orthostatic hypotension. Cardiac pacing is effective in preventing reflex syncope recurrences with best results when the indication for pacemaker implantation was based on the documentation of bradycardia or asystole during the spontaneous event by a cardiac monitor. External compression using elastic bandage or compressive stockings is able to prevent the decrease in blood pressure in patients with orthostatic hypotension. The optimal management of the complex diagnostic and therapeutic options can be achieved following a standardized and evidence-based approach to the patient with syncope.

Predictive Factors for Efficacy and Safety of Prophylactic Theophylline for Extubation in Infants with Apnea of Prematurity.

PurposeThis study aimed to evaluate predictive factors involved in efficacy and safety in Japanese infants who received theophylline therapy to prevent apnea of prematurity (AOP) after weaning from mechanical ventilation.MethodsWe retrospectively reviewed the medical records of infants who were administered intravenous aminophylline (theophylline ethylenediamine) for AOP at the neonatal intensive care unit, Kagoshima University Hospital, Japan, between January 2009 and June 2013.ResultsA total of 100 infants were evaluated as two separate groups in terms of efficacy and safety of theophylline. Sixty-seven (67.0%) infants had effective theophylline therapy. Multivariate logistic regression analysis showed that gestational age at birth was significant, with an odds ratio of 0.59 (p < 0.001). Receiver operating characteristic analysis showed that the cut-off value was 31.1 weeks old for predicting the efficacy of theophylline (specificity, 66.7%; sensitivity, 86.6%; p < 0.001; area under the curve, 0.750; 95% confidence interval, 0.45–0.74). Adverse reactions were identified in 21 (21.0%) infants. Multivariate logistic regression analysis showed that the number of days of theophylline administration from birth was associated with an increased risk of adverse reactions after theophylline administration (p = 0.01).ConclusionsPhysicians need to be aware of the possibility that theophylline fails to produce therapeutic effects for extubation in infants aged less than 31.1 weeks old, and adverse reactions can easily develop when theophylline is administered soon after birth.

LG-52THEOPHYLLINE IN VISION IMPAIRED CHILDREN WITH OPTIC PATHWAY GLIOMA

LG-52. THEOPHYLLINE IN VISION IMPAIRED CHILDREN WITH OPTIC PATHWAY GLIOMA Gail Halliday, Peter Ling, Michal Zapotocky, Arun Reginald, Uri Tabori, Iris Fried, Eric Bouffet, Lee Dupuis, and Ute Bartels; The Hospital for Sick Children, Toronto, ON, Canada PURPOSE: Preclinical models suggest that phosphodiesterase inhibitors may slow or prevent axonal damage to the optic nerve in mice with visual pathway glioma likely through elevation of cAMP. A feasibility study was performed to evaluate the safety and efficacy of theophylline in vision impaired children with optic pathway glioma (OPG) at risk of visual loss. METHODS: Patients were treated with theophylline for a planned duration of 12 months. Eight of the eleven patients received concurrent standard OPG chemotherapies. The initial theophylline dose was calculated based on ideal body mass and subsequently adjusted according to trough serum levels. The primary end point was safety, defined by grade 3-4 toxicity using the National Cancer Institute Common Toxicity Criteria version 4.0. Secondary end points included visual acuity response rate. RESULTS: Preliminary data analysis of eleven patients, with a median age of 9.2 years, treated with theophylline at the Hospital for Sick Children, Toronto between 2009 and 2015 is detailed here. After a mean duration of 10.5 months no grade 3-4 treatment related toxicities were identified. Of the three patients who discontinued therapy prematurely two experienced grade 1 toxicities. Three of eleven patients studied showed improvements in binocular vision whilst on theophylline therapy with a further three patients showing stabilization of vision. CONCLUSIONS: Combining theophylline with standard chemotherapies for OPG in children is safe and feasible. In a proportion of patients with progressive visual decline despite prior chemotherapy theophylline enabled stabilization or improvement in visual acuity. Phase III proof of efficacy trials are warranted. Neuro-Oncology 18:iii78–iii96, 2016. doi:10.1093/neuonc/now075.52 #The Author(s) 2016. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

The efficacy of theophylline in preventing cisplatin-related nephrotoxicity in patients with cancer

Objective: Cisplatin is a potent antineoplastic agent used and its major limiting side effect is nephrotoxicity. The aims of the study are early detection of acute kidney injury (AKI) with biomarkers and investigation of the potential nephron-protective effects of theophylline. Methods: Glomerular filtration rates (GFR), neutrophil gelatinase-associated lipocalin (NGAL), cystatin C were measured at 5th day of treatment in all of the patients. In addition, these parameters were measured repeatedly after the administration of cisplatin, at 2nd hour, 5th and 20th days. Patients: Sixty patients who are planned to receive cisplatin for the first time were included in the study. Patients were divided into two groups as Group 1 (n = 30) (standard treatment arm) and Group II (n = 30) (theophylline arm). Results: In both groups after the administration of cisplatin, GFR showed a significant decrease within time (p = 0.006). Urine NGAL levels were significantly high after 2 h of cisplatin administration (p < 0.001), no significant difference was observed between groups. However, when the time*group effects were considered together, higher NGAL levels were detected in the group not receiving theophylline (p = 0.025). After 5 days of cisplatin administration, urine protein levels were significantly higher in both groups (p < 0.001). Conclusion: Results showed that urine NGAL level is a superior biomarker compared to serum creatinine and serum cystatin C in the detection of early AKI. Theophylline was found not to bring a complete protection for the kidneys, but less nephrotoxicity was developed when compared to the group not receiving theophylline.

Bronchodilator and Anti-Inflammatory Action of Theophylline in a Model of Ovalbumin-Induced Allergic Inflammation.

Phosphodiesterases (PDEs) represent a super-family of 11 enzymes hydrolyzing cyclic nucleotides into inactive 5' monophosphates. Inhibition of PDEs leads to a variety of cellular effects, including airway smooth muscle relaxation, inhibition of cellular inflammation, and immune responses. In this study we focused on theophylline, a known non-selective inhibitor of PDEs. Theophylline has been used for decades in the treatment of chronic inflammatory airway diseases. It has a narrow therapeutic window and belongs to the drugs whose plasma concentration should be monitored. Therefore, the main goal of this study was to evaluate the plasma theophylline concentration and to determine its relevance to pharmacological effects after single and longer term (7days) administration of theophylline at different doses (5, 10, 20, and 50mg/kg) in guinea pigs. Airway hyperresponsiveness was assessed by repeated exposure to ovalbumin. Theophylline reduced specific airway resistance in response to histamine nebulization, measured in a double chamber body plethysmograph. A decrease in tracheal smooth muscle contractility after cumulative doses of histamine and acetylcholine was confirmed in vitro. A greater efficacy of theophylline after seven days long treatment indicates the predominance of its anti-inflammatory activity, which may be involved in the bronchodilating action.

Efficacy of theophylline in patients affected by low adenosine syncope

Background: Adenosine, an ATP derivative, may be implicated in some kinds of unexplained syncope. In patients with normal heart, normal ECG and recurrent sudden-onset syncope without prodromes have been shown to present with lowplasmatic adenosine levels and a high susceptibility to exogenous adenosine.The term “low-adenosine syncope” has been launched to describe this distinct clinical entity. Objectives: We decided to investigate whether chronic treatment of these patients with theophylline, a non-selective adenosine receptor antagonist, results in clinical benefit. Methods. We report on the prolonged clinical observation of 6 “low-adenosine” syncope patients (mean age 50±20 years, 4 females) treated with oral theophylline within the therapeutic range of 12-18 μg/ml. We were able to make an intrapatient comparison between a period with and a period without theophylline therapy. Results: In five patients, symptoms disappeared and the number of prolonged asystolic pauses detected by implantable loop recorder (ILR) fell impressively from a median of 1.11 per month (interquartile range 0.4 -1.8)during 13 months of no-treatment (range 2-36) to 0 per month(0-0.7) during 20 months of theophylline treatment (range 6-120). The 6th patient, was unresponsive to theophylline therapy, and a different mechanism of syncope was hypothesized. Conclusion: In this small series of highlyselected patients affected by syncope with low circulating adenosine levels, theophylline proved to be an effective therapy in most patients. The logical inference is that the adenosine pathway has a causal role in the mechanism of syncope in such patients.

Efficacy of theophylline plus salmeterol/fluticasone propionate combination therapy in patients with asthma

To compare the efficacy of theophylline plus salmeterol/fluticasone propionate combination product (SFC) with SFC plus placebo in asthmatic patients. In this randomized, stratified, parallel-group study, 325 patients were randomized to receive either 200mg theophylline plus 50/250μg SFC or placebo tablet plus 50/250μg SFC twice daily for 24 weeks. Outcome variables included the level of asthma control (assessed by the Asthma Control Test) and the number of patients experiencing ≥1 exacerbations during the 24-week treatment period. Testing of lung function as well as measurement of the levels of inflammatory markers in induced sputum was performed. There were significantly fewer patients with ≥1 asthma exacerbation in the theophylline plus SFC group (29.6%) when compared with the SFC plus placebo group (46.9%) (p=0.004). Theophylline plus SFC improved the FEF(25-75%) value, which indicates enhanced small airway function, to a greater extent than SFC plus placebo (66.9±18.8% and 57.4±17.6%, respectively; p<0.001). A significant decrease in eosinophil count and concentration of eosinophil cationic protein in induced sputum was also seen in the theophylline plus SFC group when compared with the SFC plus placebo group (4.1±2.2% and 6.3±2.7%, 63.6±39.5μg/L and 89.4±45.6μg/L, respectively; all p<0.01). The combination of theophylline plus SFC may provide greater protection against asthma exacerbations, and its administration is accompanied by significant improvements in small airway function and airway inflammation.

Anti-inflammatory effects and clinical efficacy of theophylline and tulobuterol in mild-to-moderate chronic obstructive pulmonary disease

Background The airway inflammation of chronic obstructive pulmonary disease (COPD) demonstrates a poor response to the anti-inflammatory actions of corticosteroids. However, long-acting β 2-agonists and low-dose theophylline are reported to have a possible anti-inflammatory effect in COPD. The aim of this study was to compare the effects of treatment between theophylline and the tulobuterol patch (transdermal patch preparation designed to yield sustained β 2-agonistic effects for 24 h) on airway inflammation in addition to quality of life (QOL) and pulmonary function in mild-to-moderate COPD. Methods The study subjects consisted of 26 patients with COPD who were treated with theophylline or tulobuterol for 8 weeks with a wash-out period of 4 weeks in a randomized open-label crossover study. We prospectively investigated the differential cell counts and levels of inflammatory markers in induced sputum before and after treatment with theophylline and tulobuterol. We also examined pulmonary function and quality of life (QOL) as assessed by St. George's Respiratory Questionnaire. Results In the induced sputum, the total inflammatory cell count and number of neutrophils were significantly reduced by treatment with low-dose theophylline. Neither of these parameters was significantly changed by treatment with tulobuterol. Pulmonary function measurements such as FEV 1, FEV 1 %pred, FVC, PEF, MEF 50, and MEF 25 were significantly improved by the treatment with low-dose theophylline but not tulobuterol. The total QOL scores, levels of interleukin 8 and myeloperoxidase in the supernatants of induced sputum, and serum levels of hypersensitive C-reactive protein were not significantly changed by either of the treatments. Conclusion These results suggest that treatment with low-dose theophylline but not the tulobuterol patch may have anti-inflammatory effects and improve pulmonary function in mild-to-moderate COPD.

A randomized trial of saline hydration to prevent contrast nephropathy in chronic renal failure patients

Contrast nephropathy (CN) is a common cause of renal dysfunction that may be prevented by saline hydration and by drugs such as theophylline or furosemide. Whether oral saline hydration is as efficient as intravenous saline hydration is unknown. The preventive efficacy of theophylline and furosemide for CN remains controversial. The purpose of the current study was to evaluate the efficacy of oral saline hydration and of intravenous saline hydration plus theophylline or furosemide for the prevention of CN. We prospectively studied 312 patients with chronic renal failure (serum creatinine 201+/-81 micromol/l, Cockcroft clearance 37+/-12 ml/min/1.73 m(2)), who were undergoing various radiological procedures with a non-ionic, low osmolality contrast agent. Patients were randomly assigned to four arms. In arm A, patients received 1 g/10 kg of body weight/day of sodium chloride per os for 2 days before the procedure. In arm B, patients received 0.9% saline intravenously at a rate of 15 ml/kg for 6 h before the procedure. In arm C, patients received the same saline hydration as in arm B plus 5 mg/kg theophylline per os in one dose 1 h before the procedure. In arm D, patients received the same saline hydration as in arm B plus 3 mg/kg of furosemide intravenously just after the procedure. Patients were well-matched with no significant differences at baseline in any measured parameters. Acute renal failure, defined as an increase in serum creatinine of 44 micromol/l (0.5 mg/dl), occurred in 27 out of 312 patients (8.7%). There was no significant difference between the rate of renal failure in the different arms of the study: five out of 76 (6.6%) in arm A, four out of 77 (5.2%) in arm B, six out of 80 (7.5%) in arm C and 12 out of 79 (15.2%) in arm D. No patient had fluid overload or a significant increase in blood pressure in the 2 days following the radiological procedure. The independent predictors of CN were diabetes mellitus, high baseline serum creatinine and high systolic blood pressure. Oral saline hydration was as efficient as intravenous saline hydration for the prevention of CN in patients with stage 3 renal diseases. Furosemide and theophylline were not protective.

Use of theophylline in chronic obstructive pulmonary disease: examining the evidence

The role of theophylline in the management of chronic obstructive pulmonary disease remains controversial. This review was undertaken to determine the efficacy of theophylline in patients with stable disease. Twenty-two good quality randomized controlled trials were included in this systematic review. The review showed that theophylline significantly improved forced expiratory volume in 1 s and forced vital capacity (weighted mean difference 0.10 L; 95% confidence interval 0.04-0.16 and weighted mean difference 0.21 L; 95% confidence interval 0.10-0.31, respectively). V also improved with theophylline (weighted mean difference 195.27 mL/min; 95% confidence interval 112.71-277.83), as did Pa and Pa (weighted mean difference 1.45 mmHg; 95% confidence interval 0.26-2.65 and weighted mean difference -1.09 mmHg; 95% confidence interval -1.83 to -0.35, respectively). Patients preferred theophylline over placebo (relative risk 2.27; 95% confidence interval 1.26-4.11). Theophylline increased the risk of nausea, however, compared with placebo (relative risk 7.67; 95% confidence interval 1.47-39.94). This review has shown that oral theophylline plays an important role in the management of patients with stable chronic obstructive pulmonary disease by improving lung function, arterial blood gas tensions and ventilatory capacity. Patients also preferred treatment with theophylline when compared with placebo. The benefits of theophylline in stable chronic obstructive pulmonary disease, however, have to be weighed against the risk of adverse effects, particularly nausea.

Theophylline versus terbutaline in treating critically ill children with status asthmaticus: A prospective, randomized, controlled trial

To compare the efficacy of theophylline, terbutaline, or theophylline combined with terbutaline treatment in critically ill children with status asthmaticus who are already receiving continuous nebulized albuterol and intravenous corticosteroids. Randomized, prospective, controlled, double-blind trial. Pediatric intensive care unit of a tertiary-care children's medical center. Forty critically ill children between the ages of 3 and 15 yrs with impending respiratory failure secondary to status asthmaticus. All patients received intravenous methylprednisolone and continuous nebulized albuterol. The three study groups received theophylline plus placebo (group 1), terbutaline plus placebo (group 2), or theophylline and terbutaline together (group 3). Differences in baseline characteristics, change in clinical asthma score over time, length of pediatric intensive care unit stay, and incidence of adverse events were determined. The three study groups were similar in age, gender, race, asthma severity, and treatment. There were no differences in clinical asthma score over time, length of pediatric intensive care unit stay, or incidence of adverse events between the three groups, with the exception of a higher incidence of nausea in children in group 3. The median hospital cost of medication and theophylline blood levels was significantly lower in group 1 compared with groups 2 and 3 (280 US dollars vs. 3,908 US dollars vs. 4,045 US dollars, respectively, p < .0001). Theophylline, when added to continuous nebulized albuterol therapy and intravenous corticosteroids, is as effective as terbutaline in treating critically ill children with status asthmaticus. The addition of theophylline to baseline therapy is more cost-effective when compared with terbutaline alone or terbutaline and theophylline together. Theophylline should be considered for use early in the management of critically ill asthmatic children.

94 Efficacy of theophylline in promoting ureteral stone passage

94 Efficacy of theophylline in promoting ureteral stone passage

Efficacy of theophylline in people with stable chronic obstructive pulmonary disease: a systematic review and meta-analysis

To determine the efficacy of oral theophylline compared with placebo in people with stable chronic obstructive pulmonary disease (COPD). Systematic review of randomized-controlled trials comparing oral theophylline with placebo for a minimum of 7 days in people with stable COPD. Twenty randomized-controlled trials were included in this review. The following outcomes showed significant improvement with theophylline compared with placebo: FEV1 and FVC both improved with theophylline (weighted mean difference [WMD] 0.10 L; 95% confidence interval [95% CI] 0.04-0.16 and WMD 0.21 L; 95% CI 0.10-0.32, respectively). VO2 max also improved with theophylline (WMD 195.27mL/ min; 95% CI 112.71-277.83), as did PaO2 and PaCO2 (WMD 3.18 mmHg; 95% CI 1.23-5.13 and WMD -2.36mmHg; 95% CI -3.52 to -1.21, respectively). Patients preferred theophylline over placebo (relative risk 2.27; 95% CI 1.26-4.11). Theophylline increased the risk of nausea compared with placebo (RR 7.67; 95% CI 1.47-39.94). This review has shown that theophylline still has a role in the management of stable COPD, and is preferred by patients over placebo. However, the benefits of theophylline in stable COPD have to be weighed against the risk of adverse effects.

RNA Binding Efficacy of Theophylline, Theobromine and Caffeine

The binding of naturally occurring methylxanthines such as theophylline, theobromine and caffeine to nucleic acids are reckoned to be pivotal as they are able to modulate the cellular activities. We explore the interaction of yeast RNA binding efficacy of the above xanthine derivatives by using UV absorption differential spectroscopy and Fourier Transform Infrared (FTIR) spectroscopy. Both the analyses show discrimination in their binding affinity to RNA. The differential UV-spectrum at P/D 3.3 reveals the greater RNA binding activity for theophylline (85 ± 5%), whereas moderate and comparatively less binding activity for theobromine (45 ± 5%) and caffeine (30 ± 5%) and the binding activity was found to depend on concentration of the drugs. In FTIR analysis we observed changes in the amino group (NH) of RNA complexed by drugs, where the NH band is found to become very broad, indicating hydrogen bonding (H-bonding) with theophylline (3343.4 cm−1), theobromine (3379.8 cm− 1) and caffeine (3343 cm−1) as compared to the free RNA (3341.6 cm−1). Furthermore in RNA-theophylline complex, it is observed that the carbonyl (C=O) vibration frequency (υC=O) of both drug (υC=O=1718, 1666 cm−1) as well as RNA (υC=O=1699, 1658 cm−1) disappeared and a new vibration band appeared around 1703 cm−1, indicating that the C=O and NH groups of drug and RNA are effectively involved in H-bonding. Whereas in RNA-theo- bromine and RNA-caffeine complexes, we found very little changes in C=O frequency and only broadening of the NH band of RNA due to complexation is observed in these groups. The changes in the vibrations of G-C/A-U bands and other bending frequencies are discussed. Thus the discrimination in the binding affinity of methylxanthines with RNA molecule shows that strong RNA binding drugs like theophylline can selectively be delivered to RNA targets of microbial pathogens having the mechanism of RNA catalysis.

The Therapeutic Effect of Theophylline on Sustained Attention in Patients with Obstructive Sleep Apnea. Die Wirkung von Theophyllin auf die Daueraufmerksamkeit von Patienten mit OSAS

Question of the Study Patients with obstructive sleep apnea syndrome (OSAS) often suffer from daytime sleepiness and reduced alertness which frequently cannot be normalized despite of nCPAP therapy. Therefore additional treatment options for residual deficits is urgently needed. The objective of this study was to prove the efficacy of Theophylline on a component of attention (tracking) in patient with untreated obstructive sleep apnea syndrome (OSAS).

Phosphodiesterase-4 inhibitors in the treatment of inflammatory lung disease.

Phosphodiesterases (PDE) belong to an important family of proteins that regulate the intracellular levels of cyclic nucleotide second messengers. Targeting PDE with selective inhibitors may offer novel therapeutic strategies in the treatment of various conditions, and in the context of respiratory disease these include asthma and chronic obstructive pulmonary disease (COPD). The rationale for such an approach stems, in part, from the clinical efficacy of theophylline, an orally active drug that is purportedly a nonselective PDE inhibitor. In addition, intracellular cyclic adenosine monophosphate (cAMP) levels regulate the function of many of the cells thought to contribute to the pathogenesis of respiratory diseases such as asthma and COPD, and these cells also selectively express PDE4. This has offered pharmaceutical companies the opportunity to selectively targeting these enzymes for the treatment of these diseases. Finally, the success of targeting PDE5 in the treatment of erectile dysfunction provides clinical proof of concept for the targeting of PDE in disease. Whether a 'Viagra' of the airways can be found for the treatment of asthma and COPD remains to be seen, but positive results from recent clinical studies examining the efficacy of selective PDE4 inhibitors such as cilomilast and roflumilast offer some optimism. However, one of the major issues to be resolved is the tolerability profile associated with this drug class that is a consequence of PDE4 inhibition. While cilomilast and roflumilast have low emetic potential they are not free from emesis and various strategies are being investigated in the hope of developing a PDE4 inhibitor without this adverse effect.

Postdural puncture headache: diagnosis, prevention and therapy

Lumbar puncture (LP) is a routine technique performed for a variety of procedures, e.g. diagnosis, administration of drugs, myelography and spinal anaesthesia. Postdural puncture headache is a common complication (30-40% in diagnostic LP). Prevention can be accomplished by using small-gauge needles (< or = 25 G) or pencil-point needles (22 G). Therapy should be carried out in a stepwise approach. The first step is bedrest, use of analgetics, i.v. fluids and an adequate guidance of the patient. The second step comprises special drug therapy. Several methods of pharmacologic management have been presented in the literature, but most of these are case reports. There is a lack of large double-blind placebo-controlled studies. Theophylline, caffeine, ACTH and sumatriptan are potentially promising agents for the treatment of postdural puncture headache. The efficacy of theophylline has been proven in a double-blind and placebo-controlled study. There are a few studies and case reports reporting that caffeine p.o. and i.v. is effective in the treatment of postdural puncture headache, but recurrence of headache after caffeine therapy is frequent. ACTH acts on a complex hormonal system. The treatment with sumatriptan has been reported in only a few case reports. The third step, and one of the most effective treatments of postdural puncture headache, is the epidural blood patch. The success rate ranges between 80 and 97%.

Anti-inflammatory Effects of Theophylline: Modulation of Cytokine Production

The basis for the efficacy of theophylline in the treatment of asthma remains enigmatic. Although commonly classified as a bronchodilator, its ability to dilate smooth muscle is considered fairly poor and clinical responses are often independent of bronchodilation. Recent studies have suggested that immunomodulatory activities may contribute to the therapeutic benefit mediated by theophylline. We performed these preliminary studies to determine whether theophylline modulates cytokine production by peripheral blood mononuclear cells. Peripheral blood mononuclear cells were obtained from 24 asthmatic subjects and were left in a resting state or stimulated with either mitogens (phytohemagglutinin, lipopolysaccharide) or antigen (tetanus, cat) with or without the additional presence of theophylline (15 micrograms/dL). Supernatants were collected and evaluated for cytokine concentration by ELISA. Theophylline neither inhibited production of allergenic cytokines such as IL-4 nor modulated the repertoire of cytokines produced by TH cells. A statistically significant inhibition of spontaneous interferon-gamma synthesis was observed (24.5 +/- 8.6 to 13.4 +/- 4.2; P < .05). Theophylline did have anti-inflammatory effects on cytokines primarily produced by mononuclear phagocytic cells. Theophylline mediated a slight inhibition of TNF-alpha production (0.26 +/- 0.08 to 0.21 +/- 0.06; P < .05). Theophylline was also associated with a 2.8-fold increase in spontaneous production of the anti-inflammatory cytokine IL-10 (0.35 +/- 0.08 to 0.98 +/- 0.16 ng; P < .01). A relative absence of IL-10 characterizes the asthmatic airways and may contribute to the development and severity of allergic inflammation. Induction of IL-10 production by theophylline may therefore mitigate inflammation and contribute to the clinical efficacy of this class of medications.