Adenosine A1 Receptor Mrna Expression and the Effects of Systemic Theophylline Administration On Respiratory Function 4 Months After C2 Hemisection

Abstract

Background: Previous studies from our laboratory have demonstrated that in an animal model of acute cervical spinal cord injury (SCI), respiratory function can be restored by theophylline. We also have shown that respiratory recovery occurs spontaneously after prolonged postinjury survival periods when a hemidiaphragm is paralyzed by an ipsilateral upper cervical (C2) spinal cord hemisection. Theophylline mediates functional recovery by central nervous system adenosine A1 receptor antagonism; however, it is unclear whether adenosine receptors are altered after prolonged postinjury periods and whether theophylline can further enhance restored respiratory function that occurs spontaneously.

Objective: To assess putative effects of systemic theophylline administration on further enhancing spontaneous respiratory muscle recovery 4 months after C2 hemisection in rats and to determine whether adenosine A1 receptor mRNA expression is altered in these animals.

Methods: Electrophysiologic assessment of respiratory activity in the phrenic nerves was conducted in C2 hemisected rats 4 months after hemisection under standardized conditions. Immediately thereafter, rats were killed and the cervical spinal cords were prepared for adenosine A1 receptor mRNA expression by in situ hybridization.

Results: Spontaneous recovery of respiratory activity in the ipsilateral phrenic nerve was detected in a majority (15/20) of C2 hemisected animals and amounted to 44.06% ± 2.3 8% when expressed as a percentage of activity in the homolateral phrenic nerve in noninjured animals. At the optimal dosage used in the acute studies, theophylline (15 mg/kg) did not enhance, but rather unexpectedly blocked, recovered respiratory activity in 4 out of 5 animals tested. At dosages of 5 mg/kg and 2.5 mg/kg, the drug blocked recovered respiratory activity in 3 out of 4 and 3 out of 5 animals tested, respectively. Quantitative analysis of adenosine A1 receptor mRNA expression did not reveal a significant difference between experimental animals and sham-operated animals.

Conclusion: The blockade or attenuation of spontaneously recovered respiratory activity following theophylline administration cannot be attributed to changes in adenosine A1 receptors because there were no significant differences in adenosine A1 mRNA expression with sham-operated animals. Lack of alteration in A1 mRNA expression 4 months after cervical SCI suggests that A1 receptor plasticity is not activated by chronic injury. Obliteration of spontaneous recovery with theophylline most likely involves a separate unknown mechanism. These findings suggest that there may be a limited therapeutic window for the clinical application of theophylline in SCI patients with respiratory deficits. Theophylline may be more effective clinically in the acute phase of injury rather than in the chronic phase.     

Anestesia geral sem opioide e recuperação induzida da anestesia em paciente com distrofia miotônica tipo‐1: relato de caso

Myotonic dystrophy type‐1 (Steinert disease) is an autosomal dominant, progressive multisystem disease in which myotonic crisis can be triggered by several factors including pain, emotional stress, hypothermia, shivering, and mechanical or electrical stimulation. In this report, dexmedetomidine‐based general anesthesia, in combination with a thoracic epidural for laparoscopic cholecystectomy in a patient with Steinert disease, is presented. An Aintree intubation catheter with the guidance of a fiberoptic bronchoscope was used for intubation to avoid laryngoscopy. Prolonged anesthetic effects of propofol were reversed, and recovery from anesthesia was accelerated using an intravenous infusion of theophylline.     

1305例茶碱血药浓度分析

目的通过分析茶碱的血药浓度分布及影响血药浓度的因素,了解茶碱临床使用的合理情况,使茶碱使用更安全、有效。方法对我院2010～2012年1305例患者的茶碱血药监测结果进行回顾性分析。结果 1305例患者中,血药浓度在5～20μg·mL-1范围的占45.7%,低于5μg·mL-1的占50.9%,而且当年龄超过70岁时,随着年龄的增长,出现中毒血药浓度（＆gt;20μg·mL-1）的可能性越大。结论茶碱血药浓度受多种因素影响,尤其是老年患者,临床使用应进行血药浓度监测,对确保临床安全合理用药具有重要意义。     

Herb–drug interactions: Effect of Ginkgo biloba extract on the pharmacokinetics of theophylline in rats

Herbal medicines have received great attention as alternative medicines in recent years and are also referred to as a dietary supplement or health food. Ginkgo biloba extract (GBE) is one of the most popular herbal medicines. However, little is known about the metabolic interactions between GBE and clinically used drugs. This study attempted to investigate the effect of GBE on the pharmacokinetics of theophylline, a cytochrome P450 (CYP) 1A2 substrate and an important therapeutic agent with narrow therapeutic window used for the treatment of asthma.

Commercial GBE (10 or 100 mg/kg, p.o.) or water (control group) was given to rats (6 rats for each group) for 5 consecutive days and on the sixth day theophylline (10 mg/kg) was administered either orally or intravenously. The results showed that pretreatment of rats with GBE resulted in an increase in the total clearance of theophylline of about 30% (GBE 10 mg/kg, P < 0.05) and 70% (GBE 100 mg/kg, P < 0.01) compared with the control group after intravenous administration of theophylline (10 mg/kg). After oral administration of theophylline (10 mg/kg), the AUC_0–24 h of theophylline was reduced by 40% following pretreatment with GBE (100 mg/kg, P < 0.01). These results demonstrate that GBE pretreatment increased CYP1A2 metabolic activity and the clearance of theophylline in rats.     

Aminophylline dosage in acute severe asthma

In 27 cases of acute severe asthma, a loading dose of 5 mg/kg of aminophylline (omitted if already receiving oral theophylline) followed by a continuous infusion of 1 mg/kg per hour gave satisfactory theophylline levels at 4 h and 24 h. Theophylline clearance rates varied widely, vomiting was common, but unrelated to blood theophylline levels.     

Long-term theophylline treatment changes the effects of angiotensin II and adenosinergic agents on the seizure threshold

The effects of angiotensin II (ANG II), sarmesin, losartan, PD 123319, and adenosine A (1) receptor agonist N(6)-cyclopentyladenosine (CPA) administered i.c.v. in untreated and in theophylline-treated male mice (50 mg/kg i.p. twice daily for 14 days) were studied on the pentylenetetrazol (PTZ) seizure threshold. The threshold was increased after long-term theophylline treatment. ANG II, sarmesin, and CPA increased the threshold in theophylline-untreated mice, whereas it decreased the threshold in theophylline-treated animals. Losartan did not change the threshold in theophylline-untreated mice but decreased it in theophylline-treated animals. PD 123319 did not change the seizure threshold both in theophylline-untreated and -treated mice. Taken together, the data demonstrated that repeated exposure to theophylline selectively changes the effects of ANG II and adenosinergic agents on the PTZ seizure threshold. The results indicate that both angiotensin AT(1) and adenosine A(1) receptor subtypes could possess interactive mechanisms of adaptation to chronic theophylline treatment.     

Effects of single and repeated doses of theophylline on aspects of performance,electrophysiology and subjective assessments in healthy human subjects

The effects of both single and repeated doses of theophylline were evaluated on a battery of nine performance tests, the EEG, the EMG and on subjective assessments of mood and side-effects. The subjects were 20 healthy adults who participated in both phases of this randomized, double-blind, placebo controlled, crossover study. The single dose of 400 mg and the repeated doses of 300 mg b.d. for 4 weeks were intended to attain therapeutic serum concentrations. The Sternberg Additive Factors Method for assessing information processing revealed enhanced performance in both phases of this study, while the Horizontal Addition Test showed improved performance in the single dose phase only. The remaining seven performance tests failed to show significant differences between theophylline and placebo. Single doses of theophylline did not significantly alter mood, but marked adverse effects were encountered in the repeated dose phase, possibly related to unpleasant side-effects. Both EEG and EMG findings indicative of stimulation were associated with a single dose of theophylline, but substantial tolerance developed during 4 weeks of therapy. These findings demonstrate CNS stimulation by both single and repeated doses of theophylline with the occurrence of adverse side-effects during repeated administrations.     

Inhibition of fluid transport in the isolated gall bladder of the guinea pig by isoprenaline,theophylline and cyclic adenosine 3′,5′-monophosphate

Summary The isolated gall bladder of guinea pigs was used to study the effects of isoprenaline and orciprenaline on fluid transport. Both drugs in the range 10^–8 M to 10^–4 M inhibited fluid transport 20–50 min after application, when applied to the serosal side. The maximum inhibition observed was 49±3.9% by a concentration of 10^–5 M. After this inhibitory phase the transport rate returned to control values. Doubling the concentration did not evoke a new inhibitory response, but washing gall bladders with fresh Ringer's solution restored the sensitivity to isoprenaline. Isoprenaline was ineffective when added to the mucosal side. Propranolol but not practolol, prevented the action of isoprenaline. Theophylline inhibited fluid transport in the range 10^–3 M to 10^–2 M. Cyclic adenosine 3,5-monophosphate (cyclic AMP) 3.3×10^–3 M decreased fluid transport only when added to the serosal side. In contrast to isoprenaline, both theophylline and cyclic AMP caused a prolonged decrease in fluid transport. The results are in accordance with the assumption that the inhibition of fluid transport in the gall bladder by -sympathomimetic drugs may be caused by an increase of the intracellular cyclic AMP level.Part of this work was presented at the 14th meeting of the Deutsche Pharmakologische Gesellschaft in Mainz, 1973.This work was supported by a grant from the Deutsche Forschungsgemeinschaft given to the Sonderforschungsbereich 160, Eigenschaften biologischer Membranen, Projekt T.     

Evaluation of honey locust (Gleditsia triacanthos Linn.) gum as sustaining material in tablet dosage forms

In this study, honey locust gum (HLG) obtained from Gleditsia triacanthos (honey locust) beans was investigated as a hydrophilic matrix material in the tablets prepared at different concentrations (5% and 10%) by wet granulation method. Theophylline was chosen as a model drug. The matrix tablets containing hydroxyethylcellulose and hydroxypropyl methylcellulose as sustaining polymers at the same concentrations were prepared and a commercial sustained release (CSR) tablet containing 200 mg theophylline was examined for comparison of HLG performance. Physical analysis on CSR tablet, matrix tablets and their granules before compression were performed. According to the results obtained from dissolution studies in distilled water, pH 1.2 HCl buffer and pH 7.2 phosphate buffer, no significant difference was found between CSR tablet and the matrix tablet containing 10% HLG in each medium (P > 0.05) and these tablets showed zero-order kinetic model in all the mediums.     

Improvement of physicochemical and biopharmaceutical properties of theophylline by poly(ethylene glycol) conjugates

In the present paper two theophylline esters with poly (ethylene glycol) (PEG) and methoxy poly (ethylene glycol) (mPEG) were prepared. Quantitative yields of the pure products were obtained. Unlike the free drug, the drug-polymer conjugates are freely water-soluble at room temperature. In vitro release experiments in aqueous buffer demonstrate that both conjugates are stable in buffer of pH 7.4 and 1.2. In vivo release studies after oral administration of theophylline conjugates demonstrate a good release of parent drug.