Administration Of Theophylline Research Articles

Bench-to-bedside review: Preventive measures for contrast-induced nephropathy in critically ill patients

An increasing number of diagnostic imaging procedures requires the use of intravenous radiographic contrast agents, which has led to a parallel increase in the incidence of contrast-induced nephropathy. Risk factors for development of contrast-induced nephropathy include pre-existing renal dysfunction (especially diabetic nephropathy and multiple myeloma-associated nephropathy), dehydration, congestive heart failure and use of concurrent nephrotoxic medication (including aminoglycosides and amphotericin B). Because contrast-induced nephropathy accounts for a significant increase in hospital-acquired renal failure, several strategies to prevent contrast-induced nephropathy are currently advocated, including use of alternative imaging techniques (for which contrast media are not needed), use of (the lowest possible amount of) iso-osmolar or low-osmolar contrast agents (instead of high-osmolar contrast agents), hyperhydration and forced diuresis. Administration of N-acetylcysteine, theophylline, or fenoldopam, sodium bicarbonate infusion, and periprocedural haemofiltration/haemodialysis have been investigated as preventive measures in recent years. This review addresses the literature on these newer strategies. Since only one (nonrandomized) study has been performed in intensive care unit patients, at present it is difficult to draw firm conclusions about preventive measures for contrast-induced nephropathy in the critically ill. Further studies are needed to determine the true role of these preventive measures in this group of patients who are at risk for contrast-induced nephropathy. Based on the available evidence, we advise administration of N-acetylcysteine, preferentially orally, or theophylline intravenously, next to hydration with bicarbonate solutions.

Role of non‐selective adenosine receptor blockade and phosphodiesterase inhibition in cisplatin‐induced nephrogonadal toxicity in rats

1. It is well documented that cisplatin (CDDP) treatment increases the expression of adenosine A(1) receptors in both kidney and testes. However, the effect of adenosine at these receptors is controversial. Adenosine A(1) receptors have been documented to be involved in either cytoprotection or aggravation of nephrotoxicity. The aim of the present study was to examine the effect of the non-selective adenosine receptor inhibitor theophylline and the phosphodiesterase inhibitor pentoxifylline on CDDP-induced renal and testicular toxicity. 2. Male Wister rats were divided into six groups. Two control groups received plain drinking water and a third control group received theophylline 0.8 mg/mL in the drinking water for 2 weeks. One group of animals drinking plain water was injected intraperitoneally (i.p.) with pentoxifylline 50 mg/kg per day for 2 weeks. The remaining groups were treated in the same manner and received single dose of CDDP 7 mg/kg, i.p., 1 week after starting theophylline and pentoxifylline treatment and all animals were killed 1 week after CDDP treatment. 3. Rats treated with CDDP developed nephrotoxicity, as demonstrated by increased kidney and testes weight as a percentage of total bodyweight, blood urea nitrogen and serum creatinine levels and decreased serum calcium and albumin levels. In addition, CDDP treatment resulted in an increase in the production of malondialdehyde (MDA) and decreases in total nitrate/nitrite levels, as well as depletion of reduced glutathione (GSH) content and glutathione peroxidase (GPX) activity in both the kidney and testes. Administration of theophylline in the drinking water to CDDP-treated rats resulted in exacerbation of the indices of nephrotoxicity, depletion of GSH content and GPX activity levels, with increased MDA production and platinum accumulation in both the kidney and testes. However, pentoxifylline administration reduced CDDP-induced biochemical changes and reduced platinum accumulation in both organs. Histopathological examination of the kidney revealed that CDDP treatment produced multifocal tubular atrophy, atypical reparative changes of the tubular epithelium and marked tubular necrosis. Animals treated with the theophylline/CDDP combination showed extensive widespread damage with intratubular calcification. However, pentoxifylline treatment ameliorated the overt changes induced by CDDP treatment. 4. Theophylline exacerbates the deleterious effects of CDDP on rat kidney and testes. However, pentoxifylline alleviates CDDP-induced renal and testicular toxicity.

Theophylline for the prevention of radiocontrast nephropathy: a meta-analysis.

Radiocontrast nephropathy is a common cause of acute renal failure in hospitalized patients. Several studies have examined the capacity of theophylline or aminophylline to prevent radiocontrast nephropathy, with conflicting results. We conducted a meta-analysis of published randomized controlled trials to determine if the pre-procedural administration of theophylline or aminophylline prevents radiocontrast-induced declines in kidney function. We searched MEDLINE, EMBASE, the Cochrane Collaboration Database, bibliographies of retrieved articles, and consulted with experts to identify relevant studies. Randomized controlled trials of theophylline or aminophylline in hospitalized patients receiving radiocontrast were included. Studies were excluded if they did not report changes in serum creatinine or creatinine clearance within 48 h after radiocontrast exposure. Seven randomized controlled trials satisfied all inclusion criteria and were included in the analysis (pooled sample size n = 480). The difference in mean change in serum creatinine was 11.5 micromol/l (95% confidence intervals 5.3-19.4 micromol/l, P = 0.004) lower in the theophylline- or aminophylline-treated groups than controls. One participant (0.6%) required dialysis. Prophylactic administration of theophylline or aminophylline appears to protect against radiocontrast-induced declines in kidney function. Whether these agents reduce the proportion of patients who experience large decrements in serum creatinine concentration, or require dialysis, is unknown.

Theophylline, a methylxanthine derivative, suppresses absence epileptic seizures in WAG/Rij rats

The effects of systemic theophylline administration on spike–wave discharge (SWD) frequency in genetically absence epileptic Wistar Albino Glaxo/Rijswijk (WAG/Rij) rats are investigated. After an hour of baseline recording, animals were injected intraperitoneally (ip) with 5, 10, and 20 mg/kg theophylline and electroencephalograms (EEGs) were recorded for 2 h postinjection. Then, the number and total duration of SWDs were analyzed. Spontaneous behaviors of the animals was also observed before and after drug administration. Our results show that systemic administration of theophylline suppresses the occurrence of SWDs in a dose-dependent manner. The greatest suppression was seen in the group administered 20 mg/kg theophylline. Theophylline also induced a mild increase in exploratory and automatic behavior. These results indicate that blockage of adenosinergic receptors via the methylxanthine derivative theophylline decreases the occurrence of SWDs, probably by augmenting the efficacy of excitator neurotransmission and increasing vigilance and arousal levels.

Evaluation of the bioavailability and pharmacokinetics of two extended-release theophylline formulations in dogs

To evaluate the bioavailability and pharmacokinetic characteristics of 2 commercially available extended-release theophylline formulations in dogs. Randomized 3-way crossover study. 6 healthy adult dogs. A single dose of aminophylline (11 mg x kg(-1) 15 mg x lb(-1)], i.v., equivalent to 8.6 mg of theophylline/kg 13.9 mg x lb(-1) or extended-release theophylline tablets (mean dose, 15.5 mg x kg(-1) [7.04 mg x lb9-1), PO) or capsules (mean dose, 15.45 mg x kg(-1) [7.02 mg x lb(-1)], PO) was administered to all dogs. Blood samples were obtained at various times for 36 hours after dosing; plasma was separated and immediately frozen. Plasma samples were analyzed by use of fluorescence polarization immunoassay. Administration of theophylline i.v. best fit a 2-compartment model with rapid distribution followed by slow elimination. Administration of extended-release theophylline tablets and capsules best fit a 1-compartment model with an absorption phase. Mean values for plasma terminal half-life, volume of distribution, and systemic clearance were 8.4 hours, 0.546 L x kg(-1), and 0.780 mL x kg(-1) x min(1), respectively, after i.v. administration of theophylline. Systemic availability was > 80% for both oral formulations. Computer simulations predicted that extended-release theophylline tablets or capsules administered at a dosage of 10 mg x kg(-1) (4.5 mg x lb(-1)), PO, every 12 hours would maintain plasma concentrations within the desired therapeutic range of 10 to 20 microg x mL(-10. Results of these single-dose studies indicated that administration of the specific brand of extended-release theophylline tablets or capsules used in this study at a dosage of 10 mg x kg(-1), PO, every 12 hours would maintain plasma concentrations within the desired therapeutic range (10 to 20 microg x mL(-1)) in healthy dogs.

Effects of theophylline administration and intracranial abnormalities on protective head turning response in preterm infants.

To determine effects of theophylline therapy for recurrent apnoea of prematurity and abnormal early (within the first 24 hours) cranial ultrasound abnormalities on protective neck turning response in preterm infants. A cross sectional descriptive study. The Neonatal Unit of Hammersmith Hospital, London over a period of four months (February to May 1987) and the babies followed up for six months after discharge. Preterm babies of gestation 25 to 33 weeks confirmed by early postnatal Dubowitz assessment were studied. All infants had cranial ultrasound examination within the first 24 hours of birth. Protective side turning response was recorded for each baby weekly until discharge. The pattern of maturation of the response was then analysed. Thirty preterm infants (mean gestation 30 weeks) were studied. The babies treated with theophylline had significant (p=0.004) delay in the maturation of the response. This improved within two weeks of stopping treatment. Eight infants had intracranial haemorrhage and seven had periventricular density. Both these groups were similar with respect to the maturation of the response. No significant interaction was found between theophylline therapy and abnormal cranial ultrasound as regards the protective side turning response. Six months follow up showed no serious neurological abnormalities among the infants. Theophylline administration and perinatal brain injury may have a delaying effect on protective head turning response in the neonatal period and therefore should be taken into account during neurological examination of the preterm neonate. This effect does not seem to result in any significant long-term neurological sequelae.

Changes in motor cortical excitability in humans following orally administered theophylline

The effects of theophylline on human corticospinal excitability were studied using transcranial magnetic stimulation (TMS) before and after double-blind oral administration of theophylline or placebo in 20 healthy volunteers. TMS measurements included resting and active motor threshold, silent period, intracortical inhibition (ICI), and intracortical facilitation. F-wave and compound muscle action potential (CMAP) were also measured. Theophylline produces a reduction in ICI, while other parameters of corticospinal excitability remained unaffected. Since ICI is thought to depend on GABA A intracortical inhibitory mechanisms, our data suggest that the increase of human motor cortex excitability is the result of a decrease in GABAergic transmission. Our results further support the hypothesis that theophylline might induce convulsions by inhibiting GABA A receptor binding.

Occurrence of Convulsions after Administration of Theophylline in a Large Japanese Pediatric Population with Asthma

The main objective of this study was to evaluate the incidence of convulsions in a large Japanese pediatric population (60,634 patients from 79 centers) treated with theophylline (T). Moreover, further details were obtained from the affected patients. Two sequential questionnaires were sent to centers in order to obtain data. The incidence rate of convulsions was 0.24% (127/54,066) in asthmatic patients treated with T vs. 0.36% (27/7,568) in asthmatic patients not treated with T (p = NS). Eight patients showed convulsions related to T treatment: this group included three infants≤1 year, high mean serum T concentration at the time of convulsion attack (16.7 ± 1.6 μg/mL), and high concomitant medication rate. The rate of recurrent convulsions after readministration of theophylline was higher for patients with epilepsy than for patients with febrile convulsions. In conclusion, the incidence of convulsions in pediatric patients was not affected by the use of theophylline as treatment for asthma. The low frequ...

Stimulation by theophylline and sildenafil of rat submandibular secretion of protein, epidermal growth factor and flow rate

In the present study, the effects of cAMP- and cGMP-phosphodiesterase (PDE) inhibitors, theophylline, and sildenafil on secretion of protein, amylase and epidermal growth factor (EGF) and the flow rate from rat submandibular saliva were examined in an acute experiment. Theophylline at doses of 25, 50, 85 mg kg −1 and sildenafil at doses of 1, 2, 5 mg kg −1 were administered intraperitoneally 2 h before saliva collection. Pure submandibular saliva was collected intraorally by microployethylene tubes under anesthesia using dissecting microscope. Theophylline at doses of 25, 50, 85 mg kg −1 increased salivary flow rate to 197% ( P<0.01), 186% ( P<0.01), and 209% of control, respectively. Sildenafil at doses of 1, 2, 5 mg kg −1 also increased flow rate to 232% ( P<0.01), 182% ( P<0.01), and 197% of control, respectively. Theophylline at doses of 25, 50, 85 mg kg −1 increased total protein concentration to 98% ( P<0.01), 84% ( P<0.01), and 210% of control, respectively. Sildenafil at doses of 2 and 5 mg kg −1 increased total protein concentration to 75% ( P<0.01), and 240% of control, respectively. Theophylline at dose of 85 mg kg −1 increased EGF concentration to 60% ( P<0.01) of control. Sildenafil at doses of 2 and 5 mg kg −1 increased EGF concentration to 44% ( P<0.05) and 90% ( P<0.01) of control, respectively. No statistically significant change was observed in amylase activity by administration of theophylline or sildenafil. The present results indicate that increasing intracellular levels of cAMP and cGMP have stimulatory effects on salivary functions. Regarding beneficiary effects of increased salivary flow rate and secretion of EGF in maintaining oral health, theophylline and sildenafil may find good places in some oral diseases.

Theophylline treatment may adversely affect the anoxia-induced erythropoietic response without suppressing erythropoietin production.

To investigate the influence of theophylline on erythropoiesis in chronic obstructive pulmonary disease (COPD) and explore the potential underlying mechanisms. We evaluated the haematological parameters and erythropoietin (EPO) values in 38 COPD patients, 18 of which had been treated with theophylline (8 mg/kg daily) for at least 1 year, and the other 20 had never received this drug; 38 sex- and age-matched healthy volunteers served as controls. We further studied the development of BFU-E (bursts forming units of erythrocyte precursors) -derived colonies in semisolid methylcellulose cultures in blood samples from 7 patients randomly selected from both groups. In addition, we studied the effects of theophylline on the erythroid cell development by adding this agent to erythroid cell cultures from 6 healthy volunteers at various concentrations. Haemoglobin values were found to be significantly lower in COPD patients treated with theophylline than in those untreated ( P<0.05). Both groups of patients exhibited significantly higher haemoglobin values than normal subjects ( P<0.01 and P<0.001 for treated and untreated patients, respectively). Serum EPO levels did not differ among the three studied groups. Unlike untreated patients and controls, the serum of the theophylline-treated patients produced a significant growth inhibition of erythroid bursts ( P<0.05); the in vitro use of theophylline showed a concentration-dependent inhibition ( P<0.001). Our findings confirm the decrease of red cell production, which occurs following administration of theophylline, exclude the possibility of decreased EPO synthesis and suggest a direct inhibitory action of theophylline on erythropoiesis.

Benefit of theophylline administration in tacrolimus-induced nephrotoxicity in rats.

Tacrolimus (TAC), a widely used nephrotoxic calcineurin inhibitor, is associated with renal vasoconstriction possibly through adenosine receptor activation. Theophylline (THEO), an adenosine receptor inhibitor, protects against the nephrotoxicity of drugs associated with renal vasoconstriction. We hypothesized that coadministration of low dose THEO in rats would prevent TAC-induced nephrotoxicity. Sprague-Dawley rats pair-fed a low-sodium diet were randomized into three groups ( n=10/group): the control (CONTROL) group received the vehicle for both medications; the TAC group received TAC 6 mg/kg/day and vehicle; and the TAC+THEO group received TAC and THEO 17 mg/kg/day. On day 21, a timed urine collection was obtained for creatinine clearance. On day 22, serum creatinine, THEO and whole blood TAC concentrations were determined. One kidney was removed for formalin fixation and histological assessment. In the TAC group, serum creatinine increased while creatinine clearance decreased compared to CONTROL (0.3+/-0.0 vs. 0.4+/-0.0 mg/dl and 0.53+/-0.06 vs. 0.34+/-0.04 ml/min/100 g body weight respectively, p<0.05), while TAC+THEO did not differ from control. There were no significant differences in renal histology. Concurrent administration of low-dose THEO prevented the TAC-induced decline in renal function, consistent with a role for adenosine in TAC-induced nephrotoxicity.

Effects of long-term theophylline exposure on recovery of respiratory function and expression of adenosine A1 mRNA in cervical spinal cord hemisected adult rats

Our lab has previously shown that when administered acutely, the methylxanthine theophylline can activate a latent respiratory motor pathway to restore function to the hemidiaphragm paralyzed by an ipsilateral C2 spinal cord hemisection. The recovery is mediated by the antagonism of CNS adenosine A1 receptors. The objective of the present study was to assess quantitatively recovery after chronic theophylline administration, the effects of weaning from the drug, and the effects of the drug on adenosine A1 receptor mRNA expression in adult rats subjected to a C2 hemisection. Rats subjected to a left C2 hemisection received theophylline orally for 3, 7, 12, or 30 days and were classified as 3D, 7D, 12D, or 30D respectively. Separate groups of 3D animals were weaned from drug administration for 7, 12, and 30 days before assessment of respiratory recovery. Additional groups of 7D and 12D animals were also weaned from drug administration for 7 and 12 days prior to assessment. Sham-operated controls received theophylline vehicle for similar periods. Quantitative assessment of recovered respiratory activity was conducted under standardized electrophysiologic recording conditions approximately 18 h after each drug application period. Serum theophylline analysis was conducted at the end of electrophysiologic recordings. Adenosine A1 receptor mRNA expression in the phrenic nucleus was assessed with in situ hybridization and immunohistochemistry. Chronic theophylline induced a dose-dependent effect on respiratory recovery over a serum theophylline range of 1.2–1.9 μg/ml. Recovery was characterized as respiratory-related activity in the left phrenic nerve and expressed as a percentage of activity in the homolateral nerve in noninjured animals under similar recording conditions. Recovered activity was 34.13 ± 2.07, 55.89 ± 2.96, 74.78 ± 1.93, and 79.12 ± 1.75% respectively in the 3D, 7D, 12D, and 30D groups. Theophylline-induced recovered activity persisted for as long as 30 days when drug administration was stopped and serum levels of the drug were virtually undetected. Furthermore, recovered activity in 3D and 7D animals increased significantly as a function of duration of weaning. Adenosine A1 receptor mRNA expression was not significantly changed by theophylline administration. It is concluded that recovery of respiratory function in C2-hemisected rats induced by chronic theophylline is unrelated to adenosine A1 receptor mRNA expression. Recovered activity persists even when drug administration has been stopped. The significance of our results is that in the clinical application of theophylline to improve respiratory impairment, intermittent drug administration may be sufficient to engender and maintain the therapeutic benefits of the drug.

Nucleotides modulate renal ischaemia-reperfusion injury by different effects on nitric oxide and superoxide.

1. The present study investigated the effects of kidney ischaemia duration on nitric oxide (NO) and superoxide (O2-) generation at reperfusion and the role of xanthine and adenosine as mediators of NO/O2- generation. 2. The effect of the duration of ischaemia on renal nucleotide levels was studied in two ischaemic groups (10 and 30 min). The role of adenosine and xanthine was studied in ischaemic-reperfused groups (subjected to 10 and 30 min ischaemia and 60 min reperfusion). 3. Tissue levels of adenosine decreased significantly after 30 min ischaemia, whereas xanthine/hypoxanthine levels increased concomitantly with renal dysfunction and histological damage. 4. Nitric oxide production increased significantly after 10 min ischaemia and 60 min reperfusion, whereas lipoperoxidation increased significantly after 30 min ischaemia and 60 min reperfusion. The administration of theophylline (40 mg/kg, i.p.) reversed the early increase in NO production. 5. Xanthine supplementation decreased renal function and increased lipoperoxidation. 6. In conclusion, NO/O2- production and the subsequent renal injury/dysfunction may be modified by changes in the adenosine and xanthine levels of the injured kidney, although the present data show a significant in vivo role only for xanthine.

Resveratrol provides late-phase cardioprotection by means of a nitric oxide- and adenosine-mediated mechanism

We used two experimental models to prove that resveratrol ( trans-3,4′,5-trihydroxystilbene) reduces cardiac ischemic-reperfusion injury by means of a nitric oxide- and adenosine-dependent mechanism. (1) Acute ex vivo: resveratrol (10 μM, 10 min) infusion in Langendorff-perfused normoxic rat hearts significantly increased adenosine release and coronary flow compared with baseline. After 30-min low-flow ischemia, vasodilation, still present at reperfusion, was completely abolished by resveratrol plus adenosine antagonist 8-( p-sulfophenyl)theophylline (SPT, 50 μM) administration. (2) Chronic in vivo: rats received tap water containing 25 mg/l resveratrol for 15 days or normal water. Twenty-four hours after, their hearts were Langendorff-perfused and submitted to 60-min low-flow ischemia and reperfusion. The resveratrol-treated hearts showed better functional recovery at reperfusion and significant vasodilation, but no variation in high-energy phosphates ( 31P Nuclear Magnetic Resonance). N G-nitro- l-arginine methyl ester ( l-NAME, 30 μM), a nonselective nitric oxide synthase inhibitor, or SPT (50 μM) administered for 10 min prior to the low-flow ischemia cancelled the effects. This suggests that long-term moderate resveratrol consumption could play an important role in late cardioprotective effects.

Morphological Changes in Salivary Glands Induced by Theophylline in Rats

Theophylline, a phosphodiesterase inhibitor, is known to induce enlargement of the salivary glands. This enlargement has been thought to be associated with enhanced cellular levels of cyclic AMP as a result of inhibition of phosphodiesterase. In the present study, to clarify the sequential changes in salivary glands following the administration of theophylline, a four-day repeated dose study and a single dose study were carried out in male rats, and the parotid and submaxillary glands were examined histologically. The results from the glands were almost identical. In the repeated dose study, the increased organ weight just before the last administration was reduced at 4 hr and then restored at 8 hr after the last administration. In the single dose study, a slight but significant increase in organ weight was observed at 24 hr after administration, following a transient reduction. Changes in acinus histology were consistent with these organ weight changes. Acinar cells were loaded with excessive secretory granules just before the last administration in the repeated dose study. After the last administration, granules were reduced at 4 hr, and then reaccumulated at 8 hr. Such time-course variability in the number of secretory granules corresponded well to clinically observed salivation. These results suggest that inhibition of phosphodiesterase is primarily involved in the discharge of secretory granules, and that the salivary hypertrophy previously reported is an adaptive response caused by the repeated stimulation of saliva secretion.

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

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.

Huber W, Ilgmann K, Page M, Hennig M, et al. Effect of Theophylline on Contrast Material-Induced Nephrotoxicity in Patients with Chronic Renal Insufficiency: Controlled, Randomized, Double Blinded Study. Radiology 2002; 223(3); 772-779

WHAT IS THE QUESTION BEING ASKED? Does the administration of intravenous Theophylline given thirty minutes prior to the introduction of intravascular contrast material reduce the risk of contrast induced nephrotoxicity in patients with underlying renal

The effects of pituitary adenylate cyclase-activating polypeptide on acute and chronic morphine actions in mice.

The effects of pituitary adenylate cyclase-activating polypeptide (PACAP) on pain sensitivity, on morphine analgesia, on morphine tolerance and withdrawal were investigated in mice. The heat-radiant tail-flick test was used to assess antinociceptive threshold. Intracerebroventricular (i.c.v.) administration of PACAP alone had no effect on pain sensitivity but in a dose of 500 ng, it significantly diminished the analgesic effect of a single dose of morphine (2.25 mg/kg, s.c.). PACAP (500 ng, i.c.v.) significantly increased the chronic tolerance to morphine and enhanced the naloxone (1 mg/kg, s.c.)-precipitated withdrawal jumping. Theophylline (1 mg/kg, i.p.) pretreatment significantly enhanced the effect of PACAP on morphine analgesia but the effects of PACAP on tolerance and withdrawal were unaffected upon theophylline administration. On the grounds of our previous studies with vasoactive intestinal polypeptide (VIP), it appears that different receptors are involved in the effects of PACAP in acute and chronic morphine actions. Our results indicate that PACAP-induced actions likely participate in acute and chronic effects of morphine and suggest a potential role of PACAP in opioid analgesia, tolerance and withdrawal.

The role of adenosine in regulation of cerebral blood flow during hypoxia in the near-term fetal sheep.

The aim of this study was to determine in the near-term ovine fetus the role of adenosine in the basal regulation of cerebral blood flow and in the increases in cerebral blood flow in response to acute hypoxic insult. We measured cerebral blood flow in chronically instrumented fetal sheep (127-135 days gestation, term approximately 145 days) using laser Doppler flowmetry probes implanted in the parietal cortices. Hypoxia was administered for 30 min by lowering the ewe's inspired oxygen to 10-12 % during an infusion of either saline or theophylline, a non-specific adenosine receptor antagonist. The theophylline infusion was begun 30 min prior to and ended 30 min after the completion of the hypoxic insult. The administration of theophylline had no significant effect on cerebral blood flow during the baseline period. During control hypoxic periods, cerebral blood flow increased by approximately 45 %. During theophylline experiments, however, there was no significant increase in cerebral blood flow during hypoxia. In the control experiments, cerebral blood flow returned to baseline levels during the recovery period, while in the theophylline experiments cerebral blood flow fell below baseline levels. We conclude that, in the near-term ovine fetus, adenosine plays a minimal role in the regulation of basal cerebral blood flow. However, these data are strong evidence for the involvement of adenosine in increased fetal cerebral blood flow during an acute hypoxic insult. Finally, adenosine may also play an important role in the maintenance of fetal cerebral blood flow immediately following hypoxic insult.

The Effects of Adenosine Receptor Agonists and Antagonists on Morphine State-Dependent Memory of Passive Avoidance

Pretraining administration of morphine (5 mg/kg, intraperitonically) in a step-down passive avoidance task led to state-dependent learning with impaired retrieval on the test day that was dose-dependently restored by pretest administration of morphine (0.5, 1, 3, and 5 mg/kg). This restoration was reversible by pretest naloxone administration. Pretest administration of adenosine receptor antagonists theophylline or 8-phenyltheophylline (8-PT) did not alter morphine-induced amnesia. However, both the antagonists inhibited the restoration of memory by pretest morphine (5 mg/kg). Adenosine A 1 receptor agonists N 6-cyclohexyladenosine (CHA) or N 6-phenylisopropyladenosine (R-PIA) only at the higher doses used, and adenosine A 2 receptor agonist 5′-N-ethylcarboxaminoadenosine (NECA), at all doses used, decreased morphine-induced amnesia in a dose-dependent manner. Pretest administration of low doses of CHA, R-PIA, or NECA significantly showed additive effects with low dose pretest morphine (1 mg/kg) in restoring memory. The promnestic effects of high-dose CHA and R-PIA were inhibited by theophylline or 8-PT but not by naloxone. The additive effects of low-dose CHA or R-PIA and morphine were inhibited by theophylline, 8-PT, or a higher dose of naloxone. The promnestic effect of NECA and its additive effect with low-dose morphine were both inhibited by theophylline and naloxone but not by 8-PT. It is concluded that activation of the adenosinergic system, through both A 1 and A 2 receptors, can reverse morphine-induced amnesia and is involved in morphine state of memory.