Cerebral Oximetry Monitoring in Extremely Preterm Infants.

BACKGROUND: The use of cerebral oximetry monitoring in the care of extremely preterm infants is increasing. However, evidence that its use improves clinical outcomes is lacking. METHODS: In this randomized, phase 3 trial conducted at 70 sites in 17 countries, we assigned extremely preterm infants (gestational age, <28 weeks), within 6 hours after birth, to receive treatment guided by cerebral oximetry monitoring for the first 72 hours after birth or to receive usual care. The primary outcome was a composite of death or severe brain injury on cerebral ultrasonography at 36 weeks' postmenstrual age. Serious adverse events that were assessed were death, severe brain injury, bronchopulmonary dysplasia, retinopathy of prematurity, necrotizing enterocolitis, and late-onset sepsis. RESULTS: A total of 1601 infants underwent randomization and 1579 (98.6%) were evaluated for the primary outcome. At 36 weeks' postmenstrual age, death or severe brain injury had occurred in 272 of 772 infants (35.2%) in the cerebral oximetry group, as compared with 274 of 807 infants (34.0%) in the usual-care group (relative risk with cerebral oximetry, 1.03; 95% confidence interval, 0.90 to 1.18; P = 0.64). The incidence of serious adverse events did not differ between the two groups. CONCLUSIONS: In extremely preterm infants, treatment guided by cerebral oximetry monitoring for the first 72 hours after birth was not associated with a lower incidence of death or severe brain injury at 36 weeks' postmenstrual age than usual care. (Funded by the Elsass Foundation and others; SafeBoosC-III ClinicalTrials.gov number, NCT03770741.).

L-citrulline supplementation in the treatment of pulmonary hypertension associated with bronchopulmonary dysplasia in preterm infant: A case report.

INTRODUCTION: the aim of this case report is to present that oral L-citrulline supplementation may attenuate chronic pulmonary hypertension and reduce oxygen requirement in infants with severe bronchopulmonary dysplasia. IMPORTANT CLINICAL FINDINGS: a boy, with a birth weight of 700 g, born by cesarean section after 25 weeks of pregnancy complicated with preeclampsia, was admitted to the neonatal intensive care unit. He was ventilatory dependent for the next 3 months with significantly increased oxygen requirements. A severe stage of bronchopulmonary dysplasia, complicated with increased pulmonary vascular resistance, was diagnosed. Treatment with inhaled nitric oxide and oral sildenafil was included in the therapy of chronic pulmonary hypertension. The results of screening echocardiograms and increased plasma brain natriuretic peptide concentrations, suggested right ventricle dysfunction. THE MAIN INTERVENTION: at the beginning of the sixth month of hospitalization, oral supplementation of L-citrulline in a single dose of 150 mg/kg/day was introduced and continued for 70 days. During the first 3 weeks after L-citrulline was started, the patient was weaned from mechanical ventilation and he was never intubated again until he was discharged. Plasma brain natriuretic peptide concentrations decreased significantly during the first month of L-citrulline administration and became stable until the termination of L-citrulline supplementation. At discharge, the patient required 22%-25% concentration of oxygen supplemented intermittently, exclusively during feeding. CONCLUSION: these results indicate that L-citrulline supplementation may deserve coverage as an additional, potentially beneficial alternative in the prophylaxis or therapy of chronic pulmonary hypertension in newborns.

Shifting the boundaries for early caffeine initiation in neonatal practice: Results of a prospective, multicenter study on very preterm infants with respiratory distress syndrome.

BACKGROUND: There is growing evidence that supports the benefits of early use of caffeine in preterm neonates with RDS; however, no formal recommendations specifying the exact timing of therapy initiation have been provided. OBJECTIVES: We compared neonatal outcomes in infants receiving early (initial dose on the 1st day of life) and late (initial dose on day 2+ of life) caffeine therapy. METHODS: Using data from a prospective, cohort study, we identified 986 infants ≤32 weeks' gestation with RDS and assessed the timing of caffeine therapy initiation, need for ventilatory support, mortality and incidence of typical complications of prematurity. To adjust for baseline severity, the early and late caffeine groups were propensity score (PS) matched to 286 infants (1:1). Clinical outcomes were compared between the PS-matched groups. RESULTS: Early treatment with caffeine citrate was associated with a significantly reduced need for invasive ventilation (71.3% vs 83.2%; P = 0.0165) and total duration of mechanical ventilation (mean 5 ± 11.1 days vs 10.8 ± 14.6 days; P = 0.0000) and significantly lower odds of intraventricular hemorrhage (IVH) (OR 0.4827; 95% CI 0.2999-0.7787) and patent ductus arteriosus (PDA) (OR 0.5686; 95% CI 0.3395-0.9523). The incidence of bronchopulmonary dysplasia (BPD) (36.4% vs 45.8%) and rates of moderate and severe BPD were not significantly different between the two groups. The mortality rates were comparable between the two groups (8.6% vs 8.5%, P = ns). CONCLUSION: Early caffeine initiation was associated with a decreased need for invasive ventilatory support and lower incidence of IVH and PDA.

Nasal CPAP (Infant Flow) applied at birth in extremely low birth weight newborns.

OBJECTIVE: Evaluation of nasal CPAP (Infant Flow) as a ventilatory support, applied at birth in spontaneously breathing, extremely low birth weight newborns (ELBW). MATERIAL AND METHODS: Retrospective analysis of the clinical course of respiratory distress syndrome (RDS) in 97 ELBW, who needed ventilatory support. In all patients the noninvasive ventilatory support was introduced within the first minute of life. RESULTS: Among all analyzed newborns, 37.1% of patients were not intubated during hospitalization. Moreover, another 10.3% patients were intubated only due to surfactant administration according to the INSURE method and after 2-3 minutes of invasive ventilation they were switched to n-CPAP. Nearly half (47.4%) of all evaluated ELBW newborns who needed ventilatory support avoided mechanical ventilation. We found the frequency of bronchopulmonary dysplasia in 97 analyzed patients markedly lower when compared to data presented in literature (19% vs 34%; p=0.026). CONCLUSION: We suggest that starting ventilatory support with the n-CPAP from the first minute of life is a safe and effective strategy in extremely low birth weight infants. It also reduces the costs of treatment, associated with surfactant administration.

Fish-oil fat emulsion supplementation reduces the risk of retinopathy in very low birth weight infants: a prospective, randomized study.

BACKGROUND: Preliminary studies suggest that fish-oil lipid emulsion given parenterally to very preterm infants reduces the severity of retinopathy (ROP) and cholestasis. METHODS: Infants weighing <1250 g at birth were randomly allocated to 2 groups: an experimental group of 60 infants that received an intravenous (IV) soybean, olive oil, and fish oil emulsion, and a control group of 70 infants that was given a parenteral soybean and olive oil emulsion. Plasma and erythrocyte concentrations of docosahexaenoic acid (DHA) were determined using a high-performance liquid chromatography-mass spectrometry analysis. RESULTS: Nine infants in the fish oil group required laser therapy for ROP compared with 22 infants in the standard intralipid group (risk ratio [RR], 0.48; 95% confidence interval [CI], 0.24-0.96). Three infants in the fish oil group developed cholestasis compared with 20 infants in the standard intralipid group (RR, 0.18; 95% CI, 0.055-0.56). The mean plasma DHA concentrations in treated infants were 2.9-fold higher in the fish oil group than in control infants on the 7th and 14th days of life. The mean DHA content in erythrocytes of treated infants was 4.5-fold and 2.7-fold higher compared with controls at 7 and 14 days of age. CONCLUSIONS: Premature infants receiving an IV fat emulsion containing fish oil had less ROP requiring laser treatment and less cholestasis than those receiving a standard lipid emulsion. These infants also had higher plasma and erythrocyte DHA levels at 7 and 14 days, suggesting potential long-term neurodevelopmental benefits.

The efficacy of fish-oil based fat emulsion administered from the first day of life in very low birth weight newborns.

BACKGROUND: DHA has been shown to be important for foetal brain development, optimal development for motor skills and visual acuity in infants. Newborns born prematurely are at increased risk for DHA (docosahexaenoic acid) insufficiency because they may not have benefited from a full trimester of the mother's lipid stores and have very limited ability to synthesize DHA. Moreover, within the first 2-3 weeks of life, the main sources of lipids for most prematurely delivered infants are soyabean/safflower/olive oil emulsions which are rich in n-6 fatty acids and do not contain DHA. AIM: To perform a retrospective analysis, which compares the safety and efficacy outcomes of an intravenous fat emulsion based on fish-oil (containing docosahexaenoic acid- DHA), and is administered from the first day of life in very low birth weight newborns, with data obtained in preterm neonates with birthweight below 1500 g, receiving soyabean/olive oil emulsion, which do not contain DHA. MATERIALS AND METHODS: Infants from the two groups (the study group n=152; the control group n=185) were comparable with regard to demographic and clinical characteristics and were subjected to the same conventional therapy. Determination of plasma and erythrocytes DHA concentrations in newborns was made using a high-performance liquid chromatography-mass spectrometry (LC-ESI/MS) method. Detection of parent ions with negative ionization mode, m/z 327.5 amu. Method validation was according to the ICH and FDA requirements. RESULTS: There was a significantly lower risk of cholestasis in infants, who were receiving the soyabean/ olive oil/fish-oil emulsion (p=0.025). Also, there was a markedly lower risk of laser therapy in infants, who were receiving a fish-oil emulsion however, the difference did not reach statistical significance. CONCLUSIONS: Fish-oil-based fat emulsion administered as a component of total parenteral nutrition from the first day of life is safe in the prophylaxis of cholestasis and severe retinopathy of prematurity. Further clinical investigations are needed.

Docosahexaenoic acid (DHA) concentration in very low birth weight newborns receiving a fish-oil based fat emulsion from the first day of life. Preliminary clinical observation.

BACKGROUND: Preterm infants are at increased risk for DHA deficiency because from 26th weeks of pregnancy until term, 80% of the brain this acid accrues in the fetus. Moreover, the main sources of lipids for preterm newborns are fat emulsions which do not contain DHA. AIM: 1) to investigate the plasma DHA concentration in prematurely delivered newborns who are receiving a fish-oil emulsion in amount equal to one third of total daily intravenous lipid intake or soybean/olive oil fat emulsion from the first day of life. 2) to compare plasma DHA concentration, evaluated immediately after birth in prematurely born infants, with the respective data obtained in full term newborns. MATERIALS AND METHODS: Twenty one preterm infants in the two groups: the study group n=12 (newborns fed parenterally with a partially replaced a soybean/olive oil emulsion with a fish-oil emulsion); the control group n=9 (newborn fed parenterally with a soybean/olive oil emulsion) comparable with regard to demographic and clinical characteristics. Determination of plasma and erythrocytes DHA concentrations in newborns was made using a high-performance liquid chromatography-mass spectrometry (LC-ESI/MS) method. Detection of parent ions with negative ionization mode, m/z 327,5 amu. Method validation was according to the ICH and FDA requirements. RESULTS: The mean values of plasma DHA level measured on the 7th, 14th, 21st, 28th day of life, were statistically significantly lower in the control group when compared with respective data obtained in the study group (7th day: 7.98 vs 42.4 emol/L, p=0.0002; 14th day: 6.8 vs 21.14 emol/l, p=0.000001; 21st day: 11.56 vs 19.1 emol/L, p=0.035; 28th day: 11.4 vs 25.4 emol/L, p=0.0004). The mean value of plasma DHA level in full-term newborns measured in the first hours of life was 164.7 emol/L whereas in preterm neonates it reached 15.9 emol/L (p=0.000001). CONCLUSIONS: The administration of fish-oil-based fat emulsion as a component of total parenteral nutrition from the first day of life may alleviate a marked decrease in plasma DHA level observed in preterm infants within the first weeks after birth. Established method allows for routine determination of DNA concentrations in plasma erythrocytes of newborns.

Fish-oil fat emulsion supplementation may reduce the risk of severe retinopathy in VLBW infants.

OBJECTIVE: The retina contains rods and cones that have membranes highly enriched with docosahexaenoic acid (DHA). Infants born prematurely are at risk of DHA insufficiency, because they may not have benefited from a full third trimester of the mother's lipid stores. Moreover, within the first 2 to 3 weeks of life, the main sources of lipids for premature infants are fat emulsions, which do not contain DHA. PATIENTS AND METHODS: This observational study was designed to compare the safety and efficacy outcomes of an intravenous fat emulsion that consists of fish-oil emulsion (contains DHA) with soybean and olive oil, administered from the first day of life to 40 infants who weighed <1250 g; results were obtained from a historical cohort of 44 preterm neonates who were given an emulsion of soybean and olive oil. The primary study outcomes were the occurrence of retinopathy and need for laser therapy and cholestasis. Infants in the 2 groups were comparable with regard to demographic and clinical characteristics and were subjected to the same conventional therapy. RESULTS: There was a significantly lower risk of laser therapy for infants who received an emulsion of soybean, olive oil, and fish oil (P = .023). No significant differences were found in acuity and latency of visual evoked potentials between infants in the 2 groups. There was no infant with cholestasis among those who received fish-oil emulsion, and there were 5 subjects with cholestasis in the historical group (P = .056). CONCLUSION: Fish-oil-based fat emulsion administered from the first day of life may be effective in the prophylaxis of severe retinopathy.

[Prevalence and risk factors of bronchopulmonary dysplasia among extremely low birth weight newborns of regional birth cohort of south-east Poland]. / Wystepowanie i czynniki ryzyka dysplazji oskrzelowo-plucnej u noworodków urodzonych w województwie malopolskim z ekstremalnie mala masa ciala (< or =1000g).

BACKGROUND: Advances in intensive health care within the last 30 years have resulted in increased survival of most immature neonates. The results of epidemiological studies indicate, however, that late complications of prematurity, including bronchopulmonary dysplasia (BPD), have become more frequent since the late 1990s. The identification of risk factors predisposing to severe BPD might help in developing treatment methods directed at the group of children with high risk of developing the disease. AIM: Analysis of prevalence and risk factors of bronchopulmonary dysplasia among extremely low birth weight newborns of regional birth cohort of south-east Poland. METHODS: The study included newborns of birth weight < or = 1000g born in south-east district of Poland within one calendar year. The data assessed were: the need of oxygen therapy of at least 28 days' duration and the need of oxygen therapy at 36 weeks of postmenstrual age (PMA). RESULTS: During the study period 109 newborns with birth weight < or = 1000g) were hospitalized in three third-level departments of neonatology in south-east Poland. The final assessment for BPD included 56 children (51%), whose mean birth weight was 839g (SD: 128) and mean gestational age was 27.3 weeks (SD: 2.2). Thirty-nine children (70%) required oxygen therapy for at least 28 days, and 27 children (48%) required oxygen therapy at 36 weeks of PMA. Gestational age of the newborn, the need of respiratory support at birth, and the need of surgical treatment of PDA were found to be independent risk factors of oxygen therapy lasting for at least 28 days. Only the need of respiratory support at 7 days of life and the need for surgical treatment of PDA were found to be independent risk factors of oxygen therapy at the 36 weeks of PMA. CONCLUSION: The analysis of several risk factors of BPD in children with birth weight < or =1000g revealed that the need for respiratory support at seven days of life is a major risk factor of developing chronic respiratory disease. The risk of BPD may be significantly reduced by adequate care aimed at shortening the time of conventional respiratory support and at limiting the persistence of ductus arteriosus.

[Current neonatal resuscitation practices in Polish neonatal units - national survey]. / Stan przygotowania pod wzgledem merytorycznym i organizacyjnym oddzialów neonatologicznych o róznym stopniu referencji do prowadzenia resuscytacji noworodka po urodzeniu.

AIM: We surveyed current neonatal resuscitation practices in Polish neonatal units to determine the factors, relevant to improving practices in this area. MATERIAL AND METHODS: The study was performed within the framework of the National Standardization Programme on Neonatal Practices and Procedures in 2007. An 11 question survey included questions concerning the frequency of neonatal resuscitation, type of procedure performed during resuscitation ie.: medicaments and oxygen administration, umbilical vein catetherisation, equipment availability, resuscitation of extremely preterm babies. The survey included also questions concerning problems in resuscitation and their causes. 420 questionnaires were sent out and 274 were returned completed (65.2% response rate). 266 units providing delivery room resuscitation were included in the study. RESULTS: Neonatal resuscitation procedures were needed significantly more frequently in the centres of the highest degree reference (p<0.001). There were also marked differences between the centres according to the frequency of umbilical vessels catetherisation and availability of the necessary medical equipment. In 44.6% of neonatal units, resuscitated newborns are successfully ventilated with room air. However, in 23.5% of the surveyed units, 100% oxygen is used for ventilation. The finding of great importance is that 30.7% of neonatal units stated the need for a trained resuscitator to attend a high risk pregnancy delivery and to resuscitate asphyxiated newborns. CONCLUSIONS: There are substantial differences in neonatal resuscitation practices in different neonatal centres. These findings should stimulate appropriate authorities to start an educational programme to establish suitable polices in newborn resuscitation.

Nebulized pentoxifylline for prevention of bronchopulmonary dysplasia in very low birth weight infants: a pilot clinical study.

OBJECTIVE: To evaluate the effectiveness of nebulized pentoxifylline (PTXF) compared to intravenous dexamethasone (DX) or placebo (nebulized distilled water) for the prevention of bronchopulmonary dysplasia (BPD). METHODS: One hundred and fifty very low birth weight infants were randomly assigned to three groups. Entry criteria were the need for oxygen administration on the fourth day of life, irrespective of whether ventilatory support was required. PTXF was administered with a nebulizer every 6 hours on three consecutive days (a single course) in a dose of 20 mg/kg when infants were breathing spontaneously or 10 mg/kg when they needed ventilatory support. DX was given every 12 hours on three consecutive days in a dose of 0.25 mg/kg. Nebulized distilled water was administered with the schedule of inhalation as in the PTXF group. When the need for ventilatory support or oxygen dependency persisted, the course of both drugs and placebo administration was repeated every seven days until the diagnosis of BPD was established. RESULTS: Both PTXF and DX reduced the incidence of disease when compared with placebo. The respective data obtained for the PTXF-group versus the placebo group were as follows: difference in risk, 27%; OR: 0.32; CI: 0.11-0.94; p = 0.039; whereas the results for the DX-group versus the placebo group were: difference in risk, - 23%; OR: 0.39; CI: 0.14-1.14; p = 0.07. CONCLUSION: Our data show that nebulized PTXF reduces the risk of BPD and may be a potential alternative to steroids in the prevention of this disease.

[Influence of ureaplasma infection on the clinical state of newborns]. / Wplyw zakazenia ureaplazmami na stan kliniczny noworodków.

UNLABELLED: The aim of this study was the analysis of the clinical state of newborns infected with various species of ureaplasma. METHODS: 50 prematurely born patients with respiratory disturbances and confirmed presence of ureaplasma in the respiratory tract were analyzed. Endotracheal aspirates were collected for examination. Presence of ureaplasma was confirmed by culture and a commercial test (Biomerieux), the ureaplasma species were identified using PCR. RESULTS: In 40 examined newborns Ureaplasma parvum (U.p.) was found, in 10 Ureaplasma urealyticum (U.u.). Newborns infected with U.u. were subject to more frequent and longer therapeutic procedures supporting respiration (respirator, nCPAP), needed more frequent surfactant and antibiotic administration. In the mentioned group the mortality rate was 33%, while in newborns infected with U.p. it was 15%. CONCLUSIONS: Initial results suggest worse clinical status and higher mortality of prematurely born infected with Ureaplasma urealyticum.

Inhibition of glutathione-related enzymes augments LPS-mediated cytokine biosynthesis: involvement of an IkappaB/NF-kappaB-sensitive pathway in the alveolar epithelium.

The regulation of lipopolysaccharide (LPS)-mediated pro-inflammatory cytokine biosynthesis by reduction-oxidation (redox)-sensitive enzymes involved in maintaining intracellular glutathione homeostasis was investigated in fetal alveolar type II epithelial cells (fATII). Inhibition of glutathione-oxidized disulfide reductase, which recycles GSSG --> 2GSH, by the action of 1,3-bis-(2-chloroethyl)-1-nitrosourea (BCNU) augmented LPS-dependent secretion of interleukin (IL)-1beta, IL-6 and tumor necrosis factor (TNF)-alpha. BCNU increased [GSSG] concentration at the expense of [GSH], thereby favoring oxidation equilibrium. Inhibition of gamma-glutamylcysteine synthetase, the rate-limiting enzyme in the biosynthesis of GSH, by the action of L-buthionine-(S,R)-sulfoximine (BSO), potentiated LPS-induced IL-1beta, IL-6 and TNF-alpha production. Similar to BCNU, BSO depleted [GSH] and induced the accumulation of [GSSG]. BCNU and BSO reduced LPS-mediated phosphorylation of inhibitory-kappaB (IkappaB-alpha), allowing its cytosolic accumulation. This effect was associated with the inhibition of the nuclear translocation of selective nuclear factor (NF)-kappaB subunits: NF-kappaB1 (p50), RelA (p65), RelB (p68) and c-Rel (p75), but not NF-kappaB2 (p52). BCNU and BSO reduced LPS-induced NF-kappaB activation as determined by the electrophoretic mobility shift DNA-binding assay. Analytical analysis of the effect of modulating the dynamic redox ratio ([GSH]+[GSSG])/[GSSG] revealed a novel role for GSSG as a disulfhydryl compound which mediates an inhibitory effect on NF-kappaB activation. It is concluded that selective modulation of redox-sensitive enzymes has an immunopharmacological potential in regulating pro-inflammatory cytokines and that the TkappaB-alpha/NF-kappaB pathway is redox-sensitive and differentially involved in mediating redox-dependent regulation of cytokine signaling.

Immunopharmacological potential of selective phosphodiesterase inhibition. I. Differential regulation of lipopolysaccharide-mediated proinflammatory cytokine (interleukin-6 and tumor necrosis factor-alpha) biosynthesis in alveolar epithelial cells.

In an attempt to elaborate in vitro on a therapeutic strategy that counteracts an inflammatory signal, we previously reported a novel immunopharmacological potential of glutathione, an antioxidant thiol, in regulating inflammatory cytokines. In the present study, we investigated the hypothesis that selective regulation of phosphodiesterases (PDEs), a family of enzymes that controls intracellular cAMP/cGMP degradation, differentially regulates proinflammatory cytokines. Selective PDE1 inhibition (8-methoxymethyl-3-isobutyl-1-methylxanthine) blockaded lipopolysaccharide-endotoxin (LPS)-mediated biosynthesis of interleukin (IL)-6, but this pathway had no inhibitory effect on tumor necrosis factor-alpha (TNF-alpha). Furthermore, inhibition of PDE3 (amrinone) abolished the effect of LPS on IL-6, but attenuated TNF-alpha production. Reversible competitive inhibition of PDE4 (rolipram) exhibited a potent inhibitory effect on IL-6 and a dual, biphasic (excitatory/inhibitory) effect on TNF-alpha secretion. Blockading PDE5 (4-[[3',4'-(methylenedioxy)benzyl] amino]-6-methoxyquinazoline) showed a high potency in reducing IL-6 production, but in a manner similar to the inhibition of PDE4, exhibited a biphasic effect on TNF-alpha biosynthesis. Simultaneous inhibition of PDE5, 6, and 9 (zaprinast), purported to specifically elevate intracellular cGMP, reduced, in a dose-independent manner, IL-6 and TNF-alpha biosynthesis. Finally, nonselective inhibition of PDE by pentoxifylline suppressed LPS-mediated secretion of IL-6 and TNF-alpha. The involvement of specific PDE isoenzymes in differentially regulating LPS-mediated inflammatory cytokine biosynthesis indicates a novel approach to unravel the potential therapeutic targets that these isozymes constitute during the progression of inflammation within the respiratory epithelium.

Immunopharmacological potential of selective phosphodiesterase inhibition. II. Evidence for the involvement of an inhibitory-kappaB/nuclear factor-kappaB-sensitive pathway in alveolar epithelial cells.

In this report we investigated the immunopharmacological role of selective and nonselective phosphodiesterase (PDE) inhibition in regulating the inhibitory-kappaB (IkappaB-alpha)/nuclear factor-kappaB (NF-kappaB) signaling transduction pathway. In fetal alveolar type II epithelial cells, PDE blockade at the level of the diverging cAMP/cGMP pathways differentially regulated the phosphorylation and degradation of IkappaB-alpha, the major cytosolic inhibitor of NF-kappaB. Whereas selective inhibition of PDEs 1, 3, and 4, by the action of 8-methoxymethyl-3-isobutyl-1-methylxanthine, amrinone, and rolipram, respectively, exhibited a tendency to augment the translocation of NF-kappaB(1) (p50), RelA (p65), RelB (p68), and c-Rel (p75), selective blockade of PDE 5, 6, and 9, by the action of 4-[[3',4'-(methylenedioxy)benzyl]amino]-6-methoxyquinazoline and zaprinast, attenuated lipopolysaccharide-endotoxin (LPS)-mediated NF-kappaB translocation. Pentoxifylline, a nonspecific PDE inhibitor, reversed the excitatory effect of LPS on NF-kappaB subunit nuclear localization, in a dose-dependent manner. Furthermore, analysis of NF-kappaB activation under the same conditions revealed a biphasic effect mediated by LPS. PDEs 1, 3, and 4 inhibition was associated with up-regulating NF-kappaB transcriptional activity. In contrast, blockading the activity of PDEs 5, 6, and 9 negatively attenuated LPS-mediated NF-kappaB activation, similar to the effect of 3,7-dihydro-3,7-dimethyl-1-(5-oxohexyl)-1H-purine-2,6-dione (pentoxifylline). These results indicate that selective and nonselective interference with the control of the dynamic equilibrium of cyclic nucleotides via PDE isoenzyme regulation represents an immunoregulatory mechanism that requires the differential, biphasic targeting of the IkappaB-alpha/NF-kappaB pathway.