The resolution of acute inflammation induced by cyclic AMP is dependent on annexin A1.

Annexin A1 (AnxA1) is a glucocorticoid-regulated protein known for its anti-inflammatory and pro-resolving effects. We have shown previously that the cAMP-enhancing compounds rolipram (ROL; a PDE4 inhibitor) and Bt2cAMP (a cAMP mimetic) drive caspase-dependent resolution of neutrophilic inflammation. In this follow-up study, we investigated whether AnxA1 could be involved in the pro-resolving properties of these compounds using a model of LPS-induced inflammation in BALB/c mice. The treatment with ROL or Bt2cAMP at the peak of inflammation shortened resolution intervals, improved resolution indices, and increased AnxA1 expression. In vitro studies showed that ROL and Bt2cAMP induced AnxA1 expression and phosphorylation, and this effect was prevented by PKA inhibitors, suggesting the involvement of PKA in ROL-induced AnxA1 expression. Akin to these in vitro findings, H89 prevented ROL- and Bt2cAMP-induced resolution of inflammation, and it was associated with decreased levels of intact AnxA1. Moreover, two different strategies to block the AnxA1 pathway (by using N-t-Boc-Met-Leu-Phe, a nonselective AnxA1 receptor antagonist, or by using an anti-AnxA1 neutralizing antiserum) prevented ROL- and Bt2cAMP-induced resolution and neutrophil apoptosis. Likewise, the ability of ROL or Bt2cAMP to induce neutrophil apoptosis was impaired in AnxA-knock-out mice. Finally, in in vitro settings, ROL and Bt2cAMP overrode the survival-inducing effect of LPS in human neutrophils in an AnxA1-dependent manner. Our results show that AnxA1 is at least one of the endogenous determinants mediating the pro-resolving properties of cAMP-elevating agents and cAMP-mimetic drugs.

Effect of bucladesine, pentoxifylline, and H-89 as cyclic adenosine monophosphate analog, phosphodiesterase, and protein kinase A inhibitor on acute pain.

The aim of this study was to determine the effects of cyclic adenosine monophosphate (cAMP) and its dependent pathway on thermal nociception in a mouse model of acute pain. Here, we studied the effect of H-89 (protein kinase A inhibitor), bucladesine (Db-cAMP) (membrane-permeable analog of cAMP), and pentoxifylline (PTX; nonspecific phosphodiesterase (PDE) inhibitor) on pain sensation. Different doses of H-89 (0.05, 0.1, and 0.5 mg/100 g), PTX (5, 10, and 20 mg/100 g), and Db-cAMP (50, 100, and 300 nm/mouse) were administered intraperitoneally (I.p.) 15 min before a tail-flick test. In combination groups, we injected the first and the second compounds 30 and 15 min before the tail-flick test, respectively. I.p. administration of H-89 and PTX significantly decreased the thermal-induced pain sensation in their low applied doses. Db-cAMP, however, decreased the pain sensation in a dose-dependent manner. The highest applied dose of H-89 (0.5 mg/100 g) attenuated the antinociceptive effect of Db-cAMP in doses of 50 and 100 nm/mouse. Surprisingly, Db-cAMP decreased the antinociceptive effect of the lowest dose of H-89 (0.05 mg/100 g). All applied doses of PTX reduced the effect of 0.05 mg/100 g H-89 on pain sensation; however, the highest dose of H-89 compromised the antinociceptive effect of 20 mg/100 g dose of PTX. Co-administration of Db-cAMP and PTX increased the antinociceptive effect of each compound on thermal-induced pain. In conclusion, PTX, H-89, and Db-cAMP affect the thermal-induced pain by probably interacting with intracellular cAMP and cGMP signaling pathways and cyclic nucleotide-dependent protein kinases.

Reduction of autophagy markers mediated protective effects of JNK inhibitor and bucladesine on memory deficit induced by Aß in rats.

Autophagy, the process of self-degradation of cellular components, has an important role in neurodegenerative diseases, such as Alzheimer's disease. In this study, we investigated the effects of SP600125 as c-Jun N-terminal kinase (JNK) inhibitor and bucladesine as a cyclic adenosine 3',5'-monophosphate (cAMP) analog on spatial memory and expression of autophagic factors in Aß-injected rats. Male Wistar rats were used. Rats were randomly allocated into five groups as following: amyloid beta (Aß)-only group, Aß + SP600125 (30 µg/1 µ/side, n = 7) and/or bucladesine (100 µM/1 µl/side, n = 7), and the normal control (vehicle only) group. The treatments were administered bilaterally to the CA1 sub-region of the hippocampus stereotaxically. Spatial reference memory was performed using Morris Water Maze 21 days later. The expression of authophagy markers (beclin1, Atg7, Atg12, and LC3 II/LC3 I) in the hippocampus was evaluated using western blotting. Compared to the vehicle group, Aß administration reduced spatial reference learning (P < 0.001) and memory (P < 0.01) and upregulated the expression of beclin1, Atg7, Atg12, and LC3 II/I (P < 0.0001). Compare to Aß-only group, the administration of SP600125 and/or bucladesine improved spatial reference learning (P < 0.001) and memory (P < 0.01). Compared to the Aß-only group, the treatment with SP600125 and/or bucladesine also reduced beclin1, Atg7, Atg12, and LC3 II/I (P < 0.0001) which was similar to amount of normal rats. In summary, it seems that the improvement of spatial memory by SP600125 and/or bucladesine in Aß-injected rats is in relation with normalizing of autophagy to the physiologic level, possibly through neuroprotection and/or neuroplasticity.

Zinc Chloride and Lead Acetate-Induced Passive Avoidance Memory Retention Deficits Reversed by Nicotine and Bucladesine in Mice.

It is very important to investigate the neurotoxic effects of metals on learning and memory processes. In this study, we tried to investigate the effects and time course properties of oral administration of zinc chloride (25, 50, and 75 mg/kg, for 2 weeks), lead acetate (250, 750, 1,500, and 2,500 ppm for 4, 6 and 8 weeks), and their possible mechanisms on a model of memory function. For this matter, we examined the intra-peritoneal injections of nicotine (0.25, 0.5, 1, and 1.5 mg/kg) and bucladesine (50, 100, 300, and 600 nM/mouse) for 4 days alone and in combination with mentioned metals in the step-through passive avoidance task. Control animals received saline, drinking water, saline, and DMSO (dimethyl sulfoxide)/deionized water (1:9), respectively. At the end of each part of studies, animals were trained for 1 day in step-through task. The avoidance memory retention alterations were evaluated 24 and 48 h later in singular and combinational studies. Zinc chloride (75 mg/kg) oral gavage for 2 weeks decreased latency times compared to control animals. Also, lead acetate (750 ppm oral administrations for 8 weeks) caused significant lead blood levels and induced avoidance memory retention impairments. Four-days intra-peritoneal injection of nicotine (1 mg/kg) increased latency time compared to control animals. Finally, findings of this research showed that treatment with intra-peritoneal injections of nicotine (1 mg/kg) and/or bucladesine (600 nM/mouse) reversed zinc chloride- and lead acetate-induced avoidance memory retention impairments. Taken together, these results showed the probable role of cholinergic system and protein kinase A pathways in zinc chloride- and lead acetate-induced avoidance memory alterations.

Sustained delivery of dbcAMP by poly(propylene carbonate) micron fibers promotes axonal regenerative sprouting and functional recovery after spinal cord hemisection.

This study describes the use of poly(propylene carbonate) (PPC) electrospun fibers as vehicle for the sustained delivery of dibutyryl cyclic adenosine monophosphate (dbcAMP) to the hemisected spinal cord. The dbcAMP and PPC were uniformly mixed with acetonitrile; then, electrospinning was used to generate micron fibers. The release of dbcAMP was assessed by ELISA in vitro. Our results showed that the encapsulation of dbcAMP in the fibers led to stable and prolonged release in vitro. The PPC micron fibers containing dbcAMP and the PPC micron fibers without dbcAMP were then implanted into the hemisected thoracic spinal cord, followed by testing of the functional recovery and immunohistochemistry. Compared with the control group, sustained delivery of dbcAMP promoted axonal regenerative sprouting and functional recovery and reduced glial scar formation, and the PPC micron fibers without dbcAMP did not have these effects. Our findings demonstrated the feasibility of using PPC electrospun fibers containing dbcAMP for spinal cord injury. The approach described here also will provide a platform for the potential delivery of other axon-growth-promoting or scar-inhibiting agents.

The stable cyclic adenosine monophosphate analogue, dibutyryl cyclo-adenosine monophosphate (bucladesine), is active in a model of acute skin inflammation.

Anti-inflammatory therapeutic options for the topical treatment of skin diseases with inflammatory or allergic contribution are mostly limited to topical glucocorticoids and calcineurin inhibitors. Both compound classes induce adverse effects. Elevation of intracellular cyclic adenosine monophosphate (cAMP) by inhibition of phosphodiesterase 4 was shown to induce potent anti-inflammatory effects, but the safety profile of currently available compounds is not sufficient. A different approach to increase intracellular cAMP is the substitution of chemically stabilized cAMP analogues. Bucladesine is a stabilized cAMP analogue with an excellent safety profile which had been marketed as topical treatment of impaired wound healing. In the current study, a novel water free emulsion containing bucladesine was evaluated for anti-inflammatory effects. In the arachidonic acid induced ear oedema model in mice, single or multiple administration of an emulsion containing 1.5% was capable of significantly reducing the inflammatory oedema. The data indicate that bucladesine represents an interesting treatment option for skin diseases where an anti-inflammatory activity is indicated. Due to the established clinical safety, this agent may bridge the gap between potent agents such as glucocorticoids or calcineurin inhibitors and emollients without active compounds.

Effects of pentoxifylline and H-89 on epileptogenic activity of bucladesine in pentylenetetrazol-treated mice.

The present study shows interactive effects of pentoxifylline (PTX) as a phosphodiesterase (PDE) inhibitor, H-89 as a protein kinase A (PKA) inhibitor and bucladesine (db-cAMP) as a cAMP agonist on pentylenetetrazol (PTZ)-induced seizure in mice. Different doses of pentoxifylline (25, 50, 100 mg/kg), bucladesine (50, 100, 300 nM/mouse), and H-89 (0.05, 0.1, 0.2 mg/100g) were administered intraperitoneally (i.p.), 30 min before intravenous (i.v.) infusion of PTZ (0.5% w/v). In combination groups, the first and second components were injected 45 and 30 min before PTZ infusion. In all groups, the control animals received an appropriate volume of vehicle. Single administration of PTX had no significant effect on both seizure latency and threshold. Bucladesine significantly decreased seizure latency and threshold only at a high concentration (300 nM/mouse). Intraperitoneal administration of H-89 (0.2 mg/100g) significantly increased seizure latency and threshold in PTZ-treated animals. All applied doses of bucladesine in combination with PTX (50 mg/kg) caused a significant reduction in seizure latency. Pretreatment of animals with PTX (50 and 100 mg/kg) attenuated the anticonvulsant effect of H-89 (0.2 mg/100g) in PTZ-exposed animals. H-89 (0.05, 0.2 mg/100g) prevented the epileptogenic activity of bucladesine (300 nM) with significant increase of seizure latency and seizure threshold. In conclusion, we showed that seizure activities were affected by pentoxifylline, H-89 and bucladesine via interactions with intracellular cAMP and cGMP signaling pathways, cyclic nucleotide-dependent protein kinases, and related neurotransmitters.

Effects of dibutyryl cyclic-AMP on survival and neuronal differentiation of neural stem/progenitor cells transplanted into spinal cord injured rats.

Neural stem/progenitor cells (NSPCs) have great potential as a cell replacement therapy for spinal cord injury. However, poor control over transplant cell differentiation and survival remain major obstacles. In this study, we asked whether dibutyryl cyclic-AMP (dbcAMP), which was shown to induce up to 85% in vitro differentiation of NSPCs into neurons would enhance survival of transplanted NSPCs through prolonged exposure either in vitro or in vivo through the controlled release of dbcAMP encapsulated within poly(lactic-co-glycolic acid) (PLGA) microspheres and embedded within chitosan guidance channels. NSPCs, seeded in fibrin scaffolds within the channels, differentiated in vitro to betaIII-tubulin positive neurons by immunostaining and mRNA expression, in response to dbcAMP released from PLGA microspheres. After transplantation in spinal cord injured rats, the survival and differentiation of NSPCs was evaluated. Untreated NSPCs, NSPCs transplanted with dbcAMP-releasing microspheres, and NSPCs pre-differentiated with dbcAMP for 4 days in vitro were transplanted after rat spinal cord transection and assessed 2 and 6 weeks later. Interestingly, NSPC survival was highest in the dbcAMP pre-treated group, having approximately 80% survival at both time points, which is remarkable given that stem cell transplantation often results in less than 1% survival at similar times. Importantly, dbcAMP pre-treatment also resulted in the greatest number of in vivo NSPCs differentiated into neurons (37±4%), followed by dbcAMP-microsphere treated NSPCs (27±14%) and untreated NSPCs (15±7%). The reverse trend was observed for NSPC-derived oligodendrocytes and astrocytes, with these populations being highest in untreated NSPCs. This combination strategy of stem cell-loaded chitosan channels implanted in a fully transected spinal cord resulted in extensive axonal regeneration into the injury site, with improved functional recovery after 6 weeks in animals implanted with pre-differentiated stem cells in chitosan channels.

Lovastatin induces neuronal differentiation and apoptosis of embryonal carcinoma and neuroblastoma cells: enhanced differentiation and apoptosis in combination with dbcAMP.

Differentiation-based therapeutics are an underutilized but a potentially significant treatment option for cancer patients. We show that lovastatin, a competitive inhibitor of the rate-limiting enzyme of mevalonate synthesis HMG-CoA reductase, is able to induce tumour cell differentiation and apoptosis in vitro. We used embryonal carcinoma (EC) and neuroblastoma (NB) cell lines and found that lovastatin promoted apoptosis and induced expression of the neuronal differentiation markers, tyrosine hydroxylase (TH), and growth-associated protein 43. The apoptotic and differentiation responses were time and dose-dependant and rescued by the co-administration of mevalonate. The expression of TH is regulated primarily by a cyclic AMP (cAMP) response element (CRE) in its promoter. Lovastatin enhanced the expression of a CRE-driven luciferase construct in P19 cells. Furthermore, combining lovastatin with 1 mM dibutyryladenosine 3',5'-cyclic monophosphate treatments induced higher expression from the CRE construct, enhanced differentiation and cytotoxicity. This study suggests the potential of combining these therapeutic approaches in EC and NB patients.

Dose and chemical modification considerations for continuous cyclic AMP analog delivery to the injured CNS.

In this investigation, two cell-permeable synthetic analogs of cAMP, dibutyryl-cAMP (db-cAMP) and 8-bromo-cAMP, which are widely used to elevate intracellular cAMP levels under experimental conditions, were investigated for their ability to dose-dependently improve histological and functional outcomes following continuous delivery in two models of incomplete spinal cord injury (SCI). The cAMP analogs were delivered via osmotic minipumps at 1-250 mM through an indwelling cortical cannula or by intrathecal infusion for up to 4 weeks after either a T8 unilateral over-hemisection or a C2-3 dorsolateral quadrant lesion, respectively. In both SCI models, continuous db-cAMP delivery was associated with histopathological changes that included sporadic micro-hemorrhage formation and cavitation, enhanced macrophage infiltration and tissue damage at regions beyond the immediate application site; no deleterious or beneficial effect of agent delivery was observed at the spinal injury site. Furthermore, these changes were accompanied by pronounced behavioral deficits that included an absence of progressive locomotor recovery, increased extensor tone, paralysis, and sensory abnormalities. These deleterious effects were not observed in saline-treated animals, in animals in which the db-cAMP dose did not exceed 1 mM, or in those animals that received a high dose (250 mM) of the alternative cAMP analog, 8-bromo-cAMP. These results demonstrate that, for continuous intraparenchymal or intrathecal administration of cAMP analogs for the study of biological or therapeutic effects within the central nervous system (CNS), consideration of the effective concentration applied as well as the potential toxicity of chemical moieties on the parent molecule and/or their activity needs to be taken into account.

Combined therapy of pentastarch, dexamethasone, and dibutyryl-cAMP or beta 2-agonist attenuates ischaemia/reperfusion injury of rat lung.

We hypothesised that combined therapy with macromolecules that seal endothelial damage [pentastarch (Penta)], an anti-inflammatory agent [dexamethasone (Dex)], and an agent that reabsorbs alveolar fluid [beta(2)-agonist or dibutyryl-cAMP (Bt(2)-cAMP)] would have additive ameliorating effects on ischaemia/reperfusion (I/R) injury of the lung. We perfused one of the following solutions into isolated rat lungs in a closed circulating system, either prior to I/R injury (groups 1-5) or following 60 min of ischaemia (groups 6-10): (1) 0.9% normal saline (NS), (2) Penta, (3) Penta+Dex, (4) Penta+Bt(2)-cAMP, (5) Penta+beta(2)-agonist inhalation, (6) Penta+Dex, (7) Penta+Bt(2)-cAMP, (8) Penta+beta(2)-agonist inhalation, (9) Penta+Dex+Bt(2)-cAMP, or (10) Penta+Dex+beta(2)-agonist inhalation. Haemodynamics, lung weight gain (LWG), capillary filtration coefficient (K(fc)), cytokine mRNA levels, and lung pathology were assessed. Results showed that Dex, Bt(2)-cAMP, or beta(2)-agonist as an additive to Penta decreased K(fc) and LWG below values seen with Penta alone. Furthermore, LWG and K(fc) values in groups with three protective agents were lower than those in groups with two protective agents. Significantly lower levels of TNF-alpha and IL-1 mRNAs were observed in groups treated with Dex. Histopathological studies showed decreased injury profiles for all combined therapy groups. We conclude that the addition of Dex, Bt(2)-cAMP, or beta(2)-adrenergic agonist to Penta solution promoted attenuation of I/R injury. Furthermore, combination therapy with three protective agents (Penta+Dex+beta(2)-adrenergic agonist) caused the greatest attenuation of I/R.

Efecto del extracto acuoso de hojas de Bauhinia megalandra sobre la glucogenólisis hepática en ratas / Effect of aqueous extract of leaves of Bauhinia megalandra glucogenólisis on the liver in rats

El extracto acuoso de las hojas de Bauhinia megalandra ha sido muy empleado en Venezuela en el tratamiento empírico de la diabetes mellitus. En el presente trabajo se estudió el efecto del extracto acuoso de B. megalandra sobre la glucogenolísis hepática estimulada por adrenalina o dibutiril AMPc. La administración oral del extracto de la planta, a ratas alimentadas, disminuyó de una manera estadísticamente significativa el incremento de la glicemia promovido por la adrenalina. De igual manera, rebanadas de hígado de ratas alimentadas incubadas en presencia del extracto de B. megalandra produjeron menos glucosa en respuesta a la adrenalina o al dibutiril AMPc que los controles. Estos resultados indican una disminución de la glucogenolísis hepática por efecto del extracto acuoso de hojas de B. megalandra, probablemente por inhibición de la enzima glucosa-6-fosfatasa.

Combinatorial therapy with neurotrophins and cAMP promotes axonal regeneration beyond sites of spinal cord injury.

Previous attempts to promote regeneration after spinal cord injury have succeeded in stimulating axonal growth into or around lesion sites but rarely beyond them. We tested whether a combinatorial approach of stimulating the neuronal cell body with cAMP and the injured axon with neurotrophins would propel axonal growth into and beyond sites of spinal cord injury. A preconditioning stimulus to sensory neuronal cell bodies was delivered by injecting cAMP into the L4 dorsal root ganglion, and a postinjury stimulus to the injured axon was administered by injecting neurotrophin-3 (NT-3) within and beyond a cervical spinal cord lesion site grafted with autologous bone marrow stromal cells. One to 3 months later, long-projecting dorsal-column sensory axons regenerated into and beyond the lesion. Regeneration beyond the lesion did not occur after treatment with cAMP or NT-3 alone. Thus, clear axonal regeneration beyond spinal cord injury sites can be achieved by combinatorial approaches that stimulate both the neuronal soma and the axon, representing a major advance in strategies to enhance spinal cord repair.

Vancomycin ointment for MRSA infection at a cranioplasty site.

OBJECTIVE: To report a case illustrating therapeutic success with long-term topical application of aseptic vancomycin ointment to treat methicillin-resistant Staphylococcus aureus (MRSA) infection at a cranioplasty site. CASE SUMMARY: A 63-year-old Japanese woman underwent evacuation of a subdural hematoma complicated by subarachnoid hemorrhage. Subsequent craniotomy for clipping and external decompression of an aneurysm of the neck was followed by cranioplasty using an autologous bone graft. The graft became infected with MRSA, which responded to intravenously infused vancomycin. The graft was then replaced with a ceramic implant. The implant site became reinfected with MRSA. Vancomycin infusion failed on this occasion, despite a favorable in vitro sensitivity test. After obtaining patient consent, investigative treatment was begun using long-term aseptic application of vancomycin 2.5% ointment, resulting in control of the infection and negative cultures. DISCUSSION: The care of an infection at the site of cranioplasty with a ceramic artificial bone implant is difficult. Our patient's infection resolved with the use of vancomycin ointment. In this case, blood concentrations of vancomycin remained below detectable levels, and no adverse effects resulted from application of vancomycin ointment. CONCLUSIONS: Topical administration of vancomycin was more effective than systemic administration in the treatment of our patient's MRSA skull implant infection. No adverse effects from topical treatment were encountered over 3 years.

Local interstitial chemotherapy with sustained release bucladesine in de novo glioblastoma multiforme: a preliminary study.

This clinical study was designed to evaluate the safety and efficacy of the sustained release form of dibutryl adenosine-3',5'-cyclic monophosphate (dB-cAMP, bucladesine) placed in the tumor resection cavity at the time of recurrence of the de novo glioblastoma multiforme (GBM) patients. In a randomized prospective manner, 40 patients who were diagnosed as GBM in their first operations were included in this study. Four different therapy protocols were used: First group of 10 patients had tumor resection only. Second group assessed had only systemic chemotherapy as six i.v. infusions of fotémustine after tumor resection. Third group had implantation of bucladesine-loaded biodegradable polymeric sustained release (bcl-SR) pellets while the last group received six i.v. infusions of systemic fotémustine as in the second group in addition to local implantation of bcl-SR pellets. A biodegradable polymer, poly-DL-lactide-co-glycolide with molecular weight of 80000, was used as carrier matrix for the drug with an approximately 4-5 months of release time. Maximal doses of 20 mg of bucladesine with a mean dose of 15.5 mg were implanted. No bone marrow suppression occurred and there were no wound infections as far as the local bucladesine-loaded polymer therapy is concerned. In this randomized prospective trial of local interstitial chemotherapy with long acting bcl-SR did show a statistically significant delay of recurrence on the treatment of GBM patients. Best treatment results obtained from the local bcl-SR + systemic fotémustine treated group in which survival rate estimated by the Kaplan-Meier method was 70% in de novo GBM at 12 months.

Systemic adenosine given after ischemia protects renal function via A(2a) adenosine receptor activation.

Ischemia and reperfusion during renal transplant and aortic surgery result in renal ischemic-reperfusion injury. Previously, we showed that preischemic adenosine treatment protects renal function via A(1) adenosine receptor (AR) activation. In contrast, in the cardiac and pulmonary systems, postischemic adenosine has potent anti-inflammatory attributes and is protective against reperfusion injury via activation of A(2a) ARs. We questioned whether adenosine given after an ischemic insult protects renal function in rats, and we sought to determine the AR subtype and intracellular second messengers involved. Rats were randomized to a sham operation, 45 minutes of renal ischemia and reperfusion and treatments with systemic adenosine or selective AR agonists and antagonists, or treatments of dibutyryl cyclic adenosine monophosphate (cAMP) after 45 minutes of renal ischemia but before reperfusion. Forty-five minutes of renal ischemia followed by 24 hours of reperfusion led to severe renal dysfunction as indicated by marked rises in creatinine and histologically evident renal tubular damage. Adenosine treatment after ischemia protected renal function and improved tubular histology. This protection was mediated via A(2a) AR activation because the A(2a)-selective AR agonist [4-((N-ethyl-5'-carbamoyadenos-2-yl)-aminoethyl)-phenylpropionic acid (CGS-21680)] mimics adenosine-induced renal protection, and the A(2a)-selective AR antagonist [8-(3-chlorostyryl)caffeine (CSC)] blocks adenosine-induced renal protection. A(1) or A(3) AR agonists and antagonists did not mimic and block adenosine-induced renal protection. The signaling intermediates of A(2a) AR-mediated renal protection appear to include cAMP because dibutyryl cAMP mimicked adenosine and CGS-21680 mediated renal protection. Rat kidneys can be protected against reperfusion injury via postischemic A(2a) AR activation or cAMP. These data suggest that A(2a) adenosine agonists may have clinically beneficial implications when renal ischemia is unavoidable.

Protection by a cyclic AMP-specific phosphodiesterase inhibitor, rolipram, and dibutyryl cyclic AMP against Propionibacterium acnes and lipopolysaccharide-induced mouse hepatitis.

OBJECTIVE AND DESIGN: To study the effect of cellular cAMP-increasing agents on Propionibacterium acnes (P. acnes) and lipopolysaccharide (LPS)-induced mouse hepatitis. MATERIAL: Male BALB/c mice were used. Macrophages/Kupffer cells isolated from P. acnes-primed murine liver were used for the in vitro study. TREATMENT: Type IV phosphodiesterase (PDE)-specific inhibitor, rolipram, was administered (10, 30 mg/kg, p. o.). Dibutyryl cyclic AMP (dbcAMP) was injected (10, 100 mg/kg, i.p.) into the mice. METHOD: Plasma TNFalpha estimated by the use of an L-929 cell cytotoxic assay and plasma transaminase activities were measured for the in vivo study. The LPS-induced production of TNFalpha in vitro from the cultured macrophage/Kupffer cells was determined by ELISA. RESULTS: Rolipram suppressed the elevation of plasma transaminases induced by injection of LPS, and dbcAMP had a tendency to suppress them. Both agents attenuated the LPS-induced release of TNFalpha in vivo, and suppressed the TNFalpha production from the cultured macrophage/Kupffer cells. CONCLUSIONS: These results suggest that rolipram and dbcAMP have potential to inhibit TNFalpha production from activated macrophage/Kupffer cells, and it may be partially involved in the protecting effect in the P. acnes/LPS hepatitis model.

Dibutyryl cAMP prevents increased vascular permeability caused by air embolism in isolated rat lungs.

BACKGROUND AND HYPOTHESIS: Venous gas bubbles are routinely detected in astronauts undergoing extravehicular activities at lower suit pressure. Venous air embolism increases the pulmonary arterial pressure and the vascular permeability leading to acute lung injury. In the present study we evaluated the protective effect of dibutyryl cAMP, aminophylline, and pentoxifylline on the pulmonary vasculatures after air embolism. METHOD: In isolated and perfused rat lungs, we induced air embolism by introducing air bubbles into the pulmonary artery. We measured the pulmonary arterial pressures and capillary pressure. Vascular permeability was determined by measuring the filtration coefficient (Kf) and the protein concentration in the lung lavage fluid. RESULTS: Air infusion caused pulmonary hypertension and increased vascular permeability, resulting in pulmonary edema. The Kf (in g.min-1.cm H2O-1.100 g-1) increased from 0.44 +/- 0.05 at baseline to 2.98 +/- 0.47 after air infusion. Pretreatment with DBcAMP prevented the increase in Kf (0.63 +/- 0.09) caused by air embolism without altering the hemodynamics. Aminophylline and pentoxifylline did not prevent lung injury induced by air embolism. Although aminophylline did not alter the response of pulmonary arterial pressure to air infusion, it elevated the capillary pressure to 5.1 +/- 0.4 mmHg, which was significantly greater than that in the lung receiving air infusion alone. CONCLUSION: Our results suggest that DBcAMP prevents the increase in vascular permeability caused air embolism. The ineffectiveness of aminophylline and pentoxifylline on the prevention of air embolism-induced lung injury remains for further investigation.

Foot ulcer due to arteriovenous malformation: report of a case.

A 41-year-old woman had erosive eruptions surrounded by irregularly shaped pigmentation on the lateral aspect of her right foot, where she had noted gradually increasing warmth and pain for 10 years. The eruptions waxed and waned without complete healing, and an ulcer which had formed one year previously did not respond to topical treatments. Arteriography performed on the right lower extremity disclosed multiple diffuse arteriovenous malformations in the right lower leg and foot. The ulcer was treated by bed rest, surgical debridement, and topical application of bucladesine sodium ointment. After three months, the ulcer healed, leaving a shallow scar and pigmentation.