Systemic control mechanisms of pain are based on interplay between nervous autonomic and immune systems. The aim of this study was to examine a possible role of the vagus nerve in regulation of nocyception. Peritoneal inflammation increased vagal activity. Pretreatment of PTX had an analgesic effect confirmed by amount of WT and decreased vagal activity. The vagotomy decreased nociceptive threshold.
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To review the pharmacology and clinical utility of cilostazol, an antiplatelet and vasodilator agent approved for the management of intermittent claudication.
Camptothecin (CAM) and cisplatin (cis-diamminedichloroplatinum(II), cis-Pt) were used as inducers of apoptosis in the mouse leukemic L1210 cells. Relatively high concentrations of 50 micromol cis-Pt and 50 micromol CAM, respectively, were used to induce the apoptotic DNA ladder. The simultaneous treatment of L1210 cells by the drug and pentoxifylline (PTX) resulted in a decrease of drug concentrations necessary for the induction of apoptosis. This study revealed that a cell cycle G2 checkpoint inhibitor PTX reduces time intervals necessary for the onset of drug-induced apoptosis in these cells. This fact might be important as the earlier onset of programmed cell death may decrease a risk of tumor cells to become resistant to drug therapy.
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We included 13 studies with a total of 445 participants. The quality of the trials was generally poor and no results could be pooled due to the treatments being so heterogeneous. Treatment with thalidomide showed a significant remission of skin lesions compared to acetylsalicylic acid (aspirin) (RR 2.43; 95% CI 1.28 to 4.59) (1 trial, 92 participants). Clofazimine treatment was superior to prednisolone (more treatment successes; RR 3.67; 95% CI 1.36 to 9.91) (1 trial, 24 participants), and thalidomide (fewer recurrences; RR 0.08; 95% CI 0.01 to 0.56) (1 trial, 72 participants). We did not find any significant benefit for intravenous betamethasone compared to dextrose (1 trial, 10 participants), pentoxifylline compared to thalidomide (1 trial, 44 participants), indomethacin compared to prednisolone, aspirin or chloroquine treatments (2 trials, 80 participants), or levamisole compared to placebo (1 trial, 12 participants). Mild to moderate adverse events were significantly lower in participants taking 100 mg thalidomide compared to 300 mg thalidomide daily (RR 0.46; 95% CI 0.23 to 0.93). Significantly more minor adverse events were reported in participants taking clofazimine compared with prednisolone (RR 1.92; 95% CI 1.10 to 3.35). None of the studies assessed quality of life or economic outcomes.
We investigated pentoxifylline (PTF) as a pretreatment of septic syndrome in pigs with fecal peritonitis. In the untreated group there was a progressive decrease in mean arterial pressure (MAP), cardiac output, mean pulmonary artery wedge pressure (WP), and a progressive rise in mean pulmonary artery pressure (MPAP), pulmonary vascular resistance (PVR), systemic vascular resistance (SVR), heart rate (HR), and core temperature (T). In those pigs given PTF there was a significantly smaller increase in SVR throughout and in PVR after 270 min. No significant differences were seen in MAP, MPAP, WP, HR, and T. Neutrophil adhesiveness did not change in the untreated group. However, it decreased markedly with PTF, both before and after peritonitis induction. Electron microscopy of the lungs, liver, and spleen in the test group showed severe damage, with endothelial disruption, capillary or sinusoidal occlusion, leukostasis, and neutrophil degranulation. Pretreatment with PTF attenuated these changes.
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Acute lung inflammation is complicated by altered pulmonary surfactant phospholipid and protein composition. The proinflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) and the phorbol ester 12-O-tetradecanoyl phorbol-13-acetate (TPA) inhibit expression of surfactant-associated proteins A and B (SP-A and SP-B), both important for normal surfactant function. The transcription factor nuclear factor-kappa B (NF-kappa B) frequently mediates regulation of gene expression by TPA and TNF-alpha. In the present study, electrophoretic mobility shift assays (EM-SAs) and pyrrolidine dithiocarbamate (PDTC), an inhibitor of NF-kappa B activation, were utilized to determine the role of NF-kappa B activation in TPA and TNF-alpha inhibition of the surfactant proteins in NCI-H441 cells. Pentoxifylline (PTX), which inhibits TNF-alpha cellular effects without preventing NF-kappa B activation, was also tested. By EMSA, TPA and TNF-alpha increased nuclear NF-kappa B binding activity in temporally distinct patterns. PDTC decreased TPA- and TNF-alpha-induced NF-kappa B binding activity but did not limit their inhibition of SP-A and SP-B mRNAs. PDTC independently decreased both SP-A and SP-B mRNAs. PTX partially reversed TNF-alpha-but not TPA-mediated inhibition of SP-A and SP-B mRNAs without altering NF-kappa B binding. The effects of PDTC and PTX on NF-kappa B and the surfactant proteins suggest that NF-kappa B activation does not mediate TPA or TNF-alpha inhibition of SP-A and SP-B mRNA accumulation.
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These studies indicate that PAF, a known stimulator of aggregation, secretory and/or contractile activity of platelets, neutrophils, smooth muscle and other cells, is produced by skeletal muscle during IRI. The maximum increase occurs at 10 to 15 minutes and continues for at least an hour. Infusions of PAF into skeletal muscle subjected to 20 minutes of ischemia and 20 hours of reperfusion resulted in tissue necrosis similar to that produced by 5 hours of ischemia and 20 hours of reperfusion. 25 mg/kg of pentoxifylline, infused immediately prior to reperfusion of ischemic skeletal muscle, decreased PAF production and muscle necrosis. It was also demonstrated that skeletal muscle necrosis can be reduced by infusion of PAF antagonists (WEB-2086) into the muscle immediately prior to reperfusion. Thus, PAF has an important role in skeletal muscle IRI and additional studies of PAF inhibition during IRI are warranted.
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40 type 2 nonhypertensive diabetic patients were randomly allocated to receive either pentoxifylline 400 mg t.i.d. or placebo daily for 16 weeks. Eligible subjects were those with urinary albumin excretion between 20 and 200 microg/min. Subjects receiving angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), calcium antagonists, and diuretics as well as those with reduced renal function, pregnancy, urinary tract infection, and smoking were not included. A 6-month pretreatment stabilization phase aimed to reduce and stabilize fasting serum glucose levels was carried out. Urinary proteins were identified by electrophoresis, and immunodetection was identified by Western blot. Electrophoretic analysis was performed using molecular weight markers of 150, 132, 77, and 66 kDa to identify high-weight proteins, and 54, 41, 36, 27, 21, 14.3, and 12 kDa to identify low-weight proteins.
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Livedoid vasculopathy is a bilateral painful and recurrent cutaneous ulcerative disorder of the legs that leads to atrophie blanche, atrophic white-porcelain scars, and is associated with disorders of fibrinolysis and/or coagulation. We present a young boy with an association between livedoid vasculopathy in the area of a previous involuted cutaneous hemangioma. We found 4 uncommon abnormalities associated with thrombo-occlusive events: heterozygous 20210 A→G genotype of prothrombin, reduced activity of anticoagulation proteins C and S, and elevated lipoprotein (a).
Given the high prevalence and rising incidence of non-alcoholic fatty liver disease (NAFLD), the absence of approved therapies is striking. Although the mainstay of treatment of NAFLD is weight loss, it is hard to maintain, prompting the need for pharmacotherapy as well. A greater understanding of disease pathogenesis in recent years was followed by development of new classes of medications, as well as potential repurposing of currently available agents. NAFLD therapies target four main pathways. The dominant approach is targeting hepatic fat accumulation and the resultant metabolic stress. Medications in this group include peroxisome proliferator-activator receptor agonists (eg, pioglitazone, elafibranor, saroglitazar), medications targeting the bile acid-farnesoid X receptor axis (obeticholic acid), inhibitors of de novo lipogenesis (aramchol, NDI-010976), incretins (liraglutide) and fibroblast growth factor (FGF)-21 or FGF-19 analogues. A second approach is targeting the oxidative stress, inflammation and injury that follow the metabolic stress. Medications from this group include antioxidants (vitamin E), medications with a target in the tumour necrosis factor α pathway (emricasan, pentoxifylline) and immune modulators (amlexanox, cenicriviroc). A third group has a target in the gut, including antiobesity agents such as orlistat or gut microbiome modulators (IMM-124e, faecal microbial transplant, solithromycin). Finally, as the ongoing injury leads to fibrosis, the harbinger of liver-related morbidity and mortality, antifibrotics (simtuzumab and GR-MD-02) will be an important element of therapy. It is very likely that in the next few years several medications will be available to clinicians treating patients with NAFLD across the entire spectrum of disease.
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To evaluate the influence of pentoxifylline (PTX), a phosphodiesterase inhibitor, on cytokines and inflammatory proteins in patients suffering from septic shock.
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It is recommended that the diagnosis of veno-occlusive disease (sinusoidal obstruction syndrome) [VOD (SOS)] be based primarily on established clinical criteria (modified Seattle or Baltimore criteria) (1A). Ultrasound imaging may be helpful in the exclusion of other disorders in patients with suspected VOD (SOS) (1C). It is recommended that liver biopsy be reserved for patients in whom the diagnosis of VOD (SOS) is unclear and there is a need to exclude other diagnoses (1C). It is recommended that liver biopsies are undertaken using the transjugular approach in order to reduce the risks associated with the procedure (1C). It is suggested that the role of plasminogen activator inhibitor 1 levels remains an area for further research but that these levels should not form part of the routine diagnostic work-up for VOD (SOS) at present (2C).
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Peripheral neuropathy, infection, and peripheral vascular disease can produce serious problems in diabetic patients, particularly in the lower limbs. Ulceration of the foot may progress to gangrene and ultimately necessitate amputation. Distal symmetric polyneuropathy causes sensory loss. Such loss in patients with peripheral vascular disease creates a high risk for foot ulcers, which are vulnerable to infection. Treatment includes relief of neuropathic pain and antibiotic therapy for infection. Pentoxifylline (Trental) improves microvascular flow and appears to be effective against peripheral vascular disease. Aldose reductase inhibitors are being investigated as therapy for diabetic neuropathy. Prevention is the mainstay of management in these patients. Patient education is essential to help maintain health and prevent the potential adverse effects of diabetes.
At doses greater than 0.1 ng/Ml, TGF-beta1 increased messenger ribonucleic acid (mRNA) and protein expression of elastin in a time-dependent fashion in TADF. PTX did not interfere with TGF-beta1 mediated upregulation of elastin mRNA and protein in TADF. However, pretreatment of TADF with PTX was associated with decreased expression of AAT1, decreased activity of the Smad1/5 pathway, and enhanced phosphorylation of the inhibitory Smad6.
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Eleven studies met our inclusion criteria. Two studies did not report any outcome data relevant to the review, so the results of the review are based on nine trials that contributed data. Primary outcomes were perinatal mortality, serious maternal or infant outcomes, adverse drug reactions, birth before 48 hours of trial entry, birth before 34 weeks' gestation and preterm neonates delivered without a full course of antenatal steroids completed 24 hours before birth. The quality of evidence in included trials was mixed; only three of the trials were placebo controlled.The included trials examined seven different comparisons: intravenous (IV) ritodrine plus oral or IV magnesium (sulphate or gluconate) versus IV ritodrine alone (three trials, 231 women); IV ritodrine plus indomethacin suppositories versus IV ritodrine alone (one trial, 208 women); IV ritodrine plus vaginal progesterone versus IV ritodrine alone (one trial, 83 women); IV hexoprenaline sulphate plus IV magnesium hydrochloride versus IV hexoprenaline sulphate alone (one trial, 24 women); IV fenoterol plus oral naproxen versus IV fenoterol alone (one trial, 72 women); oral pentoxifylline plus IV magnesium sulphate plus IV fenoterol versus IV magnesium sulphate plus IV fenoterol (one trial, 125 women); and, IV terbutaline plus oral metoprolol versus IV terbutaline alone (one trial, 17 women). Few studies with small numbers of women were available for each comparison, hence very little data were pooled in meta-analysis. In all trials, not many of the primary outcomes were reported.Three trials examined intravenous (IV) ritodrine plus IV or oral magnesium (sulphate or gluconate) compared with IV ritodrine alone. One study, with 41 women, reported more adverse drug reactions in the group receiving the combined tocolytics (risk ratio (RR) 7.79, 95% confidence interval (CI) 1.11 to 54.80). Two trials reported discontinuation of therapy due to severe side effects (results were not combined due to high statistical heterogeneity, I² = 83%); one trial reported increased severe side effects in the group receiving IV ritodrine alone (RR 7.79, 95% CI 1.11 to 54.80, 41 women); in the other trial there was no clear difference between groups (RR 0.23, 95% CI 0.03 to 1.97, 107 women). Other primary outcomes were not reported.One trial assessed IV ritodrine plus indomethacin suppositories versus IV ritodrine alone. There were no significant differences between groups for perinatal mortality or serious neonatal morbidity. Results for other primary outcomes were not reported.There were no significant differences between groups receiving IV ritodrine plus vaginal progesterone compared with IV ritodrine alone for most outcomes reported, although the latency period (time from recruitment to delivery) was increased in the group receiving the combination of tocolytics.For other combinations of tocolytic agents, primary outcomes were rarely reported and for secondary outcomes results did not demonstrate differences between groups.
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A randomised, placebo-controlled, double-blind, parallel group trial was performed. Women with breast cancer were treated for 12 months with 400 mg pentoxifylline t.i.d. or placebo, in combination with 100 mg vitamin E t.i.d., starting 1-3 months after the completion of radiotherapy. The primary end-point was passive abduction of the shoulder, and the secondary end-point was difference in arm volumes. The trial is registered on the ISRCTN.org website, number ISRCTN39143623.
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Intravital microscopy was used to study changes in microvascular permeability during diabetes. The extravasation of a fluorescent macromolecular tracer (FITC-Albumin) was measured for one hour and, after computer-aided image analysis, was expressed as variations of normalized grey levels (arbitrary units).
Currently, there are 5 million individuals with chronic heart failure (CHF) in the United States who have poor clinical outcomes, including high death rates. Observational studies have indicated a reverse epidemiology of traditional cardiovascular risk factors in CHF; in contrast to trends seen in the general population, obesity and hypercholesterolemia are associated with improved survival. The temporal discordance between the overnutrition (long-term killer) and undernutrition (short-term killer) not only can explain some of the observed paradoxes but also may indicate that malnutrition, inflammation, and oxidative stress may play a role that results in protein-energy wasting contributing to poor survival in CHF. Diminished appetite or anorexia and nutritional deficiencies may be both a cause and a consequence of this so-called malnutrition-inflammation-cachexia (MIC) or wasting syndrome in CHF. Neurohumoral activation, insulin resistance, cytokine activation, and survival selection-resultant genetic polymorphisms also may contribute to the prominent inflammatory and oxidative characteristics of this population. In patients with CHF and wasting, nutritional strategies including amino acid supplementation may represent a promising therapeutic approach, especially if the provision of additional amino acids, protein, and energy includes nutrients with anti-inflammatory and antioxidant properties. Regardless of the etiology of anorexia, appetite-stimulating agents, especially those with anti-inflammatory properties such as megesterol acetate or pentoxyphylline, may be appropriate adjuncts to dietary supplementation. Understanding the factors that modulate MIC and body wasting and their associations with clinical outcomes in CHF may lead to the development of nutritional strategies that alter the pathophysiology of CHF and improve outcomes.
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High concentrations of free human neutrophil elastase in bronchial epithelial fluid are believed to be a major factor in the evolution of pulmonary injury in cystic fibrosis (CF). To test this hypothesis, we studied pentoxifylline, a compound that inhibits tumor necrosis factor alpha transcription and its stimulatory effect on polymorphonuclear neutrophils, in patients with CF who had chronic Pseudomonas bronchitis. Subjects older than 11 years of age randomly received placebo or pentoxifylline (1600 mg/day) orally, in a double-blind fashion, for 6 months. Pulmonary function and sputum elastase concentrations were determined before therapy and bimonthly during therapy; compliance was determined by measuring serum drug concentrations. Of the 16 patients who completed the study, 9 received pentoxifylline. The sputum elastase concentrations among placebo recipients were significantly increased from baseline at 4 and 6 months (F = 3.44; p < 0.05); the values remained unchanged in the treatment group. The mean forced vital capacity for the placebo group decreased from 59.2% +/- 15.4% predicted at baseline to 52.0% +/- 12.9% predicted at 6 months; the values in the treatment group remained largely unchanged. The forced vital capacity improved between baseline and 6 months for four of nine pentoxifylline recipients and none of the seven control patients (p = 0.09). During the study, four of seven placebo recipients experienced a significant pulmonary exacerbation compared with one of nine treated patients (p = 0.077). These findings support the hypothesis that polymorphonuclear neutrophil elastase is a factor in the evolution of CF lung disease; further studies are needed to define the role of pentoxifylline in the treatment of CF.
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This randomized and blinded study was performed to determine whether pentoxifylline significantly improves tissue oxygenation after hemorrhagic shock. Hepatic surface oxygen tension was measured in anesthetized rats before and after hemorrhage. Rats were then randomly assigned to either a placebo group (n = 21) receiving 1 ml of intravenous saline solution or to a treatment group (n = 23) receiving intravenous 25 mg/kg of pentoxifylline in 1 ml of saline solution. Investigators were blinded as to which solution was injected. Five minutes after injection of pentoxifylline, there was significant increase in hepatic surface oxygen tension; this increase persisted throughout 1 hour of observation and was significantly greater than in placebo-treated animals. Further study of the effects of pentoxifylline on tissue perfusion and oxygenation after hemorrhagic shock is warranted.
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The proportions of haploid cells in the ipsilateral testes of rats undergoing torsion were significantly lower than in their contralateral testes and in the ipsilateral testes of the control groups. In group 4 (6-OHD) the proportion of haploid cells in the contralateral testes was significantly higher than those in the other groups after unilateral testicular torsion, but significantly lower than those in groups 1 and 4 after a sham operation. After unilateral testicular torsion the haploid cell proportions of the contralateral tests of groups 1-3 were not significantly different from each other.