Pentoxifylline
Theobromine
Phosphodiesterase Inhibitors
Hematologic Agents
Tumor Necrosis Factor-alpha
Perceived health in a randomised trial of treatment for chronic venous ulceration. (1/482)
STUDY OBJECTIVE: To observe changes in perceived health in patients during a clinical trial of treatments for venous leg ulceration. DESIGN: Randomised prospective factorial trial in patients with venous ulceration. Each patient randomised to a bandage, dressing and a drug. Perceived health assessed at entry and after 24 weeks. SETTING: Outpatient departments and patient's home. PATIENTS: Two hundred patients presenting to two vascular services in Falkirk and Edinburgh with chronic (duration > 2 months) non-healing venous ulceration. STATISTICAL ANALYSIS AND MAIN RESULTS: Analysis using the Nottingham Health Profile revealed that after 24 weeks there were significant improvements in all subscores (p < 0.01) with the exception of social isolation (p = 0.081). Patients with healed ulceration had improved in energy, pain, emotion, sleep and mobility compared with those whose ulceration failed to heal (p < 0.05). Patients randomised to four layer bandaging had significantly better energy (diff = 7.9, 95% CI 0.2, 15.6, p = 0.04) and mobility (diff = 4.5, 95% CI 0.0, 9.0, p = 0.046). This difference could be explained largely by the improved healing of patients randomised to this bandage system (67/97 vs. 50/103, OR = 2.37, 95% CI 1.31, 4.27). CONCLUSIONS: Improvements in perceived health were significantly greater in patients whose ulcers had completely healed. Methods of treatment which offer improved healing for patients with venous leg ulceration are likely to improve patients' perceived health status. (+info)Combination therapy of pentoxifylline and TNFalpha monoclonal antibody in dextran sulphate-induced mouse colitis. (2/482)
BACKGROUND: Tumour necrosis factor-alpha (TNFalpha) has been suspected of playing an important role in the pathogenesis of inflammatory bowel diseases, and has become a target for the treatment of these diseases. Open-label, placebo controlled studies have shown that engineered CDP571 and chimeric anti-TNF antibody (cA2) provide a significant benefit in Crohn's disease. Since these antibodies have to be used repeatedly to maintain remission in inflammatory bowel disease, there is a concern that their use may compromise host defence and produce toxic side-effects. METHODS: We evaluated the combined use of mouse specific TNFalpha mab (25 microg/mouse, Endogen) and pentoxifylline (PF, 100 mg/kg/day, p.o., TNFalpha release inhibitor) in the DSS (3% dextran sulphate solution) model of mouse colitis. Colitis was induced by the feeding of 3% DSS for three cycles. The study groups were: Group I: single injection of rat anti-mouse IgG, Group II: single injection of TNFalpha mab, Group III: daily PF for three cycles, Group IV: single injection of TNFalpha mab + PF for three cycles, Group V: TNFalpha mab at the beginning of each cycle (three injections) and Group VI: TNFalpha mab (three injections) + daily PF for three cycles. Daily disease activity (DAI) was measured throughout the study. At the end of each cycle, colon tissue was processed for histology, myeloperoxidase (MPO) and plasma TNFalpha. RESULTS: Mice treated with a single injection of TNFalpha alone or TNFalpha mab + PF showed significantly lower DAI, inflammation scores and ulcer index compared with the IgG treated group. Mice treated with TNFalpha mab + PF had no ulcers. Multiple injections of TNFalpha mab or TNFalpha mab + PF showed greater inhibition in DAI and cytokines in the first two cycles. However, in the third cycle, multiple injections of TNFalpha mab showed adverse proinflammatory effects. CONCLUSION: The simultaneous administration of pentoxifylline and TNFalpha mab may enhance therapeutic outcomes in inflammatory bowel disease and reduce the side-effects associated with the repeated use of TNFalpha mab. (+info)Effects of lisofylline on hyperoxia-induced lung injury. (3/482)
Lisofylline [1-(5R-hydroxyhexyl)-3,7-dimethylxanthine] decreases lipid peroxidation in vitro and in vivo suppresses proinflammatory cytokine expression in models of lung injury due to sepsis, blood loss, and oxidative damage. In the present experiments, we used a murine hyperoxia model to examine the effects of lisofylline on the activation of nuclear transcriptional regulatory factors [nuclear factor-kappaB and cAMP response element binding protein (CREB)], the expression of proinflammatory cytokines in the lungs, and the circulating levels of oxidized free fatty acids as well as on hyperoxia-induced lung injury and mortality. Treatment with lisofylline inhibited hyperoxia-associated increases in tumor necrosis factor-alpha, interleukin-1beta, and interleukin-6 in the lungs as well as decreased the levels of hyperoxia-induced serum-oxidized free fatty acids. Although hyperoxic exposure produced activation of both nuclear factor-kappaB and CREB in lung cell populations, only CREB activation was reduced in the mice treated with lisofylline. Lisofylline diminished hyperoxia-associated increases in lung wet-to-dry weight ratios and improved survival in animals exposed to hyperoxia. These results suggest that lisofylline ameliorates hyperoxia-induced lung injury and mortality through inhibiting CREB activation, membrane oxidation, and proinflammatory cytokine expression in the lungs. (+info)The effects of two antiinflammatory pretreatments on bacterial-induced lung injury. (4/482)
BACKGROUND: Two antiinflammatory therapies that have been effective in preventing acid-induced lung injury were evaluated. Specifically, their effects on a subsequent bacterial-airspace challenge were compared. Bacteria were instilled 24 h after acid-induced lung injury. Pseudomonas aeruginosa PAO-1 was used as the bacteria, because its effects in healthy lungs was documented previously. METHODS: New Zealand white rabbits were anesthetized and three pretreatments were administered: (1) pentoxifylline pretreatment (a 20-mg/kg bolus dose and then 6 mg x kg(-1) x h(-1) given intravenously), (2) 1 ml anti-tumor necrosis factor alpha antiserum given intravenously, or (3) normal saline given intravenously. The pretreatment doses were shown previously to prevent acid-induced lung injury. Then 1.2 ml/kg hydrochloric acid (HCl), pH 1.25, was instilled into the rabbits' right lungs. All the animals underwent mechanical ventilation for 8 h. Twenty-four hours after the acid instillation, the rabbits were anesthetized again and 2 ml/kg (10(9) colony forming units/ml) PAO-1 was instilled into their left lungs. The rabbits' breathing was aided by mechanical ventilation for another 8 h, and then they were killed and exsanguinated. RESULTS: Both pretreatments attenuated the acid-induced lung injury of the noninstilled left lungs. Arterial oxygen tension and the lung edema of pretreated, acid-exposed animals were significantly and almost equally improved (compared with no pretreatments) by either of the pretreatments. However, when the bacteria were instilled into the left lungs 24 h after the acid injury, the pentoxifylline pretreatment but not the anti-tumor necrosis factor alpha pretreatment prevented much of the bacteria-induced lung injury. Pentoxifylline pretreatment significantly improved the measurements of left lung edema and epithelial and endothelial permeability. There was also a trend for improved oxygenation in the pentoxifylline-pretreated and infected animals. In contrast, the anti-tumor necrosis factor alpha pretreatment did not prevent the bacteria-induced lung injury and increased some of the measurements of lung injury. CONCLUSIONS: Two antiinflammatory therapies that prevented acid-induced lung injury to the noninstilled left lungs had significantly different effects on a subsequent bacteria-induced lung injury to the left lungs. The therapies differed in their mechanism of tumor necrosis factor alpha blockade, and this may have affected the bacteria-induced injury to the lungs. (+info)Protective effect of pentoxifylline plus thalidomide against septic shock in mice. (5/482)
Mortality caused by septic shock in experimental animals is reduced by thalidomide, an inhibitor of tumour necrosis factor alpha. Another drug that could act on the pathophysiological mechanisms of septic shock is pentoxifylline, an inhibitor of platelet aggregation that increases the flexibility of the erythrocyte membrane and has fibrinolytic activity. We studied the effect of pentoxifylline alone and combined with thalidomide in septic shock; 97 NIH mice were injected with lipopolysaccharides of Salmonella abortus equi and D galactosamine. Animals were separated in 4 groups; group A (n = 20) was used as control, group B (n = 15) received thalidomide 50 mg/kg, group C (n = 20) received pentoxifylline 40 mg/kg, and group D (n = 15) received thalidomide plus pentoxifylline. Mortality was recorded every hour. Additionally, 5 animals from each group were sacrificed 8 h after the induction of septic shock for histological analysis of heart, lung, brain, kidney, small intestine, adrenal glands and liver. Microscopic findings were rated as absent, mild, moderate and severe damage. In control animals histological analysis showed intense haemorrhage and necrosis in all organs studied. When compared with controls, treatment with pentoxifylline plus thalidomide reduced mortality (P < 0.03). The tissue damage was less severe in animals from the groups that received pentoxifylline or pentoxifylline plus thalidomide (P < 0.05). Pentoxifylline seems to potentiate the beneficial effects of thalidomide, reducing mortality and attenuating the pathological changes produced by septic shock. (+info)Pentoxifylline-stimulated capacitation and acrosome reaction in hamster spermatozoa: involvement of intracellular signalling molecules. (6/482)
We investigated the role of cAMP/cGMP, protein kinases and intracellular calcium ( [Ca2+]i) in pentoxifylline-stimulated hamster sperm capacitation and the acrosome reaction (AR) in vitro. Treatment with pentoxifylline (0.45 mM) initially increased sperm cAMP values 2.8-fold, compared with untreated controls (396 +/- 9.2 versus 141 +/- 6.0 fmoles/10(6) spermatozoa; mean +/- SEM, n = 6) after 15 min, although by 3 h, cAMP values were similar (503-531 fmoles/10(6) spermatozoa). cGMP values ( approximately 27 fmoles/10(6) spermatozoa) were the same in treated and control spermatozoa. Both sperm capacitation and the AR, determined from the absence of an acrosomal cap, were stimulated by pentoxifylline; these were almost completely inhibited by a Cl-/ HCO3- antiporter inhibitor (4,4-diisothiocyanato-stilbene-2,2 disulphonic acid; 1 mM) defined from the degree of sperm motility and by a protein kinase A inhibitor (H89; 10 microM). A protein kinase C inhibitor (staurosporine, 1 nM) did not affect pentoxifylline-stimulated capacitation but inhibited the AR by 50%. A protein tyrosine kinase inhibitor (tyrphostin A-47, 0.1 mM) had no effect on either pentoxifylline-stimulated capacitation or AR. A phospholipase A2 inhibitor (aristolochic acid, 0.4 mM) markedly inhibited the pentoxifylline-stimulated AR but not capacitation. When intracellular sperm calcium [Ca2+/-]i was measured using fura-2-AM, there was an early rise (271 nM at 0.5 h) in pentoxifylline-treated spermatozoa; this appeared to be due to intracellular mobilization rather than to uptake. In the absence of extracellular Ca2+, sperm motility was maintained in the presence of pentoxifylline, but capacitation did not occur; spermatozoa exhibited a low level of hyperactivated motility and had a poor rate of AR (20.5 +/- 2.3%). These results suggest that: (i) the pentoxifylline-stimulated early onset of sperm capacitation may be mediated by an early rise in cAMP and [Ca2+/-]i and involves protein kinase A activity; and (ii) pentoxifylline-stimulated AR may require phospholipase A2 and protein kinase C activity. (+info)Pentoxifylline inhibits superantigen-induced toxic shock and cytokine release. (7/482)
Tumor necrosis factor alpha (TNF-alpha) is a critical cytokine that mediates the toxic effects of bacterial superantigens like staphylococcal enterotoxin B (SEB) and toxic shock syndrome toxin 1 (TSST-1). Pentoxifylline, an anti-inflammatory agent that inhibits endotoxemia and lipopolysaccharide (LPS)-induced release of TNF-alpha, was tested for its ability to inhibit SEB- and TSST-1-induced activation of human peripheral blood mononuclear cells (PBMCs) in vitro and toxin-mediated shock in mice. Stimulation of PBMCs by SEB or TSST-1 was effectively blocked by pentoxifylline (10 mM), as evidenced by the inhibition of TNF-alpha, interleukin 1beta (IL-1beta), gamma interferon (IFN-gamma), and T-cell proliferation. The levels of TNF-alpha, IL-1alpha, and IFN-gamma in serum after an SEB or TSST-1 injection were significantly lower in mice given pentoxifylline (5.5 mg/animal) versus control mice. Additionally, pentoxifylline diminished the lethal effects and temperature fluctuations elicited by SEB and TSST-1. Thus, in addition to treating endotoxemias, the cumulative in vitro and in vivo data suggest that pentoxifylline may also be useful in abrogating the ill effects of staphylococcal enterotoxins and TSST-1. (+info)Intestinal crypt cell apoptosis in murine acute graft versus host disease is mediated by tumour necrosis factor alpha and not by the FasL-Fas interaction: effect of pentoxifylline on the development of mucosal atrophy. (8/482)
BACKGROUND: Murine T cell mediated acute semiallogeneic graft versus host disease (GVHD) is characterised by lymphocytic infiltrates, crypt hyperplasia, and villous atrophy. It has been shown that programmed cell death (apoptosis) of the crypt epithelium takes place during the intestinal manifestation of acute GVHD. AIMS: To investigate which of the two most investigated inductors of apoptosis (Fas ligand (FasL) and tumour necrosis factor alpha (TNF-alpha)) is responsible for the induction of apoptosis in this animal model. METHODS: Animals undergoing acute semiallogeneic GvH reaction were treated with neutralising anti-TNF-alpha, two different anti-FasL antibodies, or pentoxifylline. RESULTS: Anti-TNF-alpha application inhibited the appearance of apoptotic cells in the intestinal mucosa, whereas anti-FasL antibodies had no influence on mucosal apoptosis. In addition, the transfer of FasL deficient (gld) donor lymphocytes still induced crypt cell apoptosis, villous atrophy, and crypt hyperplasia. Furthermore, when the animals were treated with pentoxifylline, a known inhibitor of TNF-alpha secretion in vitro and in vivo, there was significant normalisation of the intestinal morphology accompanied by inhibition of epithelial apoptosis. CONCLUSIONS: The FasL-Fas interaction is not involved in the induction of apoptosis during acute GVHD. However, neutralisation of TNF-alpha by an antibody or by pentoxifylline inhibits the occurrence of apoptosis and of mucosal atrophy in this animal model. These results have implications for the treatment of immunologically mediated human atrophic gut diseases-for example, diet refractory cases of coeliac disease. (+info)Pentoxifylline is a medication that belongs to a class of drugs known as xanthines. Medically, it is defined as a methylxanthine derivative that acts as a vasodilator and improves blood flow by reducing the viscosity of blood. It is used in the treatment of intermittent claudication (pain in the legs due to poor circulation) and may also be used for other conditions that benefit from improved blood flow, such as preventing kidney damage in people with diabetes.
Pentoxifylline works by increasing the flexibility of red blood cells, allowing them to move more easily through narrowed blood vessels, improving oxygen supply to tissues and organs. It also has anti-inflammatory effects that may contribute to its therapeutic benefits.
Common side effects of pentoxifylline include gastrointestinal symptoms like nausea, vomiting, and diarrhea. Less commonly, it can cause dizziness, headache, or skin rashes. Rare but serious side effects include decreased blood pressure, irregular heartbeat, and liver damage. It is essential to follow the prescribing physician's instructions carefully when taking pentoxifylline and report any unusual symptoms promptly.
Theobromine is defined as a bitter, crystalline alkaloid of the cacao plant, and is found in chocolate, especially cocoa. It is a stimulant that primarily affects the heart and cardiovascular system, and to a lesser extent the central nervous system. Theobromine is also found in the kola nut and tea leaves.
In a medical context, theobromine may be used as a vasodilator and diuretic. It can help to relax muscles, widen blood vessels, and increase urine production. However, it is important to note that theobromine is toxic to some animals, including dogs and cats, and can cause serious medical problems or even death if ingested in large quantities.
Phosphodiesterase inhibitors (PDE inhibitors) are a class of drugs that work by blocking the action of phosphodiesterase enzymes, which are responsible for breaking down cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), two crucial intracellular signaling molecules.
By inhibiting these enzymes, PDE inhibitors increase the concentration of cAMP and cGMP in the cells, leading to a variety of effects depending on the specific type of PDE enzyme that is inhibited. These drugs have been used in the treatment of various medical conditions such as erectile dysfunction, pulmonary arterial hypertension, and heart failure.
Examples of PDE inhibitors include sildenafil (Viagra), tadalafil (Cialis), vardenafil (Levitra) for erectile dysfunction, and iloprost, treprostinil, and sildenafil for pulmonary arterial hypertension. It's important to note that different PDE inhibitors have varying levels of selectivity for specific PDE isoforms, which can result in different therapeutic effects and side effect profiles.
Hematologic agents are a class of drugs that affect the formation, function, or destruction of blood cells and related proteins. They include:
1. Hematopoietic growth factors: These are substances that stimulate the production of blood cells in the bone marrow. Examples include erythropoiesis-stimulating agents (ESAs) like epoetin alfa and darbepoetin alfa, which stimulate red blood cell production, and granulocyte colony-stimulating factors (G-CSFs) like filgrastim and pegfilgrastim, which stimulate white blood cell production.
2. Anticoagulants: These are drugs that prevent blood clots from forming or growing larger. Examples include heparin, warfarin, direct oral anticoagulants (DOACs) like apixaban and rivaroxaban, and antiplatelet agents like aspirin and clopidogrel.
3. Hemostatic agents: These are drugs that promote blood clotting to stop bleeding. Examples include fibrin glue, thrombin, and factor VIIa.
4. Hematological malignancy therapies: These are drugs used to treat cancers of the blood and bone marrow, such as leukemia, lymphoma, and multiple myeloma. They include chemotherapeutic agents, targeted therapies like monoclonal antibodies, immunomodulatory drugs, and proteasome inhibitors.
5. Iron chelators: These are drugs used to remove excess iron from the body in patients with conditions that cause iron overload, such as thalassemia and sickle cell disease. Examples include deferoxamine, deferasirox, and deferiprone.
6. Hemophilia therapies: These are drugs used to treat hemophilia, a genetic disorder that affects blood clotting. They include factor VIII replacement therapy for hemophilia A and factor IX replacement therapy for hemophilia B.
Tumor Necrosis Factor-alpha (TNF-α) is a cytokine, a type of small signaling protein involved in immune response and inflammation. It is primarily produced by activated macrophages, although other cell types such as T-cells, natural killer cells, and mast cells can also produce it.
TNF-α plays a crucial role in the body's defense against infection and tissue injury by mediating inflammatory responses, activating immune cells, and inducing apoptosis (programmed cell death) in certain types of cells. It does this by binding to its receptors, TNFR1 and TNFR2, which are found on the surface of many cell types.
In addition to its role in the immune response, TNF-α has been implicated in the pathogenesis of several diseases, including autoimmune disorders such as rheumatoid arthritis, inflammatory bowel disease, and psoriasis, as well as cancer, where it can promote tumor growth and metastasis.
Therapeutic agents that target TNF-α, such as infliximab, adalimumab, and etanercept, have been developed to treat these conditions. However, these drugs can also increase the risk of infections and other side effects, so their use must be carefully monitored.