Our library of drug research abstracts drawn from the medical literature is updated on a regular schedule, and you can be assured that new trental research articles will be listed here shortly after becoming available to us.
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Medical research on trental
Toxicol Appl Pharmacol. 2008 May 20;
Cazanave S, Vadrot N, Tinel M, Berson A, Lettéron P, Larosche I, Descatoire V, Feldmann G, Robin MA, Pessayre D
Fas stimulation recruits neutrophils and activates macrophages that secrete tumor necrosis factor-alpha (TNF-alpha), which aggravates Fas-mediated liver injury. To determine whether nonsteroidal anti-inflammatory drugs modify these processes, we challenged 24-hour-fasted mice with the agonistic Jo2 anti-Fas antibody (4 microg/mouse), and treated the animals 1 h later with saline or ibuprofen (250 mg/kg), a dual cyclooxygenase (COX)-1 and COX-2 inhibitor. Ibuprofen attenuated the Jo2-mediated recruitment/activation of myeloperoxidase-secreting neutrophils/macrophages in the liver, and attenuated the surge in serum TNF-alpha. Ibuprofen also minimized hepatic glutathione depletion, Bid truncation, caspase activation, outer mitochondrial membrane rupture, hepatocyte apoptosis and the increase in serum alanine aminotransferase (ALT) activity 5 h after Jo2 administration, to finally decrease mouse mortality at later times. The concomitant administration of pentoxifylline (decreasing TNF-alpha secretion) and infliximab (trapping TNF-alpha) likewise attenuated the Jo2-mediated increase in TNF-alpha, the decrease in hepatic glutathione, and the increase in serum ALT activity 5 h after Jo2 administration. The concomitant administration of the COX-1 inhibitor, SC-560 (10 mg/kg) and the COX-2 inhibitor, celecoxib (40 mg/kg) 1 h after Jo2 administration, also decreased liver injury 5 h after Jo2 administration. In contrast, SC-560 (10 mg/kg) or celecoxib (40 or 160 mg/kg) given alone had no significant protective effects. In conclusion, secondary TNF-alpha secretion plays an important role in Jo2-mediated glutathione depletion and liver injury. The combined inhibition of COX-1 and COX-2 by ibuprofen attenuates TNF-alpha secretion, glutathione depletion, mitochondrial alterations, hepatic apoptosis and mortality in Jo2-treated fasted mice.
J Matern Fetal Neonatal Med. 2008 Jun; 21(6): 407-13
Demir K, Kumral A, Duman N, Sarioglu S, Yilmaz O, Yesilirmak DC, Kargi A, Ozkan H
Objective. We aimed to assess the efficiency of clarithromycin, montelukast, and pentoxifylline treatments, alone and in combination, in reducing hyperoxic lung injury at the histopathologic level. Methods. The experiment was carried out with 47 newborn rat pups divided into six groups during postnatal days 3 to 13. The rats belonging to group 1 were designated as the control group and kept in room air without exposure to hyperoxia. Group 2 (clarithromycin), group 3 (montelukast), group 4 (pentoxifylline), group 5 (clarithromycin + montelukast + pentoxifylline combination), and group 6 (placebo) were kept in plexiglass chamber and exposed to hyperoxia (88-92%) throughout the experiment. Alveolar surface area percentage, fibrosis, and smooth muscle actin expression were assessed in the lungs, which were resected by thoracotomy on postnatal day 14. Results. Drug treatments, when used separately, were not detected to be superior to placebo with regard to mean alveolar surface area, fibrosis, and smooth muscle actin expression. Combination treatment resulted in significantly higher mean lung area percentages and lower actin scores with respect to the placebo treatment group (64.0% vs. 50.2%, p=0.002; 0 (0-1) vs. 7 (2-12), p=0.005, respectively). Conclusions. It was determined that clarithromycin, montelukast, and pentoxifylline combination treatment is superior to placebo treatment in the newborn rat hyperoxic lung injury model. The present study indicates that combination therapy might be successful in bronchopulmonary dysplasia, which has complex pathophysiologic processes and lacks established efficient treatment strategies.
Clinics. 2008 Jun; 63(3): 321-8
Deree J, Martins JO, Melbostad H, Loomis WH, Coimbra R
OBJECTIVE: The objective of this study was to determine the effect of nonspecific phosphodiesterase inhibition on transcription factor activation and tumor necrosis factor-alpha (TNF-a) production in lipopolysaccharide (LPS)-stimulated human mononuclear cells. INTRODUCTION: The production of TNF-a following LPS stimulation is one of the key steps in bacterial sepsis and inflammation. The mechanism by which phosphodiesterase inhibition alters TNF-a production in the presence of LPS remains unclear. METHODS: Human mononuclear cells were stimulated with LPS (1 microg/mL), in the presence and absence of Pentoxifylline (PTX; 20 mM), a nonspecific phosphodiesterase inhibitor. Western blotting of phosphorylated cytoplasmic I-kBa, nuclear factor-kB p65 (NF-kB), and nuclear cAMP-response element binding protein (CREB) was performed. DNA binding of NF-kB and CREB was verified by electrophoretic mobility shift assay. TNF-a levels were determined in the supernatant of stimulated cells in the presence and absence Protein kinase A inhibition by an enzyme-linked immunosorbent assay (ELISA). RESULTS: PTX was demonstrated to significantly reduce cytoplasmic I-kBa phosphorylation, nuclear p65 phosphorylation, and the DNA binding activity of NF-kB. In contrast, PTX markedly enhanced the phosphorylation and DNA binding activity of CREB. Cells concomitantly treated with PTX and LPS secreted similar levels of TNF-a in the presence and absence Protein kinase A inhibition. DISCUSSION: The increased level of cAMP that results from phosphodiesterase inhibition affects cytoplasmic and nuclear events, resulting in the attenuation of NF-kB and the activation of CREB transcriptional DNA binding through pathways that are partially Protein kinase A-independent. CONCLUSION: PTX-mediated phosphodiesterase inhibition occurs partially through a Protein kinase A-independent pathway and may serve as a useful tool in the attenuation of LPS-induced inflammation.
Osteoradionecrosis of the jaws: current understanding of its pathophysiology and treatment.
Br J Oral Maxillofac Surg. 2008 Jun 16;
Lyons A, Ghazali N
During the past 80 years a number of theories about the pathogenesis of osteoradionecrosis (ORN) have been proposed, with consequent implications for its treatment. Until recently tissue hypoxia and its consequences were accepted as the primary cause, and this led to the use of hyperbaric oxygen (HBO) for both treatment and prevention of complications of radiotherapy in the head and neck. The benefit of HBO has not been validated. A new theory for the pathogenesis of ORN has proposed that damage to bone is caused by radiation-induced fibrosis. Cells in bone are damaged as a result of acute inflammation, free radicals, and the chronic activation of fibroblasts by a series of growth factors. New treatments have therefore been devised that include pentoxifylline, a vasodilator that also inhibits fibrosis, and tocopherol (vitamin E) to reduce damage caused by free radicals. Impressive results in terms of reversing the process of ONR have been reported using these agents. It has been suggested that this theory and these agents could be the basis of future treatment and prevention of ORN.
Eur J Pain. 2008 Jun 11;
Wei T, Sabsovich I, Guo TZ, Shi X, Zhao R, Li W, Geis C, Sommer C, Kingery WS, Clark DJ
BACKGROUND: Tibia fracture in rats evokes chronic hindpaw warmth, edema, allodynia, and regional osteopenia, a syndrome resembling complex regional pain syndrome (CRPS). Previous studies suggest that the pathogenesis of some of these changes involves an exaggerated regional inflammatory response to injury and we postulated that inflammatory cytokines contribute to the development of CRPS-like changes after fracture. METHODS: The distal tibia was fractured and the hindlimb casted for 4 weeks. The rats were given drinking water with or without the cytokine inhibitor pentoxifylline (PTX) starting the day before fracture and continuing for 4 weeks, after which time the cast was removed and multiple assays were performed in the hindpaw. PCR and immunoassays were used to evaluate changes in cytokine expression. Bilateral hindpaw thickness, temperature, and nociceptive thresholds were determined, and bone microarchitecture was measured by microcomputed tomography (muCT). RESULTS: Tibia fracture chronically up-regulated TNFalpha, IL-1beta and IL-6 mRNA and protein levels in hindpaw skin and PTX treatment significantly reduced the mRNA expression and cytokine protein levels for all these cytokines. PTX inhibited the nociceptive sensitization and some vascular changes, but had insignificant effects on most of the bone-related parameters measured in these studies. Immunostaining of hindpaw skin was negative for immunocyte infiltration at 4 weeks post-fracture. CONCLUSIONS: These results suggest that pro-inflammatory cytokines contribute to the nociceptive and vascular sequelae of fracture and that PTX treatment can reverse these CRPS-like changes.
Eur J Heart Fail. 2008 Jun 10;
Guggilam A, Patel KP, Haque M, Ebenezer PJ, Kapusta DR, Francis J
OBJECTIVE: To investigate evidence for the interplay between cytokines, angiotensin II and nNOS in the paraventricular nucleus (PVN), for regulating sympathetic outflow in a rat model of CHF. METHODS AND RESULTS: Heart failure was induced in Sprague-Dawley rats by coronary artery ligation. One group of rats was treated with pentoxifylline (PTX, 30 mg/kg IP), a cytokine blocker, or vehicle, for 5 weeks. Another group of rats was pre-treated with PTX before coronary ligation to study prior cytokine blocking effect on survival. Both groups were combined in the analysis. Echocardiography demonstrated an increase in LV end-diastolic pressure and Tei index after 5 weeks in CHF rats. ELISA revealed a significant increase in plasma TNF-alpha and IL-1beta in CHF rats. Inducible NOS (iNOS) and angiotensin receptor-type 1 (AT-1R) mRNA expressions were increased, while neuronal NOS (nNOS) was decreased in the PVN of CHF rats; these changes were reversed by PTX. PTX treatment also decreased plasma norepinephrine and epinephrine levels and improved baroreflex control of renal sympathoexcitation in CHF rats. Immunohistochemistry revealed elevated 3-nitrotyrosine formation in the heart and the PVN of CHF rats, but not in PTX treated rats. CONCLUSION: PTX decreased both peripheral and central cytokine expression, alleviated nitric oxide dysregulation, and inhibited the formation of peroxynitrite in the PVN resulting in decreased sympathoexcitation in CHF rats.
Anal Chim Acta. 2008 Jun 30; 619(1): 81-6
Awa K, Okumura T, Shinzawa H, Otsuka M, Ozaki Y
The idea of quality by design (QbD) has been proposed in pharmaceutical field. QbD is a systematic approach to control the product performance based on the scientific understanding of the product quality and its manufacturing process. In the present study, near-infrared (NIR) imaging is utilized as a tool to achieve this concept. A practical use of a chemometrics technique called self-modeling curve resolution (SMCR) is demonstrated with NIR imaging analysis of pharmaceutical tablets containing two ingredients, a soluble active ingredient, pentoxifylline (PTX), and an insoluble excipient, palmitic acid. Concentration profiles obtained by SMCR reveal that the homogenous distribution of chemical ingredients strongly depends on the grinding time and that its process plays a central role in quantitative control, say sustained-release of PTX. In addition, pure component spectra by SMCR indicate a sequential change of specific NIR peak intensities following the increase of the grinding time. The spectra change shows a molecular structure change related to its crystallinity during grinding process. Accordingly, this study clearly demonstrates that NIR imaging combined with SMCR can be a powerful tool to reveal chemical or physical mechanism induced by the manufacturing process of pharmaceutical products and that it may be a solid solution for QbD of pharmaceutical products.
Clin Exp Pharmacol Physiol. 2008 May 23;
Arab H, Hassanpour H, Bozorgi A
1. In the present study, the role of nitric oxide (NO) produced by constitutive and inducible nitric oxide synthases (cNOS and iNOS, resepctively) on the contraction and relaxation of fundus in normal and lipopolysaccharide (LPS)-treated mice was examined. 2. A whole fundic ring isolated from mice pretreated with reserpine was mounted in an organ bath containing Krebs' solution with 0.001 mmol/L atropine. Rings were contracted initially by 5-hydroxytryptamine (5-HT; 0.03 mmol/L) before relaxation was induced using ATP (0.03 mmol/L), ADP (0.03 mmol/L), pentoxifylline (0.002 mmol/L), electrical field stimulation (EFS; 50 V, 1 msec, 50 Hz, 3 min) and l-arginine (0.05 mmol/L). All drugs and EFS induced significant relaxation of isolated rings. The relaxations induced were significantly inhibited by N(G)-nitro-l-arginine methyl ester (l-NAME; 1.0 mmol/L). However, the iNOS inhibitors l-N(6)-(1-iminoethyl) lysine hydrochloride (l-NIL; 1.0 mmol/L) and amino guanidine (AMG; 1.0 mmol/L) had no significant effect on tissue relaxation. 3. Then, the relaxant effects of 0.03 mmol/L ATP were tested on precontracted isolated fundic rings taken from 10 mg/kg LPS-treated animals. The non-selective NOS inhibitor l-NAME (10 mg/kg), the iNOS inhibitors l-NIL (3 mg/kg) and AMG (20 mg/kg) and betamethasone (0.1 mg/kg) were used to examine the role of NO produced by iNOS in the relaxation responses. It was found that the level of contraction induced by 0.03 mmol/L 5-HT in rings isolated from LPS-treated animals was significantly (P < 0.5) less than that in rings from untreated mice. However, precontracted tissues from LPS-treated mice were significantly relaxed by ATP and the relaxation response to ATP was significantly inhibited by l-NIL, ANG and betamethasone, but not by l-NAME. 4. We suggest that, in LPS-treated mice, the production of NO from iNOS produces a reduction in the contractile response, as well as a decrease in NO formation by cNOS, resulting in changes to smooth muscle cell function.
Eur J Cancer. 2008 May 19;
Dua P, Gude RP
Cancer cell migration is a hallmark of metastatic cascade and compounds that can intervene in this process are clinically important. Pentoxifylline (PTX), a methyl xanthine derivative, inhibits B16F10 melanoma lung homing by inhibiting F10 invasion, MMP secretion and adhesion to matrix components. However, its effect on B16F10 migration remained unexamined, which we investigated in the present study. PTX significantly inhibits F10 migration in scratch wound assay. Elevation in cAMP levels inhibits F10 migration and PTX mediated inhibition of the process was found to be, in part, due to an increase in cellular cAMP levels. PTX induces Protein Kinase A (PKA) activity and PKA inhibitor partly reversed its effects on F10 motility. RhoA and Rac1 GTPases induce B16F10 motility and PTX was found to inhibit migration by affecting these molecules. Stress fibres and lamellipodial protrusions reduced significantly. This was accompanied with inhibition in RhoA and Rac1 membrane localisation. A stark inhibition in RhoA-GTP bound form was also observed. Taken together, the results indicate that PTX, through its phosphodiesterase action, inhibits RhoGTPases and associated actin organisation in B16F10 melanoma, thereby inhibiting cell motility.
Wound healing in radiated skin: pathophysiology and treatment options.
Int Wound J. 2008 Jun; 5(2): 246-57
Olascoaga A, Vilar-Compte D, Poitevin-Chacón A, Contreras-Ruiz J
Ulcers in radiated skin continue to be a challenge for health care practitioners. Healing impairment in the setting of radiation-damaged tissue will most of the time lead to chronic wounds that reduce the patient's quality of life. In this review, we present an update of the pathophysiology of tissue damage caused by radiation that leads to chronic ulceration. We also explore the evidence available on the different prevention and treatment modalities that have been reported in the literature. The evidence for most preventive measures is inconclusive; however, sucralfate and amifostine seem to be the adequate recommendations for prophylaxis. As for treatment of ulcerated patients, the strongest level of evidence found was for the use of pentoxifylline, but proper trials are still scarce to be considered standard adjuvant therapy. Hyperbaric oxygen, cytokines and other growth factors and surgical interventions have shown some benefit in case reports and case series only. Other therapies show promise based on their mechanism of action but need to be tested in human studies and clinical trials.