Administration Of Pentoxifylline Research Articles

Activation of AMPK/mTOR-Driven Autophagy and Suppression of the HMGB1/TLR4 Pathway with Pentoxifylline Attenuates Doxorubicin-Induced Hepatic Injury in Rats.

Despite being an effective chemotherapeutic agent, the clinical use of doxorubicin (DOX) is limited by several organ toxicities including hepatic injury. Pentoxifylline (PTX) is a methylxanthine derivative with marked anti-inflammatory and anti-apoptotic features. It is unknown, however, whether PTX can mitigate DOX-evoked hepatotoxicity. This study aims to explore the potential hepatoprotective impact of PTX in DOX-induced hepatic injury and the underlying molecular mechanisms. Histopathology, immunohistochemistry, and ELISA were used to examine liver tissues. The current findings revealed that PTX administration to DOX-intoxicated rats mitigated the pathological manifestations of hepatic injury, reduced microscopical damage scores, and improved serum ALT and AST markers, revealing restored hepatic cellular integrity. These favorable effects were attributed to PTX's ability to mitigate inflammation by reducing hepatic IL-1β and TNF-α levels and suppressing the pro-inflammatory HMGB1/TLR4/NF-κB axis. Moreover, PTX curtailed the hepatic apoptotic abnormalities by suppressing caspase 3 activity and lowering the Bax/Bcl-2 ratio. In tandem, PTX improved the defective autophagy events by lowering hepatic SQSTM-1/p62 accumulation and enhancing the AMPK/mTOR pathway, favoring autophagy and hepatic cell preservation. Together, for the first time, our findings demonstrate the ameliorative effect of PTX against DOX-evoked hepatotoxicity by dampening the hepatic HMGB1/TLR4/NF-κB pro-inflammatory axis and augmenting hepatic AMPK/mTOR-driven autophagy. Thus, PTX could be utilized as an adjunct agent with DOX regimens to mitigate DOX-induced hepatic injury.

Pentoxifylline as a Novel Add-on Therapy for Major Depressive Disorder in Adult Patients: A Randomized, Double-Blind, Placebo-Controlled Trial.

Evidence indicates an association between immune dysregulation and major depressive disorder (MDD). Pentoxifylline (PTX), a phosphodiesterase inhibitor, has been shown to reduce pro-inflammatory activities. The aim of this study was to evaluate changes in depressive symptoms and pro-inflammatory markers after administration of PTX as an adjunctive agent to citalopram in patients with MDD. One hundred patients were randomly assigned to either citalopram (20 mg/day) plus placebo (twice daily) (n=50) or citalopram (20 mg/day) plus PTX (400 mg) (twice daily) (n=50). The Hamilton Depression Rating Scale-17 (HAM-D-17) scores at baseline, weeks 2, 4, 6, 8, 10, and 12 and serum levels of interleukin1-β (IL-1-β), tumor necrosis factor-α, C-reactive protein, IL-6, serotonin, IL-10, and brain-derived neurotrophic factor (BDNF) at baseline and week 12 were evaluated. HAM-D-17 score in the PTX group significantly reduced in comparison to the control group after weeks 4, 6, 8,10, and 12 ((LSMD): - 2.193, p=0.021; - 2.597, p=0.036; - 2.916, p=0.019; - 4.336, p=0.005; and - 4.087, p=0.008, respectively). Patients who received PTX had a better response (83%) and remission rate (79%) compared to the placebo group (49% and 40%, p=0.006 and p=0.01, respectively). Moreover, the reduction in serum concentrations of pro-inflammatory factors and increase in serotonin and BDNF in the PTX group was significantly greater than in the placebo group (p<0.001). These findings support the safety and efficacy of PTX as an adjunctive antidepressant agent with anti-inflammatory effects in patients with MDD.

INDICES OF THE CAPILLARY DIAMETER IN NORMAL RETINA AT DIFFERENT TERMS OF EXPERIMENTAL OPIOID INFLUENCE AND IN THE SUBCHRONIC AND CHRONIC PERIODS OF THEIR CORRECTION

In Ukraine, according to the latest biobehavioral research, the estimated number of people who inject drugs was 317000 people (on the controlled territory of Ukraine), of which 200661 people (63.3% of the total number) use only opioids, 38674 people use stimulants (12.2% of the total number), 77665 people practiced mixed use of narcotic substances (24.5%). Increasingly, doctors of various specialties face the problem of treating various nosologies in people with opioid addiction. It dramatically complicates the process of correcting the main pathology due to the consequences arising from the chronic use of opioid drugs. One of these factors is the long-term use of opioid analgesics for therapeutic purposes, as well as the use of opioid drugs without medical indications by people belonging to the category of drug addicts. At present, the issue of structural reorganization in the layers of the retina and links of its hemomicrocirculatory bed during long-term use of opioid drugs and the possibility of correcting the resulting changes in the subchronic and chronic periods of experimental opioid exposure remains unclear. That is why we decided to supplement, expand and deepen information about these processes by conducting our own research in this direction.The purpose of the study is to find out the dynamics of changes in the diameter of the capillary link of the hemomicrocirculatory bed of the retina at different times of experimental opioid exposure and to establish the possibility of correcting these changes in the subchronic and chronic periods. Material and methods. The research material was sexually mature, outbred, white male rats, in number 125 animals weighing 160-270 g, aged 4.5-7.5 months. The initial dose of nalbuphine during the first 2 weeks was 0.212 mg/kg, the next 2 weeks (III-IV weeks) – 0.225 mg/kg, the next (V-VI weeks) – 0.252 mg/kg, the next (VII-VIII weeks ) – 0.260 mg/kg, the next (IX – X weeks) – 0.283 mg/kg, the next (XI – XII weeks) – 0.3 mg/kg, and during (XIII – XIV weeks) – 0.45 mg/ kg Correction was carried out in the early and late periods of opioid exposure, where the dose of pentoxifylline was 2.857 mg/kg. The morphometric study of the diameter of retinal capillaries in normal conditions at different times of experimental opioid exposure and during correction was performed using histological preparations according to generally accepted methods.Research results. With the help of our statistical analysis of the capillary component of the retina, we established the diameter parameters of the retinal capillaries, which were 5.9 [5.6; 6.1] μm., which made it possible to assess the degree of vascularization of the retina in the norm. When corrected at the subchronic period, we found that there was no significant difference between the average values of capillary diameters (p&gt;0.05) between the control group and the 14th subgroup (2 weeks of nalbuphine administration with withdrawal followed by 4 weeks of pentoxifylline administration). There was a significant increase in mean capillary diameter when comparing subgroup 10 (2 weeks of nalbuphine followed by 4 weeks withdrawal) (p&lt;0.05) with subgroup 12 (2 weeks of nalbuphine followed by 4 weeks of pentoxifylline) (p&lt;0.05). 0.001), compared to the data of the control group. Capillary diameters in subgroup 10 (2 weeks of nalbuphine administration followed by 4 weeks withdrawal) were increased by 18.7% (p&gt;0.05), compared to subgroup 5 (6 weeks of nalbuphine administration). The situation was significantly unfavorable in comparison with the previous results in subgroup 12 (2 weeks of nalbuphine administration with the addition of 4 weeks of pentoxifylline) - by 32%, compared to the diameters of capillaries in subgroup 14 (2 weeks of nalbuphine administration with withdrawal and followed by 4 weeks of pentoxifylline administration). When corrected for the chronic period, we found that, compared to the control group, capillary diameters increased the least in the 15 subgroup of 10 weeks (6 weeks of administration of nalbuphine with withdrawal and followed by 4 weeks of administration of pentoxifylline) (by 35%). Capillary diameters were significantly larger in the 11-week 10-week subgroup (6 weeks of nalbuphine followed by 4-week withdrawal) (by 49%), while in the group with ten weeks of experimental opioid exposure (by 57%). The most unfavorable situation was in the 13th subgroup of 10 weeks (6 weeks of administration of nalbuphine with the addition of pentoxifylline for 4 weeks) (by 63%).Conclusion. As a result of our research, we can conclude that in the subchronic and chronic periods of correction of opioid exposure, the situation was most unfavorable in the subgroups where correction was carried out with simultaneous administration of nalbuphine and pentoxifylline. From the above, it is possible to draw a clear conclusion that in no case can these drugs be combined during the medical correction of pathomorphological changes in the retina and links of its hemomicrocirculatory bed in experimental opioid retinopathy.

Pentoxifylline and Vitamin E in Preventing Pneumonitis Using Stereotactic Ablative Radiotherapy in Previously Irradiated Patients

Despite radiotherapeutic advancements, patients with non-small cell lung cancer (NSCLC) experience recurrence rates from 30-40% (1) (2). For these cases, stereotactic ablative radiotherapy (SABR) is an attractive retreatment option as studies have reported upwards of 96% local control rates at 3 years follow up (3) (4). However, thoracic reirradiation poses threat for radiation-induced pneumonitis. Particularly, the rate of grade 3 pneumonitis from institutional data was 30% in patients undergoing SABR for recurrent thoracic malignancies (4). Prior studies have tried to mitigate SABR toxicities with administration of pentoxifylline (Ptx) and vitamin E (VE), which has reduced lung damage in breast cancer patients (5) (6). The addition of Ptx and VE in retreatment of NSCLC may similarly reduce radiation-induced pneumonitis. The purpose of this study is to prospectively evaluate the efficacy of Ptx and VE in reducing grade 3 pneumonitis in patients undergoing SABR with loco-regionally recurrent lung cancer or new lung primary tumors in the setting of prior thoracic radiation. We hypothesize that these patients will experience rates of grade 3 pneumonitis lower than 30% at 3, 6, and 12-months post-treatment follow up. Patients who received radiation for a prior thoracic malignancy with a diagnosis of a recurrent or new NSCLC were recruited from our institution. Ptx and VE were administered at the time of simulation, approximately 1 week prior to starting treatment and continued for 12 weeks after the completion of treatment. SABR was delivered using standard stereotactic techniques to a dose of 5000 cGy at 1000 cGy per fraction over 2 weeks. The following demographic information was collected: baseline performance status, time interval between initial radiation and retreatment radiation, central or peripheral recurrent tumor, and pre-treatment FEV1. Patients were assessed clinically and radiographically for grades of pneumonitis at 3, 6, and 12-months post treatment. Demographic and follow-up data were collected from the initial cohort of 40 patients. There were no statistically significant correlations between pretreatment characteristics and pneumonitis. 92% of participants were medication compliant. Crude rates of pneumonitis at any time point were grade 1 (23%), grade 2 (10%), and grade 3 (2%). Only one of our patients experienced grade 3 pneumonitis. The rate of grade 3 pneumonitis in our Ptx and vitamin E treated cohort was significantly less than 30% at 3-months (p = 0.001), 6-months (p = 0.001), and 12-months (p = 0.014) post-treatment. Thus, we conclude that Ptx and VE are safe interventions that may prophylactically reduce rates of grade 3 pneumonitis for patients receiving subsequent SABR for recurrent NSCLC. Additional studies should be performed to evaluate the use in of Ptx and VE in the retreatment setting.

CHANGES IN THE STRUCTURAL ORGANIZATION OF CELLULAR COMPONENTS IN THE RETINAL LAYERS AND LINKS OF ITS HEMOMICOCIRCULATORY BED DURING THE CHRONIC PERIOD OF EXPERIMENTAL OPIOID EXPOSURE AND THE CORRECTION OF THESE CHANGES AT THE ULTRASTRUCTURAL LEVEL

Over the past twenty years, the experimental direction of research has been the most relevant in morphology to study the dynamics of the course of nosologies. In terms of the dynamics of the occurrence of pathomorphological manifestations at the cellular, tissue, organ, and organism levels, it off ers a larger variety of pathology investigations. The study of the retina in the norm and the processes of modifying its structural reorganisation under the eff ect of various nosologies are accorded high importance in the scientifi c literature written by both domestic and international professionals. Despite these eff orts, the problem of opioid retinopathy on prolonged experimental opioid exposure remains essential. It is still unknown, in particular, if the correction of the chronic period of experimental opioid exposure may stabilise pathomorphological symptoms in the retinal layers and linkages of its hemomycrocirculatory bed. The purpose of the research is to fi nd out the features of structural reorganization in the retinal layers and links of its hemomicrocirculatory bed in the chronic period of experimental opioid exposure and the correction of these changes with pentoxifylline.Material and methods. The research used 34 male, sexually mature, non-breeding rats that ranged in weight from 160 to 270 g and were 4.5 to 7.5 months old as its subject matter. The correction dose of pentoxifylline was 2.857 mg/kg. At the end of the 10th week, the material was taken for ultrastructural examination of the retina. Before the sampling of the experimental site material, the animal was withdrawn from the experiment using diethyl ether. The eyeballs of rats were used as a material for ultrastructural examination. Ultrastructural preparations were prepared according to the generally accepted method. As a result of our research of the retina at the end of the tenth week in rats, which were injected with an opioid for six weeks, and subsequently discontinued for four weeks, the phenomena of degeneration of the pigment epithelium, destruction of the membrane discs of the outer segments of the photoreceptors, degenerative changes in the inner segments of the photoreceptors, degenerative and necrotic changes of individual photoreceptors developed. Degeneration and necrosis processes were detected in bipolar and amacrine neurons. Rats were injected with the opioid for six weeks, with its cancellation and subsequent four-week correction with pentoxifylline. After ten weeks of the experiment, degenerative changes in the apical microvilli of the pigment epithelium, destruction of the membrane discs of the outer segments of the photoreceptors, degeneration of bipolar and amacrine neurons, moderately pronounced discirculatory changes, and reactive processes of glial elements were detected. In rats given an opioid for six weeks, followed by four weeks of an opioid with pentoxifylline administration, fl ushing, stasis, and perivascular oedema in the choroidal arteries were established ten weeks later. Degeneration and necrosis of the pigment epithelium, degeneration and destruction of the membrane discs of the outer segments of photoreceptors with separation of individual outer segments, degeneration of the inner segments of photoreceptors, degeneration and necrotic changes of photoreceptors, degeneration and necrotic changes of bipolar and amacryne neurons, Muller cells, degeneration of ganglion neurons, hyperemia, stasis and perivasal oedema in the vessels of the ganglion layer, the layer of nerve fi bers, in the inner mesh layer.

Influence of Long-Term Continuous Intravenous Administration of Pentoxifylline on Endothelial-Related Coagulation in Critically Ill Patients: Retraction.

Influence of Long-Term Continuous Intravenous Administration of Pentoxifylline on Endothelial-Related Coagulation in Critically Ill Patients: Retraction.

Retraction Note: Does long-term continuous administration of pentoxifylline affect platelet function in the critically ill patient?

Retraction Note: Does long-term continuous administration of pentoxifylline affect platelet function in the critically ill patient?

Method Development and Validation for the Simultaneous Quantitation of Pentoxifylline, Its Pharmacologically Active Metabolites, and Donepezil Using LC-MS/MS in Rat Plasma: Its Application to a Pharmacokinetic Study

This study developed a simple, rapid, reproducible, and analytical method using liquid chromatography and electrospray ionization (ESI) with tandem mass spectrometry (LC-MS/MS) to simultaneously quantify pentoxifylline (PTX), its pharmacological active metabolites, lisofylline (PTX-M1) and 1-(3-carboxypropyl)-3,7-dimethylxanthine (PTX-M5), and donepezil (DNP) in rat plasma, using PTX-d6 and DNP-d7 as the internal standards. The LC-MS/MS procedure was performed at the ESI interface, operating in positive ionization and multiple reaction monitoring (MRM) modes; the monitoring of transitions comprised m/z 279.3 &gt; 181.1 for PTX, m/z 281.1 &gt; 263.1 &gt; 160.90 for PTX-M1, m/z 267.1 &gt; 249.0 &gt; 220.9 for PTX-M5, m/z 380.3 &gt; 90.9 for DNP, m/z 285.3 &gt; 187.1 for PTX-d6 (IS1), and m/z 387.3 &gt; 98.3 for DNP-d7 (IS2). After plasma protein precipitation (PP) with methanol, chromatographic separation was performed with an Imtakt Cadenza® CD-C18 (100 × 3 mm, 3 µm) column, using an isocratic mobile phase consisting of 0.1% formic acid in water and methanol (20:80, v/v) at a flow rate of 0.2 mL/min. The retention times of DNP, PTX-M5, PTX, and PTX-M1 were 2.24, 2.50, 2.68, and 2.72 min, respectively, with a total run time of 5 min. This method was validated over a linear concentration range of 5–8000, 10–5000, 20–15,000, and 2–500 ng mL−1 for PTX, PTX-M1, PTX-M5, and DNP, respectively, with a high correlation coefficient (r2 ≥ 0.99). The established method was fully validated in terms of selectivity, the lower limit of quantitation, precision, accuracy, recovery, matrix effect, stability, and dilution integrity according to the regulatory guidelines from the U.S. Food and Drug Administration and the Korea Ministry of Food and Drug Safety. The validated method was successfully applied to a pharmacokinetic study on the concurrent administration of DNP and PTX in rats.

ВЛИЯНИЕ ЛЕКАРСТВЕННЫХ СРЕДСТВ, НОРМАЛИЗУЮЩИХ КРОВОСНАБЖЕНИЕ И ТРОФИКУ ОБЛУЧЕННЫХ ТКАНЕЙ, А ТАКЖЕ АНТИБИОТИКА ШИРОКОГО СПЕКТРА ДЕЙСТВИЯ НА ТЕЧЕНИЕ ТЯЖЕЛЫХ МЕСТНЫХ ЛУЧЕВЫХ ПОРАЖЕНИЙ У КРЫС

Purpose: To study in the experiment the therapeutic efficacy of drugs that normalize blood supply and trophism of irradiated tissues, as well as a complex broad-spectrum antibiotic, for the course of severe local radiation lesions to justify the clinical use of these drugs in this pathology. Material and methods: Wistar-Kyoto inbred rats were exposed to local X-rays in the ilio-lumbar region of the back at a dose of 110 Gy (tube voltage 30 kV, current 6.1 mA, Al filter 0.1 mm thick), at a dose rate of 20.1 Gy / min. Irradiation field area was 8.5 cm2. Radiation exposure caused the formation of long-term (up to 3.5–4 months) non-healing radiation ulcers of the skin without a critical radiation load on the underlying tissues. For the treatment of radiation lesions, an antibiotic was used – levotetrasulfin forte, as well as drugs that affect the blood supply and trophism of irradiated tissues – pentoxifylline and detralex. The drugs were administered daily both in isolation from each other and together during the period (from the 21st to the 42nd or from the 28th to the 48th day after irradiation), when the radiation ulcer formed and its gradual healing began. The everity of radiation skin lesions and the effects of therapy were assessed in dynamics by clinical manifestations and using planimetry. Results: It was found that the separate use of drugs in the treatment of severe local radiation lesions was not very effective. However, with the combined administration of drugs, a noticeable increase in the rate of healing of radiation ulcers was revealed. Thus, it was shown that with the joint administration of pentoxifylline (intraperitoneal, 50.0 mg / kg), detralex (75.0 mg / kg, per os) and levotetrasulfin forte (intraperitoneal, 0.1 ml / kg), the area of radiation ulcers in treated animals in the period from 98 to 126 days after irradiation was 26–80 % less compared to irradiated controls. Conclusion: The experiments show the possibility of successful use of a complex antibiotic in combination with drugs that improve blood supply and trophism of irradiated tissues, in the treatment of severe local radiation lesions.

144. Efficacy of pentoxifylline-tocopherol-clodronate in the management of mandibular osteoradionecrosis: A multicentre retrospective case series

Osteoradionecrosis (ORN) is a long-term and debilitating complication related to radiotherapy-based treatment for head and neck cancer (HNC). With no universal consensus on an optimal treatment regime, ORN management remains challenging. Treatment for advanced or refractory ORN has historically been limited to surgical resection and reconstruction. The fibroatrophic hypothesis for the aetiopathogenesis of ORN led to administration of pentoxifylline, tocopherol and clodronate (PENTOCLO) in the management of ORN.

Effect of pentoxifylline and tocopherol for MRONJ patients: A systematic review

MRONJ (medication related osteonecrosis of the jaw) is a disease characterized by necrosis of the jaw that occurs after administration of anti-resorptive or anti-angiogenic drugs. However, etiology and effective treatment methods of MRONJ are not yet clearly identified. In this study, a systematic review was conducted to investigate the effects of pentoxifylline and tocopherol on MRONJ. A total of 5 clinical studies using pentoxifyllie and tocopherol in MRONJ patients among the papers registered in Pubmed/medline were reviewed. Pentoxifyllie and tocopherol were used for therapeutic purposes in 32 patients, and the mean age was 68 years for men and 74.21 years for women. Of the 32 patients, 20 patients were stage 2, 11 patients were stage 3, and one patient was stage 0. In the most cases, the triggering factor was extraction. All patients com-plained of pain in the lesion area before drugs administration. The average follow-up period was 10.6 months. After drugs administration, 29 patients (90.6%) showed improvement in symptoms in terms of bone exposure and pain. Administration of pentoxifylline and tocopherol in MRONJ may improve symptoms of pain and bone exposure. However, it seems that additional studies on the appropriate use and dose, timing and duration of administration are needed.

Pentoxifylline inhibits phosgene-induced lung injury via improving hypoxia

Inhalation of high concentrations of phosgene often causes pulmonary edema, which obstructs the airway and causes tissue hypoxia. There is currently no specific antidote. This study was performed to investigate the effect behind pentoxifylline (PTX) treatment for phosgene-induced lung injury in rat models. Rats were exposed to phosgene. The protein levels of hypoxia-inducible factor-1α (HIF-1α), vascular endothelial growth factor (VEGF), and occludin proteins in lung tissue were determined. The effect of both prophylactic and therapeutic administration of PTX (50 mg/kg and 100 mg/kg) was evaluated. The lung permeability index and HIF-1α protein level increased, the arterial blood oxygenation index (PaO2/FIO2 ratio) and occludin protein level decreased significantly 6 h after phosgene exposure (P < 0.05). PTX exerted protective effects by HIF-1α-VEGF-occludin signaling pathway to some extent. Moreover, prophylactic, but not therapeutic administration of PTX (100 mg/kg), exhibited a significant protective effect. Pretreatment with PTX protected against phosgene-induced lung injury, possibly by inhibiting differential expression of HIF-1α, VEGF, and occludin.

Inhibitory effect of pentoxifylline on the synthesis and deposition of glycosaminoglycans in hypothyroid skin

The skin manifestations in hypothyroidism are common but their advanced forms do not have adequate therapy. Along with achievement of euthyroidism, thyroid-associated dermatopathy (TAD) needs an inhibition of the proliferation and activation of fibroblasts, and of the glycosaminoglycans synthesis. Pentoxifylline (PTX) exerts multifaceted effects and has shown properties to inhibit certain constitutive activities of dermal fibroblasts. The aim of this study was to determine the histopathological changes and to establish the amount and distribution of mucin in hypothyroid skin, with or without treatment with PTX. Hypothyroid skin showed abundant diffuse mucin deposition in all dermal compartments in comparison with euthyroid skin. After administration of PTX in dose 100 mg/kg daily, there was a significant decreased amount of mucin in the dermis. The improvement of the dermal histological manifestations, in general demonstrated by narrowing between the dermal collagen fibers and by a decrease in mucin deposition, might be explained with dose-dependent PTX inhibition of the synthesis and accumulation of glycosaminoglycans. The histological results of this study confirmed several clinical observations about the beneficial effect of PTX on clinical skin manifestations in hypothyroid state. Therefore, we may propose PTX as a new potential therapeutic agent for TAD treatment. Further studies are needed to fully establish the effect of PTX on dermal fibroblasts after continuous administration.

MICROSTRUCTURAL ORGANIZATION OF PERIODONTIUM UNDER CONDITIONS OF COMPLEX CORRECTION AGAINST THE BACKGROUND OF EXPERIMENTAL TEN-WEEK OPIOID EXPOSURE

In order to develop an adequate scheme of drug correction of periodontal tissue damage on the background of long-term action of the opioid analgesic nalbuphine, experimental studies were performed using the drugs pentoxifylline and ceftriaxone. The study was performed on male rats (24), which were divided into 3 groups. And the group is a control group. Group II – administration to rats of opioid analgesic in increasing doses for 10 weeks, where the initial dose was – 0.212 mg / kg, 9-10 weeks – 0.283 mg / kg. Group III – administration of pentoxifylline (7-10 weeks) and ceftriaxone (9-10 weeks) at a dosage of 2.86 mg against a 10-week opioid effect (from 0.212 to 0.283 mg / kg). For histological examinations, fragments of the dental segment of rats were collected using complex decalcification of the hard tissues of the dental organ. Microscopic studies in animals at 10 weeks of opioid action indicated pronounced inflammatory-dystrophic changes in periodontal tissues, which were manifested by necrotic changes in the mucous membrane of the gums, dystrophic periodontal damage and vascular disorders. Drug correction with pentoxifylline and ceftriaxone on the background of ten weeks of opioid action led to a protective effect on the microstructural organization of periodontal tissues of rats. Although complete restoration of periodontal structures in comparison with the control did not occur, however, the use of etiopathogenetic treatment contributed to a certain stabilization of the inflammatory process. The results showed that the use of pentoxifylline and ceftriaxone prevented the generalized progression of dystrophic changes in the periodontium with long-term opioid action, compared with the detected pathological changes in periodontal tissues in animals under ten weeks of opioid administration without corrective action.

Rolipram and pentoxifylline combination ameliorates experimental diabetic neuropathy through inhibition of oxidative stress and inflammatory pathways in the dorsal root ganglion neurons.

Diabetic neuropathy (DN) is the most challenging microvascular complication of diabetes and there is no suitable treatment for it, so the development of new agents to relieve DN is urgently needed. Since oxidative stress and inflammation play an essential role in the development of DN, clearance of these factors are good strategies for the treatment of this disease. According to key role of cyclic adenosine monophosphate (cAMP) in the regulation of oxidative stress and inflammatory pathways, it seems that phosphodiesterase inhibitors (PDEIs) can be as novel drug targets for improving DN through enhancement of cAMP level. The aim of this study was to evaluate the effects of rolipram, a selective PDE4 inhibitor, and pentoxifylline, a general PDE inhibitor on experimental model of DN and also to determine the possible mechanisms involved in the effectiveness of these agents. We investigated the effects of rolipram (1mg/kg) and pentoxifylline (100mg/kg) and also combination of rolipram (0.5mg/kg) and pentoxifylline (50mg/kg), orally for five weeks in rats that became diabetic by STZ (55mg/kg, i.p.). After treatments, motor function was evaluated by open-field test, then rats were anesthetized and dorsal root ganglion (DRG) neurons isolated. Next, oxidative stress biomarkers and inflammatory factors were assessed by biochemical and ELISA methods, and RT-PCR analysis in DRG neurons. Rolipram and/or pentoxifylline treatment significantly attenuated DN - induced motor function deficiency by modulating distance moved and velocity. Rolipram and/or pentoxifylline treatment dramatically increased the cAMP level, as well as suppressed DN - induced oxidative stress which was associated with decrease in LPO and ROS and increase in TAC, total thiol, CAT and SOD in DRG neurons. On the other hand, the level of inflammatory factors (TNF-α, NF-kB and COX2) significantly decreased following rolipram and/or pentoxifylline administration. The maximum effectiveness was with rolipram and/or pentoxifylline combination on mentioned factors. These findings provide novel experimental evidence for further clinical investigations on rolipram and pentoxifylline combination for the treatment of DN.

Beneficial effects of pentoxifylline in the evolution of subclinical atherosclerosis in chronic kidney disease patients

Background and Aims : Chronic kidney disease (CKD) patients present increased cardiovascular (CV) morbidity and mortality, with atherosclerosis being the underlying phenomenon in most of CV events. Clinical trials and metanalyses have linked administration of pentoxifylline (PTX) with renoprotection secondary to anti-inflammatory and antifibrotic effects in CKD patients, together with increased levels of the anti-aging protein Klotho. However, the effect of PTX on atherosclerosis in CKD patients has not been analysed.

Pentoxifylline Inhibits Pulmonary Fibrosis by Regulating Cellular Senescence in Mice.

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive disease, and its occurrence and development are mediated by cellular senescence. Drugs targeting senescent cells seem like a promising and efficacious strategy for IPF treatment. Previous studies have illustrated that pentoxifylline (PTX) may play a certain role in inhibiting pulmonary fibrosis and combating cellular senescence. In this study, we demonstrated that PTX administration inhibits pulmonary fibrosis development and cellular senescence in the bleomycin (BLM)-induced IPF mice model. Moreover, the expression levels of fibrosis-related genes and senescence-related genes in mice lung tissue and primary pulmonary fibroblasts illustrated lung fibroblasts’ vital role in these two processes. And the curative effect of PTX was completed mainly by acting on lung fibroblasts. Besides, during the whole treatment, delayed initiation or advanced halt of PTX administration would influence its effectiveness in reducing fibrotic and senescent traits in various degrees, and the latter influenced more. We further determined that a long period of PTX administration could bring noticeable benefits to mice in recovering BLM-induced lung fibrosis and suppressing age-associated cellular senescence. Moreover, it was still effective when PTX administration was used to treat senescent human fibroblasts. Thus, our findings manifested that PTX therapy is an efficient remedy for pulmonary fibrosis by suppressing cellular senescence.

Use of pentoxifylline during ovarian stimulation to improve oocyte and embryo quality: A retrospective study.

ObjectiveThis study aims to investigate if the administration of pentoxifylline during ovarian stimulation have an impact on the quantity and quality of oocytes recovered for in vitro fertilization (IVF), the quality of zygotes and embryos resulting from IVF, the serum estradiol and progesterone concentrations, the endometrial thickness and pregnancy outcomes after embryo transfer. MethodsRetrospective crossover study including 18 women with recurrent implantation failur, defined as having a history of at least two consecutive cycles of implantation failure and 25-45 years of age at the time of embryo transfer. Pentoxifylline was added during their following IVF attempt aiming to improve endometrial function. Oocyte, zygote and embryo quality, serum estradiol and progesterone concentrations, endometrial thickness and IVF outcomes were compared between the two sequential attempts. ResultsCompared to the first attempt, the outcomes of the second attempt, with the addition of pentoxifylline administration, resulted in higher numbers of total and mature oocytes, better oocyte, zygote and embryo quality, higher serum estradiol concentrations, thicker endometrium and better clinical IVF outcomes. ConclusionsThe administration of pentoxifylline during ovarian stimulation seems to improve IVF outcomes, not only by the generating a thicker endometrial lining, but also by producing a higher number of oocytes, with better oocyte, zygote and embryo quality, and higher serum estradiol concentrations.

Treatment of Poor Sperm Quality and Erectile Dysfunction With Oral Pentoxifylline: A Systematic Review.

Background: Pentoxifylline (PTX) is a member of methylxanthine chemicals and a type of non-selective phosphodiesterase-5 inhibitors, which has been used in male infertility treatment to improve sperm quality and erectile dysfunction (ED) treatment. Mutually tight associations existed between ED and male infertility. Using PTX might kill two birds with one stone by improving sperm quality and erectile function in infertile men with ED. Methods: PubMed, Cochrane Library, EMBASE, and Web of Science were searched by October 2021. Based on available evidence from observational studies and randomized-controlled trials (RCTs), we conducted a systematic review to summarize the efficacy and safety of PTX in treating ED and male infertility. The protocol of the article was registered and updated in PROSPERO (CRD42021291396). Results: From 202 records, eight studies (7 RCTs) evaluating the role of PTX in ED and three studies (2 RCTs) assessing the efficacy of PTX in male infertility were included in the systematic review. Three studies (100.00%) and two studies (100.00%) reported the beneficial role of PTX in improving sperm progressive motility and normal sperm morphology rate, respectively. In contrast, only one study (33.33%) indicated the favorable role of PTX in enhancing sperm concentration. As for ED, three (60.00%) studies supported the treatment role of PTX alone in ED, and two studies (66.67%) favored the combination use of PTX and selective PDE5Is compared with selective PDE5Is alone. Safety analysis showed that PTX was a well-tolerated drug in ED and male infertility treatment. Conclusion: Given the association between ED and male infertility and satisfying findings from available evidence, PTX administration for the simultaneous treatment of poor sperm quality and mild ED in infertile men will highly enhance the treatment compliance. However, the finding should be treated carefully until validated by further studies.

Pathogenetic Justification of a New View on the Treatment of Angle-Closure Glaucoma

Purpose. To study the effectiveness of vascular, anti-inflammatory and fibrinolytic therapy, to conduct a comparative assessment with treatment without vascular therapy in patients with angle-closure (ACG) and mixed glaucoma.Methods. A total of 55 patients with angle-closure and mixed glaucoma, mainly with hypermetropic refraction of varying degrees, were examined: 7 people with acute glaucoma attack, 6 people with subacute glaucoma attack (group 1, with anti-inflammatory treatment), 7 people with acute glaucoma attack and 6 people with subacute glaucoma attack (group 2, with vascular treatment), 14 people with chronic angle-closure glaucoma (group 3) and 15 people with mixed glaucoma (group 4). All patients underwent an ophthalmological examination, which included visometry, refractometry, tonometry, computer perimetry, OCT and OCT angiography, and an ELISA analysis to determine cytokines.Results. The administration of the drug Pentoxifylline as a cytokine blocker and antiplatelet agent in ACG contributed, in our opinion, to an improvement in visual acuity, perimetry (MD), an increase in the density of capillaries of the deep vascular plexus at the level of lamina cribrosa in the peripapillary zone (%), i.e. improved blood circulation in the vessels of the optic nerve disc and also contributed to the blockade of cytokines, mainly in the 2-nd group of patients. In our opinion, a personalized approach to the treatment of ACG is to maintain the improvement of blood circulation in the peripapillary zone by prescribing a course of treatment with Pentoxifylline for 6 months after surgery. After phacoemulsification, there was a significant increase in the density of capillaries of the deep peripapillary vascular plexus at the level of lamina cribrosa (p ≤ 0.05) (51.0 ± 3.5 %), and after further treatment with Pentoxifylline, the capillary density continued to increase in 2–4 groups in the next 6 months of follow-up. The thickness of RNFL (Retinal nerve fiber layer, structural parameter) decreased due to a decrease in edema in 1–2 groups, slightly increased in 3–4 groups, in our opinion, due to improved blood circulation. Increased reperfusion in the capillaries of the deep plexus during normalization of IOP in glaucoma patients and further treatment with pentoxifylline indicates the effectiveness of the proposed treatment in addition to surgical treatment. The results obtained emphasize the advantages of the proposed therapy for the treatment of patients with angle-closure and mixed glaucoma.Conclusion. To date, there are no clear recommendations of vascular therapy for the treatment of patients with ACG and mixed glaucoma, which creates the need for its addition to treatment regimens, taking into account the vascular component of ACG and mixed glaucoma.