Pentoxifylline: A Drug with Antiviral and Anti-Inflammatory Effects to Be Considered in the Treatment of Coronavirus Disease 2019

In December 2019, a new coronavirus, named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), emerged from China, causing pneumonia outbreaks first in the Wuhan region and has now spread worldwide. There are no specific drugs for the disease caused by this virus, coronavirus disease 2019 (COVID-19). Considering that new synthesized drugs cannot be applied immediately to patients, conventional drug in new use is a feasible solution. Chloroquine, remdesivir, favipiravir, lopinavir, ribavirin, and ritonavir have shown efficacy to inhibit coronavirus in vitro. Pentoxifylline, a drug with anti-inflammatory, immunomodulatory, and bronchodilatory effects, has previously been shown to inhibit several viral infections. Immunological studies have shown that most patients with severe COVID-19 exhibit substantially elevated serum levels of pro-inflammatory cytokines. Pentoxifylline is a phosphodiesterase inhibitor that increases the levels of cyclic adenosine monophosphate, which in turn activates protein kinase, leading to a reduction in the synthesis of pro-inflammatory cytokines and immune cell migration. Here, we propose pentoxifylline, a drug with low cost and toxicity, as a possible treatment for COVID-19 based on its interesting properties.     

Orbital Fracture in a Professional Diver: Issues and Management

Background

We present a case report of a professional diver who sustained a fracture of the left orbital medial wall as well as floor exceeding 50% with orbital fat herniation blocking the maxillary sinus ostium. This may result in a closed cavity within the maxillary sinus that could potentially result in barotraumas during future diving. The aim of his surgery consists of repairing the orbital fracture and to aerating the sinus at the same sitting.

Method

A transconjunctival approach was used combined with endoscopic sinus surgery approach to the maxillary sinus. The orbital floor fracture was repaired with a titanium plate. A wide middle meatal antrostomy was performed. A size eight Foley’s catheter was inserted into the maxillary sinus and the balloon inflated to elevate and support the displaced inferior orbital floor bone fragment. The balloon was left in situ for 4 weeks to support the mobile inferior orbital fragment till adequate bone healing and stability.

Results

Patient recovered well. At 3 months post-operatively, the maxillary antrostomy remained patent, and a hyperbaric oxygen challenge test was performed with success. A repeat orbital CT scan 1 day after hyperbaric challenge showed no signs of air leakage, and the bony inferior orbital floor fracture has healed completely with the titanium plate in situ.

Conclusion

This is the first case report of repair of orbital floor fracture with simultaneous aeration of the maxillary sinus in a professional diver using a combined approach. The patient was able to resume his occupation as a professional diver following surgery.

     

重症酒精性肝炎需要关注的几个问题

重症酒精性肝炎（severe alcoholic hepatitis,SAH）是肝脏的一种无菌性炎症性损伤,大多发生在慢性肝病（脂肪肝、肝硬化）的基础上,因短期内大量饮酒所致肝病的急性恶化,是酒精性肝病（alcoholic liver disease,ALD）严重的表现形式。多数起病急骤,出现高度黄疸和严重凝血功能障碍等,迅速进展为肝功能衰竭、败血症和其他器官功能障碍（尤其是肝肾综合征）,短期病死率接近40％[1],但不少临床医生还缺乏对SAH的早期识别和及时处理的经验。在本期相关文章中已经就ALD发病机制、诊断以及治疗问题进行了阐述,本文就几个容易被忽略的问题展开讨论,提请大家关注。     

A randomized controlled pilot study of Pentoxifylline in patients with non-alcoholic steatohepatitis (NASH)

Purpose Tumor necrosis factor-α (TNF-α) is implicated in non-alcoholic steatohepatitis (NASH). Pentoxifylline inhibits TNF-α. We wanted to evaluate the efficacy of Pentoxifylline on NASH patients. Methods Patients with biopsy proven NASH and persistently elevated alanine aminotransferase (ALT) greater than 1.5 times the upper limit of normal were randomized to 3 months of treatment with a step 1 American Heart Association diet and daily exercise with Pentoxifylline or placebo. Liver function tests, serum lipids and TNF-α, Interleukin 6 (IL-6), and plasma hyaluronic acid were measured at baseline, at weeks 6 and 12. Categorical data were analyzed by Fisher’s exact test while independent sample t-test and Mann–Whitney test were used for continuous data. Results Eleven patients were randomized into the Pentoxifylline and nine to the placebo group. After 3 months of treatment body mass index (BMI), ALT and aspartate aminotransferase (AST) decreased significantly in both groups. There was no difference between the two groups in reduction of BMI (P = 0.897). There was significantly greater reduction in AST in the Pentoxifylline group (P = 0.038). There was a trend toward lower ALT level (P = 0.065) in the Pentoxifylline group. TNF-α and IL-6 decreased significantly in both groups after treatment, but there was no significant difference between the two groups. Conclusion Three months of Pentoxifylline treatment in combination with diet and exercise results in significantly greater reduction in AST levels in patients with NASH as compared with controls. This study was funded by the National Healthcare Group Small Innovative Grant NHG-grant number. RPR/04029. It received ethics approval by the National Healthcare Group Domain Specific Research Board D-registration number DSRB-D/04/083.     

24-h blood glucose pattern in type I and type II diabetics after oral treatment with pentoxifylline as assessed by artificial endocrine pancreas

Summary Based on the known action of xanthine derivatives on the insulin secretion, the effect of pentoxifylline on carbohydrate homeostasis of type I (IDDM) and type II (NIDDM) diabetics was investigated. Pentoxifylline is known to exert a favorable influence on hemorheological disturbances in such patients. Twenty-four hour blood glucose pattern and insulin requirements were evaluated in type I and type II diabetics by the use of the artificial pancreas before and after a 14-day treatment with pentoxifylline 400 mg p.o. (Trental 400^?) t.i.d. During the stabilization period before treatment with pentoxifylline, NIDDM patients required 10.1±3.8 U of insulin and the IDDM 35±13.7 U. After 2 weeks on pentoxifylline, NIDDM required only 6.3±2.8 U (p<0.05) and IDDM 28.5±9.7 U (n.s.). Average blood glucose during the 24h decreased by 15.8±3.5% in NIDDM and by 10.3±2.5% in IDDM. Moreover, a significant smoothing of glucose fluctuations during the 24h was noted in both groups. It is concluded that pentoxifylline administered concurrently to any antidiabetic type of treatment leads to better blood glucose control as well as to prevention or delay of vascular complications. This work was supported by grants from the Social Ministry, Athens, Greece; Department of Internal Medicine I, University of Ulm, FRG;Deutsche Forschungsgemeinschaft SFB87 Endokrinologie, Ulm, FRG; the Alexander Onassis Foundation, Vaduz, Liechtenstein. Dedicated to Prof. Dr. med. h.c. Ernst F. Pfeiffer on the occasion of his 65th birthday anniversary.     

已酮可可碱对神经病理性疼痛大鼠的镇痛作用及机制

目的观察已酮可可碱（PTX）对神经病理性疼痛大鼠的镇痛作用及其机制。方法成年雄性SD大鼠96只随机分为假手术组、慢性坐骨神经结扎损伤（CCI）组和PTX组，CCI组和PTX组按Bennett法建立CCI模型．PTX组于术前1d开始至取材点每天腹腔注射PTX 100mg／kg．假手术组注射相同容积的生理盐水，CCI组造模后不做任何处理。于手术后1、3、7、11、14、21d用von-Frey filaments测定机械性痛觉过敏（MWT），按Hargreaves法测定热痛觉过敏（TWL）；并于1、7、14、21d时处死大鼠，取腰段脊髓用双抗体夹心ELISA法测定细胞因子含量。结果与假手术组相比，CCI模型大鼠机械痛阈于术后1d开始下降，7d最显著，热痛阈3d时下降最显著（P〈0．01）。PTX组痛阈在各时间点均较CCI组显著升高（P〈0．05）。CCI后1d即出现IL-6、TNFα、IL-1β蛋白含量升高，于术后7d达到高峰，14d时仍然较高（p〈0．05）。TNFα和IL-1β于术后21d明显下降至接近基础值，但IL-6表达一直持续至术后21d。PTX组脊髓细胞因子含量明显低于CCI组（P〈0．05）。结论PTX可显著抑制神经病理性疼痛，此作用与其抑制脊髓细胞因子表达有关。     

Pentoxifyline versus prednisolone for severe alcoholic hepatitis: A randomized controlled trial

AIM: To compare the efficacy of pentoxifylline and prednisolone in the treatment of severe alcoholic hepatitis, and to evaluate the role of different liver function scores in predicting prognosis. METHODS: Sixty-eight patients with severe alcoholic hepatitis (Maddrey score ≥ 32) received pentoxifylline ( n = 34, group Ⅰ) or prednisolone ( n = 34, group Ⅱ) for 28 d in a randomized double-blind controlled study, and subsequently in an open study (with a tapering dose of prednisolone) for a total of 3 mo, and were followed up over a period of 12 mo. RESULTS: Twelve patients in group Ⅱ died at the end of 3 mo in contrast to five patients in group Ⅰ. The probability of dying at the end of 3 mo was higher in group Ⅱ as compared to group Ⅰ (35.29% vs 14.71%, P = 0.04; log rank test). Six patients in group Ⅱ developed hepatorenal syndrome as compared to none in group Ⅰ. Pentoxifylline was associated with a significantly lower model for end-stage liver disease (MELD) score at the end of 28 d of therapy (15.53 Maddrey score was associated with increased mortality. CONCLUSION: Reduced mortality, improved risk-benefit profile and renoprotective effects of pentoxifylline compared with prednisolone suggest that pentoxifylline is superior to prednisolone for treatment of severe alcoholic hepatitis.     

The effect of pentoxifylline on the healing of intestinal anastomosis in rats with experimental obstructive jaundice

The aims of this study were (1) to investigate the effect of experimental obstructive jaundice on the healing of intestinal anastomosis, and (2) to investigate the effect of pentoxifylline on the healing of intestinal anastomosis in rats with obstructive jaundice. Obstructive jaundice was induced in rats by the ligation and division of the common bile duct. Four days after this operation, either pentoxifylline or isotonic saline solution was administered intraperitoneally to these jaundiced rats and controls, and then intestinal anastomosis was performed. The concentrations of serum tumor necrosis factor α (TNF-α) and serum triglyceride of jaundiced and nonjaundiced rats were measured, and the quality of healing was evaluated by measuring the bursting preasure and hydroxyproline content of the anastomoses on the fifth and tenth days of anastomotic healing. Obstructive jaundice resulted in an impaired wound healing of the intestinal anastomosis in the rats. The administration of pentoxifylline to the jaundiced rats resulted in better anastomotic wound healing. The beneficial effects of pentoxifylline on anastomotic healing in rats with obstructive jaundice was attributed to its inhibitor effect on the endotoxin-induced TNF-α release from macrophages and monocytes, and the stabilizing effect on the neutrophils. Received: March 29, 1999 / Accepted: March 24, 2000     

己酮可可碱对腹膜功能的影响及其机制研究

目的探讨己酮可可碱对腹膜功能的影响和可能机制。 方法将雄性SD大鼠45只随机分成3组各15只，A组每日腹腔内注射0.9%氯化钠溶液20 mL，B组和C组每天腹腔注射4.25%腹膜透析液20 mL，并在第8，10，12天加入LPS75 μg，C组在腹腔注射液中同时加入6 mg&#8226;kg 1己酮可可碱。5周后行2 h腹膜平衡实验测定腹膜功能，留取血液及腹膜透析液，ELISA法测定血管内皮生长因子(VEGF)浓度；同时处死大鼠，留取肠系膜组织，RT PCR检测肠系膜组织VEGF mRNA表达水平。 结果B、C组超滤量及2 h透出液葡萄糖浓度/0 h透析液葡萄糖浓度(D2/D0 )比值均较A组明显减少( 均P＜ 0. 05)，B组较C组更明显；B、C组透析液尿素/血浆尿素浓度比值(D/Purea )较A组明显增加(P＜0. 05) ，B组较C组增加更明显；C组腹透液及血清中VEGF浓度，以及肠系膜VEGF mRNA表达较B组明显下降。血清及腹透液VEGF含量分别与D2/D0，D/Purea有较明显的相关性。结论己酮可可碱能有效改善腹膜功能，其机制可能与调节VEGF表达有关。