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Pentoxifylline, solution for infusion 2 mg/ml

Pharmacodynamics. Pentoxifylline is the main representative of the pharmacological group of drugs - hemorheological drugs. It increases the plasticity (deformability) of red blood cells, which allows them to penetrate into vessels with a changed lumen (diameter) and improve blood supply to tissues, especially against the background of hypoxia. It reduces their ability to aggregate, facilitates penetration into the extravascular bed, which also promotes tissue oxygenation. Pentoxifylline inhibits fibrinogen biosynthesis and reduces blood viscosity. Under the influence of the drug, the formation of pseudopodia in platelets is reduced. It is characteristic that with such a multifaceted intervention of pentoxifylline in the processes ensuring hemostasis, the risk of bleeding does not increase. During inflammation, pentoxifylline has the ability to reduce the adhesion and aggregation of polymorphonuclear leukocytes, inhibit the “metabolic explosion” and prevent their damaging effect on endothelial cells. It inhibits the activity of phosphodiesterase, inhibits the destruction of cAMP, reduces the concentration of intracellular calcium and enhances the effects of adenosine. 06/02/2014 Pentoxifylline has a weak vasodilator effect and prevents vascular contraction under the influence of vasoconstrictor stimuli. In recent years, it has been established that pentoxifylline has the ability to inhibit the production of proinflammatory cytokines (primarily tumor necrosis factor and interleukins-1,-2,-6). Pharmacokinetics. When administered intravenously, pentoxifylline enters the tissue and penetrates well through the blood-brain barrier. The half-life of pentoxifylline varies between 0.4 - 0.8 hours. It undergoes biotransformation in the liver with the formation of two main metabolites: 1-(5-hydroxyhexyl)-3,7-dimethylxanthine (metabolite-1) and 1-(3-carboxypropyl )-3,7-dimethylxanthine (metabolite-5), which have similar activity and have a half-life of 1 to 1.6 hours. 1.5 - 2 hours after infusion, the concentration of metabolites exceeds the content of the original compound by 5-8 times. By the 8th hour, the concentration of pentoxifylline and its metabolites in the blood decreases significantly (up to 10% of the initial value). Excreted mainly by the kidneys (up to 95%), mainly in the form of metabolite-5. Less than 4% of the drug is excreted in feces. In breastfeeding women it is secreted by the lactating glands. Due to the large volume of distribution and strong binding to erythrocytes, the pharmacokinetics of pentoxifylline during hemodialysis practically does not change.

Pentoxifylline solution for injection 20 mg/ml 5 ml ampoule 10 pcs. in Moscow

The dose and method of administration are determined by the severity of circulatory disorders, as well as on the basis of individual tolerability of the drug. The dosage is set by the doctor in accordance with the individual characteristics of the patient. The usual dose is from 100 mg to 600 mg of the drug, diluted in 250 ml or 500 ml of 0.9% sodium chloride solution or Ringer's solution, 1 or 2 times a day

Compatibility with other infusion solutions must be tested separately; Only clear solutions can be used.

100 mg of the drug should be administered over at least 60 minutes. In addition to infusion therapy, pentoxifylline can be prescribed for oral administration. In this case, the total daily dose of pentoxifylline (intravenous infusion + oral administration) should not exceed 1200 mg. Depending on concomitant diseases (for example, chronic heart failure), it may be necessary to reduce the injected volumes. In such cases, it is recommended to use a special infuser for controlled infusion.

In more severe cases, especially in patients with severe pain at rest, with gangrene or trophic ulcers (stages III-IV according to the Fontaine classification), a long-term intravenous infusion of the drug at a dose of 1200 mg over 24 hours is indicated. This dose can be divided into two 600 mg infusions, each administered over at least 6 hours. In this case, the individual dose can be calculated using the formula: 0.6 mg of pentoxifylline per kg of body weight per hour. The daily dose calculated in this way would be 1000 mg of pentoxifylline for a patient weighing 70 kg and ll50 mg of pentoxifylline for a patient weighing 80 kg. During maintenance therapy, switch to oral pentoxifylline.

In patients with renal failure (creatinine clearance less than 30 ml/min), it is necessary to reduce the dosage by 30-50%, which depends on the patient’s individual tolerability of the drug.

A dose reduction, taking into account individual tolerance, is necessary in patients with severe liver dysfunction.

In elderly patients, dose reduction may be required (increased bioavailability and decreased elimination rate). Treatment can be started in low doses in patients with low blood pressure, as well as in patients at risk due to a possible decrease in blood pressure (patients with severe coronary heart disease or with hemodynamically significant cerebral vascular stenoses). In these cases, the dose can only be increased gradually

Pentoxifylline in the treatment of various manifestations of atherosclerosis

In the modern pharmacological market, the formation of main groups of drugs that can in one way or another affect the properties of the vascular wall and the rheological properties of blood has already occurred. In the course of preparing various recommendations for the prevention and management of patients with various manifestations of atherosclerosis (cerebrovascular diseases, coronary heart disease, peripheral arterial diseases), the evidence base on the main active ingredients and drugs that can affect the prognosis, course and outcomes of diseases is analyzed and revised. In many scientific works, scientists often pay attention to drugs that have the ability to comprehensively improve microcirculation and at the same time can affect the vascular wall. One of these drugs is pentoxifylline (Polfilin 400 retard). It belongs to the group of vasodilators, but at the same time has many antiplatelet and angioprotective properties. Although the properties of pentoxifylline have already been sufficiently studied, various types of research are carried out again and again in various fields of medical science.

Pharmacological properties

First, it is necessary to dwell on the unique properties of pentoxifylline. It is a xanthine derivative and is similar in chemical structure to theobromine and theophylline. Today, the positive therapeutic effect of pentoxifylline is based on its influence on the biochemical properties of cellular elements of the blood, which are manifested in:

increasing the filterability (deformability) of erythrocytes, neutrophils and monocytes;
a decrease in the aggregation of erythrocytes and platelets, the level of fibrinogen in the blood plasma and a decrease in the activity of neutrophils (which causes a decrease in the formation of free radicals, adhesion and aggregation, the release of elastase, and a decrease in the levels of inflammatory cytokines in the blood) [1].

In addition, pentoxifylline affects the biochemical properties of blood: it reduces viscosity and improves its rheological properties. Active work is underway to study the effect of the drug on immune processes in the body. It can block the action of inflammatory cytokines that regulate the function of cells in the vascular wall. The effects of pentoxifylline on red blood cells and neutrophils are partly due to the inhibition of phosphodiesterase and the subsequent increase in intracellular cyclic adenosine monophosphate (cAMP), which plays an important role in controlling the activation and proliferation of monocytes, macrophages, T and B lymphocytes. The increase in cAMP levels caused by the drug occurs in parallel with a decrease in platelet aggregation, a decrease in the formation of oxygen radicals and tumor necrosis factor alpha by granulocytes [2]. Pentoxifylline also has a mild myotropic vasodilator effect, slightly reduces total peripheral resistance and has a positive inotropic effect. Due to the use of this drug, microcirculation and oxygen supply to tissues are improved. Pentoxifylline relaxes smooth muscle cells, including the vascular wall, by increasing the content of intracellular cAMP. Due to this property, it is classified as a vasodilator. Unfortunately, the contribution of the antispasmodic activity of the drug to clinical effectiveness in circulatory disorders is not decisive, since vasodilation in ischemic areas is close to maximum due to metabolic changes. Thus, at present, vasodilation as the main method of treating occluded arteries is not a priority.

Clinical Application

To date, the largest evidence base for the use of pentoxifylline and its positive effect on the outcome and course of the disease has been accumulated in the treatment of atherosclerosis of peripheral arteries and dementia (especially associated with cerebrovascular ischemia) caused by atherosclerotic changes.

Peripheral circulation disorders.

The therapeutic effectiveness of the drug for peripheral circulatory disorders is evidenced by an increase in the distance that the patient can walk, a decrease in the intensity of pain at rest, paresthesia, a decrease in spasms, healing of trophic ulcers, a decrease in swelling, cyanosis, and an improvement in local blood flow. Thus, according to the 2005 ACC/AHA recommendations for the management of patients with diseases of the peripheral arteries (lower limbs, renal, mesenteric) and abdominal aorta, pentoxifylline is prescribed at a dose of 400 mg 3 times a day as a second-line drug to cilostazol therapy in patients with intermittent claudication in order to increase walking distance. In addition, pentoxifylline is recommended as the drug of choice for borderline manifestations of intermittent claudication and in cases where the diagnosis has not yet been definitively confirmed. These claims are based on a meta-analysis of randomized placebo-controlled trials in which pentoxifylline was found to produce minimal but statistically significant improvements in pain relief and an increase in maximum walking distance from 21-29 to 43-48 m. According to the results of two large studies (128 and 150 participants), the number of patients whose maximum pain-free walking distance increased was 30 and 20%, respectively. One randomized controlled trial of 471 patients compared treatment with pentoxifylline in combination with cilostazol and placebo. The same recommendations note a study that studied this drug in patients with chronic ischemia of the lower extremities, which showed a statistically significant reduction in pain with intravenous administration of the drug. Pentoxifylline is much more effective not only than placebo, but also drugs such as naftidrofuryl, even in relatively low doses (300-600 mg/day) [4]. Some comparative trials on the effectiveness of pentoxifylline and other vasodilators (buflomedil and flunarizine) obtained the same data. A number of studies critically assessing the effect of various drugs in peripheral circulatory disorders have noted the highest therapeutic effectiveness of pentoxifylline. Only the administration of prostaglandin E1 (alprostadil) has proven to be more effective, but its parenteral administration is associated with certain problems and is very expensive [3].

Cerebrovascular disorders.

There are several large experimental studies examining the effects of pentoxifylline in the post-stroke period. One study examined post-ischemic treatment with the drug to reduce cortical infarct volume in a transient model of central cerebral ischemia in rats. Taking into account data from previous experimental studies, the drug has a neuroprotective effect against brain injury and general cerebral ischemia in experimental models. But the effect of pentoxifylline in the transient model of central cerebral ischemia remains to be studied. A study showed that administration of the drug at least 3 hours after the onset of stroke reduces cortical cerebral ischemic damage [7]. Another trial examined the possibility of administering pentoxifylline to prevent the occurrence of cerebral ischemic manifestations in rats prone to stroke and hypertension. They constituted an animal model that develops and creates the conditions that precede the appearance of brain disorders. The purpose of this trial is to evaluate the neuroprotective properties of the drug and its anti-inflammatory mechanisms of action in this stroke model. In a study using magnetic resonance imaging, it was found that brain damage when using pentoxifylline at a dose of 100 mg/kg/day developed in 80% of animals on the 70-80th day, while in 100% of rats who received this drug were not prescribed, such violations were observed on the 42nd day. Administration of 200 mg/kg/day of pentoxifylline completely protected the brain from developmental abnormalities. Pharmacotherapy prevented the accumulation of macrophages or CD4+, glial activation in brain tissue, and the appearance of inflammatory proteins in body fluids. The drug also showed protective effects when administered after the first onset of proteinuria (>40 mg/day). The findings indicate that, depending on the dose, pentoxifylline prevents the occurrence of direct brain damage and reduces inflammatory events [8]. Thus, experimental data indicate the undoubted benefit of the drug in the treatment of cerebrovascular disorders.

Although not everything is as good as we would like, and this is confirmed by official documents, which lay evidence-based medicine as the basis. According to the AHA/ASA guidelines for the early management of adult patients with ischemic stroke, the use of pentoxifylline is not recommended. However, it should be noted that this attitude for practitioners does not stem from the results of large multicenter studies, but due to the insufficient amount of statistically significant data on this issue. It follows from the text of the recommendations that in one of the trials, pentoxifylline and propentofylline were used by continuous intravenous infusion for 3 days immediately after the development of acute ischemic stroke in patients. Other studies in which the duration of drug administration was 5 and 7 days were conducted in 1993. Early fatal manifestations were recorded in the initial stage, during the first 4 weeks. These trials found a large reduction in early mortality, but these findings were not confirmed in a later study. Two subsequent trials showed a slight reduction in early mortality or significant disability. One study comparing the combination of pentoxifylline and aspirin with aspirin alone found a significant reduction in acute deaths. The same study examined the combined rate of early mortality and deterioration, but found no significant reduction in these combined events. Also, these and other trials confirmed the ability of aspirin to enhance the antiplatelet properties of pentoxifylline. In addition, patients with severe neurological symptoms had the greatest therapeutic benefit [5, 9].

Thus, most of the studies on which recent recommendations for the management of stroke patients with pentoxifylline are based are based on either outdated or few and small trials, although the majority of trials noted a positive effect of pentoxifylline. According to the Agency for Healthcare Research and Quality of Life (AHRQ) evidence-based research report for 2004, in the treatment of ischemic vascular dementia, a positive effect of pentoxifylline was noted in improving cognitive functions (general and specific) and global clinical assessment. For other clinical indicators, assessment was not made due to the small number of studies. However, when studying the effect of pentoxifylline in three placebo-controlled trials, treating 482 patients with predominantly multi-infarct dementia at a dosage of 1200 mg/day once or in three doses for 12-36 weeks, no statistically significant changes were found for all primary endpoints [6 ].

Heart failure. The last few trials have shown a beneficial effect of pentoxifylline on measures of cardiac dysfunction in patients with heart failure. Randomized, placebo-controlled trials (144 participants) tested the use of pentoxifylline versus placebo in patients with heart failure of various etiologies (idiopathic dilated cardiomyopathy, 3 studies; ischemic cardiomyopathy, 1 study). Beneficial effects on indicators of cardiac function in heart failure were noted in all classes of severity and regardless of etiology. All four studies showed a trend towards a reduction in mortality rates, but this effect was not statistically established. In summary, pentoxifylline may have beneficial effects across different NYHA functional classes of heart failure, improving ejection fraction and reducing mortality, but the trials conducted are small enough to provide conclusive conclusions. Large placebo-controlled studies involving a diverse group of patients are needed regarding the use of pentoxifylline in heart failure [10].

conclusions

Pentoxifylline, despite its fairly long existence on the pharmacological market, is an interesting drug approach to the treatment of various manifestations of atherosclerosis, in particular cerebrovascular diseases, where it is the basic drug. Surely, in the near future the drug will be used more widely for various diseases with impaired blood flow and microcirculation. As for its use in the treatment of peripheral circulatory disorders, in this area it remains an indispensable and excellent drug, with a small number of controllable side effects.

Literature

Kamchatnov P.R., Chugunov A.V., Umarova Kh.Ya., Asanov A.Yu. Secondary prevention of ischemic stroke - the use of antiplatelet agents // Consilium medicum. – 2006. – No. 11. – T. 8.
Drozdov S.A. Pentoxifylline in the treatment of cerebrovascular accidents. – M.: Center for Endosurgery and Lithotripsy
Polivoda S.N., Samura B.B., Bondur V.V. Clinical aspects of the use of agapurine in therapeutic practice // Ukrainian Medical Hours. – 2000. – No. 4 (18). – P. 7-8.
ACC/AHA 2005 Practice Guidelines for the Management of Patients With Peripheral Arterial Disease (Lower Extremity, Renal, Mesenteric, and Abdominal Aortic) // Circulation. – March 21, 2006. – P. 513.
Guidelines for the Early Management of Adults with Ischemic Stroke // Stroke. – May 2007. – P. 1682.
Pharmacological Treatment of Dementia summary Agency for Healthcare Research and Quality (AHRQ) by McMaster University Evidence-based Practice // Technology Assessment. – April 2004. – No. 97. – P. 7.
Vakili A., Khorasani MZ Post-ischemic treatment of pentoxifyline reduces cortical not striatal infarct volume in transient model of focal cerebral ischemia in rat // Brain Res. – January 2007. – Vol. 1144. – P. 186-191.
Banfi C., Sironi L. Pentoxifylline Prevents Spontaneous Brain Ischemia in Stroke-Prone Rats // Journal of Pharmacology And Experimental Therapeutics. – June 16, 2004.
Bath PM, Bath-Hextall FJ Pentoxifylline, propentofylline and pentifylline for acute ischemic stroke // Cochrane Database Syst Rev 2004; 3:CD000162.
Batchelder K., Mayosi BM Pentoxifylline for heart failure: a systematic review // S Afr Med J. – March 2005. – Vol. 95 (Suppl. 3). – P. 171-175.

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