Cognitive Vitality Reports® are reports written by neuroscientists at the Alzheimer’s Drug Discovery Foundation (ADDF). These scientific reports include analysis of drugs, drugs-in- development, drug targets, supplements, nutraceuticals, food/drink, non-pharmacologic interventions, and risk factors. Neuroscientists evaluate the potential benefit (or harm) for brain health, as well as for age-related health concerns that can affect brain health (e.g., cardiovascular diseases, cancers, diabetes/metabolic syndrome). In addition, these reports include evaluation of safety data, from clinical trials if available, and from preclinical models. Pentoxifylline Evidence Summary May help protect against vascular damage by reducing inflammation and blood viscosity. Has low potency as a monotherapy and its efficacy is enhanced when used in combination with other agents. Neuroprotective Benefit: May help protect against cerebrovascular dysfunction by reducing inflammation and promoting blood flow. Aging and related health concerns: May protect against minor inflammation or oxidative stress damage in the vasculature, kidney, and liver. May help mitigate cancer treatment- associated fibrosis. Benefits observed typically as combination rather than monotherapy. Safety: Generally well-tolerated with mild nausea as the primary side effect. Associated with an increased risk for bleeding. 1 Availability: Rx, approved Dose: 400 mg oral 3X Chemical formula: C13H18N4O3 for intermittent claudication daily for intermittent claudication MW: 278.312 g/mol Half-life: 0.4-0.8 hours BBB: Penetrant Clinical trials: Many RCTs, Observational studies: but majority <300 people. None Multiple RCTs for: vascular dementia, stroke, intermittent claudication, venous leg ulcers, heart Source: PubChem failure, kidney disease, liver disease, and cancer. What is it? Pentoxifylline, also known as oxpentifylline, is a methylxanthine that was approved for intermittent claudication in Europe in 1972 and in the US in 1985 [1]. It improves blood flow by decreasing blood viscosity. It reduces the aggregation and activation of blood cells, primarily erythrocytes and neutrophils, which improves their ability to flow through the vasculature. Its inhibition of blood cell activation also produces anti-inflammatory and antioxidant effects. Pentoxifylline is a non- selective phosphodiesterase (PDE) inhibitor, with similar affinity to PDE 1, 3, 4, and 5 subtypes, and generally has lower potency than more subtype selective inhibitors [2]. Its mechanisms of action in vivo are not completely understood because most in vitro mechanistic studies have used concentrations far higher than the levels found in human plasma after administration of the standard dose. Much of its biological activity is expected to come from its major metabolites, which are found in higher concentrations in the plasma than pentoxifylline itself [2]. While pentoxifylline has been tested in numerous clinical trials for a variety of indications, the majority of these trials were conducted outside of the US, and their interpretability is limited by small sample sizes and other methodological design flaws. Current development efforts are largely focused on its use as adjunct to mitigate side effects stemming from cancer therapies. 2 Neuroprotective Benefit: May help protect against cerebrovascular dysfunction by reducing inflammation and promoting blood flow. Types of evidence: • 1 systematic review for vascular dementia (n=4 RCT, n=469 patients) • 5 RCT (Mental deterioration n=80, Parkinson’s disease n=11, ALS n=400, Stroke prevention n=66, Major depressive disorder n=80) • Numerous laboratory studies Human research to suggest prevention of dementia, prevention of decline, or improved cognitive function? Pentoxifylline has not been directly tested for its ability to improve cognitive function, but its projected mechanisms of action affect processes implicated in risk for cognitive decline. While this suggests that pentoxifylline may be useful for dementia prevention, long-term prospective or retrospective studies evaluating the ability of pentoxifylline to reduce dementia incidence in high-risk populations have not been conducted. Although most suffer from methodological design flaws, such as underpowering, the clinical trials that have been conducted thus far have been fairly consistent in showing that, as a monotherapy, pentoxifylline tends to have little or no clinically meaningful benefit, but may improve outcomes when used as a part of a combination therapy. This likely stems from weak in vivo biological activity on the relevant targets at the standard clinical dose. Depression: Potential benefit (in combination with SSRI) Some studies indicate that depression may be a risk factor for dementia [3]. In a 12-week, placebo- controlled, double-blind RCT of adults with major depressive disorder (n=80, age 24-53), the addition of pentoxifylline (400 mg TID) to selective serotonin reuptake inhibitor (SSRI) therapy (20 mg escitalopram), significantly improved depression, based on a reduction in the Hamilton Depression Rating Scale (HAM-D) (least squared mean difference=–3.49, P = 0.000) [4]. The benefits are thought to stem from the reduction of inflammation and oxidative stress. In a rat model of stress, pentoxifylline alleviated memory impairments, and restored levels of the antioxidant glutathione and brain derived neurotrophic factor (BDNF) [5]. Similarly, in the RCT, there was a positive correlation between the reduction of the HAM-D score with the reduction of serum biomarkers of inflammation and oxidative stress (TNFα, IL-6, 8-OHdG), and an inverse correlation between HAM-D score with the induction of 3 BDNF [4]. Whether pentoxifylline offers significant benefits in the absence of an SSRI has not been established. Stroke: Potential minor benefit Stroke is the major risk factor for vascular dementia. A meta-analysis of 4 RCTs (n=90, 110, 264, 297) testing pentoxifylline for acute ischemic stroke found a non-significant reduction in mortality by 35% (95% Confidence Interval (CI) 59% reduction to 4% increase) within 4 weeks of the stroke odds ratio (OR): 0.64, (95% CI 0.41 to 1.02) [6]. There was an inadequate level of evidence to determine whether there was an impact on neurological disability. One of the RCTs found that neurological deficit scores improved over 4 weeks in both the pentoxifylline and placebo groups, suggesting that patients with mild stroke are likely to improve irrespective of treatment. Patients with the most deficit at baseline appeared to benefit most, although it was still only a trend toward improved neurological deficit scores relative to placebo (Change in total neurological deficit scores compared to baseline 9.73 ±2.68, n = 75 vs. 5.29 ±3.17, n = 70; P = 0.118) [7]. The low level of observed benefit may be related to the timing of the intervention, as this latter trial was the only one in the meta-analysis to administer pentoxifylline within 12 hours of stroke onset [6]. In preclinical rodent stroke models, modestly protective effects in terms of reducing infarct size, blood brain barrier (BBB) permeability, edema, and neurological dysfunction were achieved when pentoxifylline was given before or up to 3 hours after cerebrovascular injury [8; 9; 10]. While this suggests that pentoxifylline may not be able to be administered early enough to mitigate damage in most stroke patients in a clinical setting, it may be able to help prevent future strokes. In a one-year follow-up study of stroke patients, pentoxifylline (400 mg TID) was able to lower the incidence of new transient ischemic attacks (10% vs 28% with aspirin-dipyridamole, P<0.05) [11]. Human research to suggest benefits to patients with dementia: Vascular dementia: Potential benefit Multi-infarct dementia involves memory loss due to a disruption of blood flow to the brain following multiple strokes. Pentoxifylline is expected to be beneficial for vascular dementia based on its abilities to promote blood flow. A systematic review of 4 double-blind, placebo-controlled RCTs for vascular dementia, primarily multi-infarct dementia, found only one study where pentoxifylline treatment was associated with significantly improved cognitive outcomes for the entire study population [12]. However, significant improvements in primary outcome measures of cognitive function relative to placebo were found in all the studies within the subpopulation that met a stricter criterion for vascular dementia. A meta-analysis could not be performed due to the heterogeneity in the analytic techniques 4 and diagnostic criteria used across the trials. Pentoxifylline is thought to be beneficial for vascular dementia based on its ability to promote cerebrovascular blood flow. In patients with cerebrovascular disease, pentoxifylline treatment (400 mg TID) for 4 or 8 weeks was shown to enhance cerebral blood flow by approximately 16%, based on 133Xenon clearance. Notably, the greatest increases in regional blood flow occurred in areas that were hypoxemic (20-40%) [13; 14]. Mental deterioration: Potential benefit (in combination with piracetam) In a placebo-controlled RCT, patients within 6 months of the onset of clinical mental deterioration (n=80, age 72±1) were tested for the ability of pentoxifylline (400 mg TID), piracetam (1600 TID), or the combination, to affect neuropsychological and hematological parameters [15]. Pentoxifylline increased whole blood filterability (+24% at 28 weeks, P<0.01), while piracetam improved long-term memory by 31%, relative to placebo,