Drug Strategies to Combat Chronic Inflammation
Pentoxifylline. Pentoxifylline is a drug used to treat conditions involving poor circulation to the brain, limbs, and other areas perfused by small blood vessels. The drug effectively modulates properties of both blood vessels and red blood cells thanks to its action as a non-selective phosphodiesterase inhibitor. Phosphodiesterase inhibition is a clinically important mechanism in many additional aspects of human physiology as well, so pentoxifylline has been studied in a wide range of applications ranging from diabetic complications and non-alcoholic liver disease, to endometriosis and cardiac surgery (Groesdonk et al. 2009; Li et al. 2011; Lopes de Jesus et al. 2008; Lv et al. 2009).
The potent anti-inflammatory properties of pentoxifylline were a secondary discovery, and still are not fully understood. Studies have revealed, though, that pentoxifylline modulates TNF-α signaling, which probably contributes to the considerable suppression of inflammation it has evoked in several human trials (Hepgul et al. 2010). In a recent trial, 400 mg of pentoxifylline taken twice daily significantly suppressed hs-CRP, fibrinogen, and TNF-α levels in patients with chronic kidney disease; subjects’ renal function improved with treatment as well (Goicoechea et al. 2012). In patients with HIV-related vascular dysfunction, pentoxifylline lessened leukocyte adhesion – a process that contributes to cardiovascular disease by allowing inflammatory cells to infiltrate the endothelial lining of blood vessels (Gupta et al. 2010). Given by IV-infusion, pentoxifylline lowered TNF-α levels and pain intensity following surgical removal of kidney stones (Izadpanah et al. 2009).
Pentoxifylline dosage varies depending on individual circumstances and clinical application, however, 400 mg taken twice daily has consistently tempered inflammation in diverse human trials. For example, administered at this dose for one month to 30 diabetic individuals with high blood pressure, not only did pentoxifylline quell inflammation (20% reduction in CRP levels and an 11% improvement in erythrocyte sedimentation rate [measure of inflammatory tendency of a blood sample]), but it also bolstered plasma antioxidant status, as evidenced by a 20% reduction in malondialdehyde levels (measure of oxidative stress) and a nearly 5% increase in glutathione levels, a powerful antioxidant (Maiti et al. 2007).
Metformin. The regulation of energy metabolism and inflammation are closely associated; this is evidenced by the co-incidence of metabolic disorders (obesity, diabetes) and low-grade inflammation (Molavi et al. 2007). Metformin may reduce the activity of inflammatory cytokines by increasing the production of IL-1βreceptor antagonist (IL1Rn), a protein factor which interferes with pro-inflammatory signaling of IL-1β (Buler et al. 2012). It may also promote favorable CRP levels, although not to the same extent as weight loss (Molavi et al. 2007, Sobel et al. 2011). A randomized controlled trial of hypertensive and dyslipedemic patients taking 1700 mg/day of metformin for 12 weeks demonstrated a 26.7% reduction in IL-6 and 8.3% reduction in TNF-α from baseline levels, a degree of reduction similar to that of the potent statin drug rosuvastatin (Crestor®)(Gómez-García et al. 2007). The anti-inflammatory effects of metformin appear to be rapid; reductions in circulating TNF-α, IL-1β, CRP, and fibrinogen were observed after only 30 days in a larger study of 128 type II diabetic patients with dyslipidemia (Pruski et al. 2009).
Aspirin. Aspirin has been used as an anti-inflammatory therapy long before the molecular mechanics of inflammation had been discovered; it is now well characterized as an inhibitor of cyclooxygenase enzymes. The modification of COX molecules by aspirin has important implications for cardiovascular health. Blood platelets use cyclooxygenase to produce thromboxane A2, a pro-inflammatory molecule that is an important signal during the initial stages of the clotting process. The inhibitory effect of aspirin on COX enzymes in platelets can partially explain its protective effects against the complications of several disorders, including hypertension, heart attack, and stroke (Patrono et al., 2008). Aspirin's inhibition of cycloxygenase also helps explain its potential effect on cancer risk reduction as observed in several studies (Rothwell et al., 2011; Rothwell et al., 2010; Salinas et al., 2010; Flossmann et al., 2007), as COX-2 also appears to have roles in increasing the proliferation of mutated cells, tumor formation, tumor invasion, and metastasis, and may contribute to drug resistance in some cancers(Sobolewski et al. 2010). Aspirin has also been shown to reduce the activity of NF-kb in vitro (Weber et al. 1995), and lower levels of multiple inflammatory markers (TNF-α,CRP, IL-6) in patients with cardiovascular disease (Ikonomidis et al. 1999, Chen et al. 2006, Solheim et al. 2003, Solheim et al. 2006).
Unlike many other non-steroidal anti-inflammatory drugs (NSAIDS), the effects of aspirin on COX enzymes are permanent for the life of the COX enzyme. Interestingly, it appears that rather than rendering the enzyme inactive, aspirin modifies the function of COX. Aspirin stops the enzyme from producing pro-inflammatory prostaglandins, and enables it to begin producing anti-inflammatory molecules called resolvins (Serhan et al. 2002).
Low-Dose Statin Drugs. Statins are thought to reduce inflammation by a mechanism distinct from their effects on cholesterol metabolism; they interfere with the function of cytokine receptors on the surface of white blood cells. Therefore, pro-inflammatory signals in the blood are unable to provoke a response from white blood cells, and they are prevented from further stimulating inflammation (Stancu et al. 2001) (Bu et al. 2011). Results of the JUPITER trial presented the strongest evidence for statins as anti-inflammatory therapy; in this study of over 17,000 healthy middle-aged men and women with elevated levels of the inflammatory marker CRP but normal levels of blood lipids, 20mg/day of rosuvastatin (Crestor®) reduced CRP levels by over half, in addition to reducing heart attack and stroke incidence (Ridker et al. 2008). Smaller studies have looked at the effect of statins on other inflammatory markers as well. A randomized controlled trial of hypertensive and dyslipedemic patients taking a lower dose (10 mg/day) of rosuvastatin for 12 weeks demonstrated a ~22% reduction in IL-6 and 13% reduction in TNF-α from baseline levels (Gómez-García et al. 2007). A second uncontrolled study of simvastatin demonstrated more modest reductions in IL-6, but no changes in TNF-α from the statin treatment (Bulcão et al. 2007). To generate a substantial anti-inflammatory effect using statin drugs alone requires a high dose that is more likely to induce side effects than lower dose statin therapy.
Dietary Approaches to Reduce Chronic Inflammation
Inflammation itself is not a disease, but is featured, to varying degrees, in adverse health conditions. Information on strategies and research regarding the reduction of inflammation characteristic to specific health conditions are featured in their respective Life Extension Protocols: Allergies; Age-related Macular Degeneration; Cancer Adjuvant therapy; Cardiovascular Disease; Gout; Inflammatory Bowel Disease; Osteoarthritis and Rheumatoid Arthritis; Osteoporosis. What follows is a summary of dietary and supplemental approaches to addressing general chronic inflammation and para-inflammation. As many types of general inflammation often occur without additional symptoms, most of the strategies listed below are based on their ability to reduce circulating inflammatory cytokines, the hallmark of the para-inflammatory state.
Macronutrients and Energy Balance. Macronutrient content (particularly the types and levels of carbohydrates and fats) can have a significant effect on the progression of inflammation (as measured by increases in pro-inflammatory markers). Diets with relatively high glycemic index (GI) and glycemic load (GL) have been associated with elevated risk of coronary heart disease, stroke, and type 2 diabetes mellitus, particularly among overweight individuals, and have been associated with modest increases in proinflammatory markers in multiple studies (Galland 2010). In a study of over 18,000 healthy women ≥45 years old without diagnosed diabetes, high GI and GL diets resulted in a small but significant increase in hs-CRP (+12% for high GI) over low GI diets (Levitan et al. 2008). In the Danish Hoorne study (Du et al. 2008), for every 10 unit increase in dietary glycemic index, circulating CRP was increased by 29%. As discussed previously, some dietary fats (particularly saturated and synthetic trans- fats) increase inflammation occurrence, while omega-3 polyunsaturated fats appear to be anti-inflammatory (Mozaffarian et al. 2004).
Since fat tissue (especially abdominal fat) expresses inflammatory cytokines, obesity can be a major cause of low-grade, systemic inflammation (Ortega Martinez de Victoria et al. 2009, Weisberg et al. 2003). Thus, it is important that total energy intake be proportional to energy expenditure, to avoid the deposition of abdominal fat. Obesity-induced increases in inflammatory cytokines appear to be reversible with fat loss (North et al. 2009). In a dramatic example, weight loss (by adjustable gastric banding) in a group of 20 severely obese individuals reduced IL-6 by 22% and CRP by almost half (Moschen et al. 2010).
An inflammatory index, developed by a group from the Arnold School of Public Health at the University of South Carolina, scored 42 common dietary constituents based on their ability to raise serum CRP (Cavicchia et al. 2009). Constituents (such as saturated fat, tea polyphenols, or vitamin D) were given either a positive (anti-inflammatory) or negative (pro-inflammatory) score, the magnitude of which was weighted based on the volume of inflammation research on the isolated ingredient. Human clinical data was weighted more than animal data, and clinical trials more than observational studies. The scores were then verified by comparing them to nutrient intakes and CRP levels from a group of 494 volunteers over the course of 1 year. Amongst the most anti-inflammatory nutrients (based on the model and study data) are magnesium, beta-carotene, turmeric (curcumin), genistein, and tea; the most pro-inflammatory included carbohydrates, total- and saturated fat, and cholesterol. The index may provide a useful metric for accessing the overall inflammatory potential of an individual diet.
Exercise. Energy expenditure through exercise lowers multiple cytokines and pro-inflammatory molecules independently of weight loss. While muscle contraction initially results in a pro-inflammatory state, it paradoxically lowers systemic inflammation. This effect has been observed in dozens of human trials of exercise training in both healthy and unhealthy individuals across many age groups (reviewed in Bruunsgaard 2005).
Fiber. In an analysis of 7 studies on the relationship between weight loss and hs-CRP, increased fiber consumption correlated with significantly greater reductions in hs-CRP concentrations (North et al. 2009). In these studies, daily fiber intakes ranging from 3.3 to 7.8 g/MJ (equivalent to about 27 to 64 g/day for a standard 2000 kcal diet) reduced CRP from 25%-54% in a dose-dependent fashion. These results should be interpreted carefully, as only two of the seven studies were specifically designed to examine the effects of fiber independently (North et al. 2009). The Women’s Health Initiative failed to detect an effect of fiber consumption on hs-CRP, but found that greater intake of dietary soluble and insoluble fiber (over 24 g/day) was associated with lower levels of IL-6 and TNF-α (Ma et al. 2008).
Magnesium. In two large observation studies (the Women’s Health Initiative and Harvard Nurses Study), greater magnesium (Mg) intake was associated with lower hs-CRP, IL-6, and TNF-α receptor, a measure of TNF-α activity (Galland 2010, Chacko et al. 2010). Data from the Multi-Ethnic Study of Atherosclerosis failed to find significant differences in IL-6 or CRP levels between individuals with the highest and lowest magnesium intakes, but did find a significant association between greater dietary magnesium and the lower levels of the inflammation-associated proteins homocysteine and fibrinogen (de Oliveira Otto et al. 2011). Magnesium was rated as the most anti-inflammatory dietary factor in the Dietary Inflammatory index, which rated 42 common dietary constituents on their ability to reduce CRP levels based on human and animal experimental and observation data (Cavicchia et al. 2009).
Vitamin D. Vitamin D appears to exert anti-inflammatory activity by the suppression of pro-inflammatory prostaglandins, and inhibition of the inflammatory mediator NF-κβ (Krishnan et al. 2010). Although intervention studies of its anti-inflammatory activity in humans are lacking, several observational studies suggest vitamin D deficiency may promote inflammation. Vitamin D deficiencies are more common amongst patients with inflammatory diseases (including rheumatoid arthritis, inflammatory bowel disease, systemic lupus erythematosus, and diabetes) than in healthy individuals (Guillot et al. 2010). They also occur more frequently in populations that are prone to low-level inflammation, such as obese individuals and the elderly (Awad et al. 2012). Vitamin D levels can drop following surgery (a condition associated with acute inflammation), with a concomitant rise in CRP (Reid et al. 2011). Low vitamin D status was associated with elevated CRP in a study of 548 heart failure patients (Liu et al. 2011), and with increases in IL-6 and NF-κβ in a group of 46 middle-aged men with endothelial dysfunction (Jablonski et al. 2011).
Vitamin E. Vitamin E functions as an antioxidant in the body. Specifically, vitamin E is incorporated into low-density lipoprotein (LDL) particles and protects them against oxidative damage; it seems to guard against atherosclerosis via other mechanisms as well (Meydani 2001). The gamma-tocopherol form of vitamin E appears to complement the anti-inflammatory action of alpha-tocopherol. Gamma-tocopherol has been shown to inhibit COX-2 and attenuate IL-1β signaling (Jiang 2000; Sjoholm 2001). In a small clinical trial on subjects with metabolic syndrome, the combination of gamma-tocopherol and alpha-tocopherol effectively suppressed C-reactive protein and TNA-α levels compared to placebo (Devaraj 2008). In this study, the combination of both tocopherols performed better than either alone, prompting the investigators to remark “the combination of [alpha-tocopherol] and [gamma-tocopherol] supplementation appears to be superior to either supplementation alone on biomarkers of oxidative stress and inflammation and needs to be tested in prospective clinical trials...”
Zinc and Selenium. Zinc- and Selenium-containing antioxidant proteins (such as superoxide dismutase and glutathione peroxidase) reduce reactive oxygen species (free radicals), which indirectly inhibits NF-κβ activity and prevents the production of several inflammatory enzymes and cytokines. Zinc can also inhibit NF-κβ in a more direct manner (Prasad 2009, Duntas 2009). Zinc supplementation is associated with decreases in inflammation in populations that are prone to zinc deficiency, such as children and the elderly (Kelishadi et al. 2010, Wong et al. 2011). Low level inflammation and circulating pro-inflammatory factors (CRP, TNF-α, IL-6, and IL-8) were reduced in elderly subjects by moderate zinc supplementation in several studies (Bao et al. 2010, Kahmann et al. 2008, Mariani et al. 2006). Like zinc, selenium deficiencies are common in chronic inflammatory states associated with disease (such as sepsis) (Maehira et al. 2002), where selenium supplementation has been associated with reductions in inflammation and better patient outcomes (Duntas 2009).