Hypothesis: Pentoxifylline explores new horizons in treatment of preeclampsia

Medical Hypotheses xxx (2015) xxx–xxx

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Hypothesis: Pentoxifylline explores new horizons in treatment of preeclampsia Arsalan Azimi a,⇑, Seyyed Mohyeddin Ziaee a, Pouya Farhadi a, Mohammad Mahdi Sagheb b a b

Faculty of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran Shiraz University of Medical Sciences, Shiraz, Iran

a r t i c l e

i n f o

Article history: Received 29 January 2015 Accepted 28 June 2015 Available online xxxx

a b s t r a c t Preeclampsia, the leading cause of maternal morbidity and perinatal mortality, initiates as inappropriate immune response to trophoblastic invasion impairs placentation and placental circulation. A poorly perfused placenta generates superoxide anions as well as anti-angiogenic factors and this series of events result in impairment of endothelial function, followed by maternal morbidities such as hypertension, kidney injury and proteinuria. Renal loss of anti-coagulant proteins and subsequent hyper-coagulable state along with endothelial dysfunction accelerates progression of the disease toward eclampsia. Since Pentoxifylline, a methyl-xanthine derivative known for enhancement of vascular endothelial function, down-regulation of many inflammatory cytokines increased during preeclampsia, improvement of placental circulation, reduction of ischemia-reperfusion injury, enhancement of vasodilatation and endothelial function, ameliorating proteinuria, inhibition of platelet aggregation and decreasing risk of preterm labor, which are all amongst morbidities of preeclampsia, here it is hypothesized that Pentoxifylline prevents development of preeclampsia and/or decelerate progression of the disease. Ó 2015 Elsevier Ltd. All rights reserved.

Introduction Hypertensive pregnancy disorders are common complications of pregnancy and almost 10% of all pregnant women experience a variety of these disorder [1]. Preeclampsia is one of these varieties and it is defined as hypertension (arterial blood pressure of more than 140/90 mmHg) and proteinuria (>300 mg/liter) after 20 weeks of gestation in a previously normotensive pregnant woman [2]. Preeclampsia affects 3–5% of all pregnancies and it is estimated to cause 60,000 maternal deaths annually worldwide [3]. Development of symptoms of preeclampsia is frequently associated with increased risk for delivering newborns who are small for their gestational age (SGA), placental abruption and increased necessity for preterm interventions which are additive to adverse outcomes of the disease [4,5]. Preeclamptic patients are at increased risk of developing end-stage renal disease (ESRD), cardiovascular and cerebrovascular diseases, later in their life [6,7]. Preeclampsia is generally considered as the leading cause of maternal morbidity and perinatal mortality [8]. Preeclampsia could be categorized into two different subtypes: mild early onset and severe late onset. Some of preeclamptic patients experience the disease symptoms by their due date. ⇑ Corresponding author at: Zand Blvd., Shiraz, Iran. Tel.: +98 (0) 9379876373. E-mail address: [email protected] (A. Azimi).

These individuals develop mild symptoms of the disease with favorable fetal and maternal outcomes [9,10]. In contrast, individuals who develop the disease before 34 weeks of gestation experience more severe symptoms, followed by increased fetal and maternal mortality and morbidity [9–11]. These two different presentations of preeclampsia are subsequent of different pathogenesis mechanisms. Early onset preeclampsia, referred to as placental preeclampsia, is a result of poor placentation; while late onset preeclampsia, referred to as maternal preeclampsia, is subsequent of abnormalities within maternal factors [12,13]. There are many maternal risk factors for development of preeclampsia with relative risks ranging from 1.5 to 9.7, including personal or family history of preeclampsia, maternal age of older than 40 years or younger than 18 years, race, diabetes mellitus, obesity, chronic hypertension, chronic renal diseases, multiple gestations, collagen vascular diseases, hydrops fetalis, antiphospholipid antibody syndrome, inherited thrombophilia, hydatidiform mole, urinary tract infection, oocyte donation or donor insemination and periodontal diseases [14]. Of this high risk population, approximately 25% will develop the disease. Additionally, 5% of pregnancies from general population are complicated by preeclampsia [15]. Doppler ultrasonography is a useful noninvasive method to detect high risk individuals in first and second trimester. Assessing uterine artery by Doppler velocimetry could demonstrate the extent of trophoblastic invasion and reconnoiter

http://dx.doi.org/10.1016/j.mehy.2015.06.031 0306-9877/Ó 2015 Elsevier Ltd. All rights reserved.

Please cite this article in press as: Azimi A et al. Hypothesis: Pentoxifylline explores new horizons in treatment of preeclampsia. Med Hypotheses (2015), http://dx.doi.org/10.1016/j.mehy.2015.06.031

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high risk individuals [16,17]. There are also many factors in maternal serum and urine which may predict incidence of preeclampsia some of which include; amount of angiogenic and antiangiogenic factors in blood and urine, placental protein 13, pregnancy-associated plasma protein A, disintegrin and metalloprotease-12 (ADAM12) [18–22]. Among these markers, sFlt-1 to VEGF ratio (or sFlt-1 to PlGF ratio) seems to be clinically useful in identifying high risk individuals [23]. Several pathophysiological mechanisms have been implicated in the pathogenesis of preeclampsia. Four major mechanisms that are generally accepted include abnormal immune response, defects through placentation, endothelial dysfunction and hypercoagulability which are discussed below separately [1,2,4]. I. Immune response Impaired immune response is a well-known feature of preeclampsia. It has been proposed that in pregnancy, immune reactions shift towards Th2-mediated immune responses [24]. Different studies have shown that in individuals who develop preeclampsia, production of Th-1 activator cytokines (interleukin-1b (IL-1b), interleukin-2 (IL-2), interleukin-6 (IL-6), interferon-c (IFN-c), tumor necrosis factor-alpha (TNF-a)), is increased while production of Th-2 activator cytokines (IL-4, IL-5, IL-10) is suppressed. Such an imbalance strengthens Th-1-mediated immune responses and makes this arm the dominant effecter [22,25–28]. For instances, increased maternal serum levels of IL-6, a Th-1 activator cytokine, is associated with more severe and earlier onset of preeclampsia [29]. Chronic infusion of each one of TNF-a or IL-1b to pregnant rats would also do the same [30–32]. Infusion of even low-dose TNF-a to pregnant rats is followed by development of preeclamptic-like symptoms [31,33,34]. Production of TNF-a, IL-6 and IL-8 increases synthesis of prostaglandins which in turn increases the risk of preterm labor. Concomitant effects of prostaglandins and IL-1b, result in development of preeclamptic-like symptoms in pregnant rats [35,36]. That is because Th-1 mediated immune responses impair placentation, damage endothelial cells and accelerate ischemic-reperfusion injury [37–39]. On the other hand Th-2 activator cytokines improve the act of placentation. For instance IL-10, which is shown to be suppressed in the course of preeclampsia, plays an important role in placentation. Indeed, together with transforming growth factor-b (TGF-b), IL-10 improves trophoblastic invasion to and proliferation within maternal endometrium [35,36,40]. Th-1 mediated immune responses impair trophoblastic invasion, placentation and placental circulation [30,41–46] and these series of events result in endothelial dysfunction and increased vascular resistance [47–51]. As endothelial function deteriorates and vascular resistance increases, placental perfusion becomes worse and more impaired [52].

‘‘impaired placental perfusion’’ and ‘‘oxidative stress’’ [55]. These superoxide anions inactivate endothelium-derived-relaxing-factor (EDRF) which further impairs endothelial function and placental perfusion, worsening the vicious cycle [52]. A poorly perfused placenta also excretes some anti-angiogenic factors such as sFLT-1(soluble fms-like tyrosine kinase), sEndoglin and angiotensin II type 1 receptor autoantibody (AT1AA), which initiate symptoms of the disease [9,55–58]. sFLT-1 is a soluble receptor of two different kinds of angiogenic factors, vascular-endothe lial-growth-factor (VEGF) and placental-growth-factor (PLGF). In maternal serum, sFLT-1 binds to VEGF and PLGF and neutralizes their angiogenic effects [59]. Furthermore, sEndoglin, a soluble co-receptor of TGF-b, bind to TGF-b and neutralizes its angiogenic properties [2,60,61]. Furthermore sFLT-1 and sEndoglin could exert synergistic effects on inhibition of angiogenesis [61,62]. A poorly perfused placenta also excretes AT1AA, a factor that stimulates further expression of sFlt-1 from trophoblast cells and also affects many other different tissues. For example, it affects monocytes and they stimulate mesangial cells to produce IL-6 and plasminogen activator inhibitor-1 (PAI-1), both of which play important roles in the course of the disease [63–67]. III. Endothelial function In preeclamptic patients, the balance between ROS/RNS is impaired, formation of NO and Prostacyclins are decreased within the endothelium, and the balance between Prostacyclin and Thromboxane is disturbed, the release of vasoconstrictive endothelin is enhanced, and sensitivity of vascular smooth muscle cells to vasoconstrictive agents (e.g., angiotensin II) is increased [47–54]. Endothelial dysfunction and impairment of angiogenesis/angiore generation under influence of sFlt-1 and sEndoglin, result in hypertension, glomerular injury, edema and proteinuria [47–51]. As albumin is secreted in urine, the hypo-albuminemia and further peripheral edema ensue. Subsequent activation of RAAS (Renin–A ngiotensin–Aldosterone System) intensifies vasoconstriction and Na+/H2O reabsorption, worsening the edema [68]. IV. Coagulation In preeclampsia, anti-coagulant proteins such as anti-thrombin III, protein C and protein S are decreased as they are excreted by kidneys. In addition, Prostacyclins are produced to a lesser extent and balance between Prostacyclins and Thromboxanes is significantly disturbed. All these alterations increase coagulability and accelerate thrombus formation [47–49]. Under these circumstances, massive activation of thrombocytes will damage the erythrocytes and hemolysis ensues. Consequent production of heme further impairs endothelial function and placental perfusion, accelerating progression of the disease toward eclampsia [68].

Pentoxifylline

II. Placentation As mentioned before, a defect through placental circulation and poor placental perfusion is another well-documented feature of all pregnancies complicated by preeclampsia [30,41–46]. Impaired placentation leads to intermittent disturbances of placental perfusion, followed by ischemia and formation of reactive oxygen species (ROS) within the placenta [53]. In preeclamptic placentas, interaction of ROS with reactive nitrogen species (RNS) impairs ROS/RNS balance and decreases placental concentration of NO, a crucial molecule for regulation of placental perfusion [54]. Increased production of ROS, followed by peroxidation of lipids and generation of lipid peroxides, intensifies oxidative stress and worsens placental perfusion constituting a vicious cycle between

Pentoxifylline is a methylxanthine derivative with chemical name of 1-(5-oxohexyl)-3,7-dimethylxanthine. It is shown to reduce ischemia-reperfusion damage, inactivate superoxide anions, improve endothelial function and vasodilatation, increase erythrocyte flexibility, attenuate inflammatory reactions, reduce viscosity of blood and inhibit platelet aggregation [69,70]. FDA has approved the agent to treat symptoms of intermittent claudication resulting from peripheral arterial disease [71]. It has also been used to treat glomerular proteinuric nephropathy [72], multi-infarct dementia [73], Peyronie’s disease [74], sarcoidosis [75], peripheral neuropathy [76], sickle cell disease [77], alcoholic [78] and non-alcoholic steato-hepatitis [79], endometriosis [80] and radiation-induced fibrosis [81,82].

Please cite this article in press as: Azimi A et al. Hypothesis: Pentoxifylline explores new horizons in treatment of preeclampsia. Med Hypotheses (2015), http://dx.doi.org/10.1016/j.mehy.2015.06.031

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Hypothesis/idea Here it has been hypothesized that Pentoxifylline could have preventive effects on development of preeclampsia in high risk individuals, while it could also hinder the progression of the disease in individuals who have already developed the disease. These two probable effects of Pentoxifylline can be evaluated through two separate clinical trials. In order to evaluate the probable preventive effects of Pentoxifylline on development of preeclampsia, patients should be selected from high risk individuals screened and detected by Doppler ultrasonography of umbilical arteries, a useful method for prediction of preeclampsia with a favorable sensitivity and specificity. A systematic review of 74 studies on almost 80,000 women has discussed about sensitivity and specificity of Doppler ultrasonography in second trimester in prediction of preeclampsia.

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As mentioned in the review sensitivity and specificity of this method depends on the type of analysis technique. In low risk individuals, sensitivity ranges from 23% to 65% and specificity from 95% to 99%. In high risk individuals, the values are 19–86 for sensitivity and 78–99 for specificity [17]. Included individuals should be followed by Doppler velocimetry of umbilical arteries and sFlt-1 to VEGF ratio. On the other hand it is hypothesized that Pentoxifylline may hinder progression of the disease in individuals who have already developed the disease. In order to evaluate the probable inhibitory effects of Pentoxifylline on further progression of the disease process, patients should be selected from all individuals who have developed symptoms of the disease. This population may also be divided into two separate groups of early and late onset preeclampsia. Pentoxifylline down regulates pro-inflammatory cytokines such as TNF-a, IL-1b, IL-6 and IFN-c and decreases serum

Fig. 1. Pathophysiologic mechanisms of preeclampsia and how Pentoxifylline could affect them. (1) Increased production of Th-1 activator cytokines (IL-1b, IL-2, IL-6, IFN-c and TNF-a) and decreased production of IL-10 strengthens Th-1-mediated immune response and impairs placentation. (2) Impaired placentation is further followed by poor perfusion of placenta. Poorly perfused placenta excretes sFLT-1 and sEndoglin, which in turn impair angiogenesis/angioregeneration. (3) Intermittent disturbances of placental perfusion result in ischemia, formation of superoxide anions and endothelial dysfunction. Thereby, endothelial formation of NO and Prostacyclins is decreased while release of endothelin and Thromboxanes is increased. These changes result in vasoconstriction and increased glomerular permeability followed by proteinuria. (4) As albumin is secreted in urine, hypo-albuminemia and further peripheral edema ensue which impair renal plasma flow. Subsequent activation of RAAS (Renin–Angiotensin–Aldosterone System) intensifies vasoconstriction and Na+/H2O reabsorption, which worsens the edema and causes a vicious cycle. (5) Loss of antithrombotic proteins by kidneys, together with decreased endothelial production of NO and increased endothelial release of Thromboxane and PAI result in a hypercoagulable state and accelerates progression of preeclampsia toward eclampsia. (6) Pentoxifylline attenuates Th1-mediated immune reactions and improves placentation and placental perfusion. Pentoxifylline is an antioxidant and ameliorates oxidative stress and ischemic damage and improves endothelial function. (7) Pentoxifylline is a vasodilator and reduces vasoconstriction. It also increases flexibility of RBCs, increases RPF, improves renal function and ameliorates proteinuria. Thereby, Pentoxifylline can really unsettle the vicious cycle. (8) Since Pentoxifylline ameliorates proteinuria, kidneys stop losing anti-thrombotic proteins. Pentoxifylline also equilibrates the imbalance between Prostacyclins and Thromboxanes and it increases production of plasminogen activator. It is an anti-coagulant agent and decreases blood coagulability. Thereby, Pentoxifylline could prevent progression of preeclampsia toward eclampsia (IL-1: Interleukin 1b, IL-2: Interleukin 2, IL-6: Interleukin 6, IFN-c: Interferon c, TNF-a: Tumor necrosis factor a, IL-10: Interleukin 10, Th1: T helper type 1, Th2: T helper type 2, sFlt-1: Soluble FMS-like tyrosine kinase 1, sEndoglin: Soluble endoglin, NO: Nitric oxide, PAI: Plasminogen activator inhibitor, RPF: Renal plasma flow, RAAS: Renin–Angiotensin–Aldosterone System, RBC: Red blood cell).

Please cite this article in press as: Azimi A et al. Hypothesis: Pentoxifylline explores new horizons in treatment of preeclampsia. Med Hypotheses (2015), http://dx.doi.org/10.1016/j.mehy.2015.06.031

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levels of CRP, which were all elevated in preeclampsia [4,22,25– 28,35,83,84]. Therefore, to follow the course of the disease, assessment of the patients for these factors seems to be a necessity. In both studies, aspirin – the medication that is usually administered for preeclamptic patients in current managements – should be advised for both groups and effects of Pentoxifylline (400 mg every 12 h [72]) and aspirin together on the course of the disease should be compared with placebo alongside aspirin. Evaluation of hypothesis/idea Pentoxifylline has been shown to have inhibitory effects on progression of preeclamptic-like symptoms in ewes [62]. In this article, it has been hypothesized that Pentoxifylline could prevent or alleviate the burden of preeclampsia. In the following lines, effects of Pentoxifylline on each of the previously mentioned pathophysiological mechanisms are discussed in details (Fig. 1). I. Immune response Pentoxifylline equilibrates Th1/Th2 balance, attenuates Th1-type immune reactions and helps shifting the immune responses towards Th2-type immune reactions and as discussed earlier, this is a necessary step for a successful pregnancy; while impaired switching of the immune response could be followed by preeclampsia [24,85,86]. Considering the issue, it is hypothesized that Pentoxifylline improves immune responses to placentation and decreases the risk for initiation of preeclampsia. Pentoxifylline also down-regulates pro-inflammatory cytokines such as TNF-a, IL-1b, IL-6 and IFN-c and decreases serum level of CRP which are all up-regulated in preeclamptic patients [4,22,2 5–28,35,83,84,87]. In therapeutic doses, Pentoxifylline increases plasma concentration of IL-10, the anti-inflammatory cytokine that plays an important role in placentation [35,36,40,83]. By suppressing TNF-a, IL-6 and IL-8, Pentoxifylline decreases prostaglandin synthesis [88] and it is shown that Pentoxifylline could postpone preterm labor and improve neonatal outcomes in pregnancies threatened with preterm labor [89]. Thereby it is hypothesized that Pentoxifylline decreases the risk of preterm labor in preeclamptic patients. Hypertension, glomerular injury, edema and proteinuria are some other complications of preeclampsia [47–51]. Regardless of the major cause of proteinuria, filtration and subsequent re-absorption of inflammatory cytokines make tubular cells release further inflammatory cytokines (e.g., TNF-a, IL-1b and MCP-1), recruiting monocytes to interstitium, which leads to progressive interstitial nephritis [90,91]. Pathological effects of preeclampsia on renal capillary vessels are the same as those seen in de novo renal disease [92]. Furthermore, inflammatory cytokines are up-regulated and activity of monocytes is increased during preeclampsia [65,66,22,25–28]. Pentoxifylline, not only down-regulates inflammatory cytokines, but also suppresses chemo-attraction of monocytes toward interstitium. Pentoxifylline significantly suppresses renal Monocyte Chemoattractant Protein 1 (MCP-1) which is the strongest known chemotactic factor for monocytes/macrophages [72]. Also, Pentoxifylline ameliorates proteinuria in patients with proteinuric primary glomerular diseases [25–27,72]. Thereby it is hypothesized that Pentoxifylline could ameliorate kidney injury and proteinuria in preeclamptic patients. II. Placentation Pentoxifylline improves placental circulation and perfusion and since impairment of that process is the leading cause of preeclampsia, this intervention could significantly interfere with the disease

process [30,42–46,89]. In addition, 8-oxopentoxifylline is a metabolite of Pentoxifylline and it is a potent antioxidant and free radical scavenger which inhibits lipid-peroxidation and reduces ischemia-reperfusion injury [70]. As mentioned earlier, increased generation of superoxide anions along with generation of lipid peroxides from placenta, inactivation of EDRF and impairment of ROS/RNS balance are of major causes of the disease [54,55]. Pentoxifylline enhances EDRF production, equilibrates ROS/RNS balance, increases endothelial NO synthesis in placenta and improves placental perfusion [89,93–95], which are all disturbed in preeclampsia [34,52,54,60]. Impaired placental circulation leads to placental ischemia and an ischemic placenta produces anti-angiogenic factors [30,42–46]. As Pentoxifylline is metabolized to a potent antioxidant it ameliorates oxidative stress and improves endothelial function and placental circulation [89] and it is hypothesized that Pentoxifylline unsettles the vicious cycle of ‘‘impaired placental perfusion/oxidative stress’’ and countervail the pathogenesis of the disease. III. Endothelial function The balance between Prostacyclins/Thromboxanes and ROS/RNS are significantly disturbed in preeclamptic patients [47– 49,54]. As a non-selective phosphodiesterase inhibitor, Pentoxifylline increases intra-cellular cAMP and potentiates endogenous Prostacyclins, inhibits Thromboxane synthesis and recovers ROS/RNS imbalance [95–99]. Thereby Pentoxifylline equilibrates Prostacyclins/Thromboxanes and ROS/RNS imbalances and all of these processes confirm anti-aggregatory and vasodilatory properties of Pentoxifylline [95–99]. Accordingly it is hypothesized that Pentoxifylline prevents initiation of the disease process and it also ameliorates symptoms of the disease. IV. Coagulation As hypothesized earlier, Pentoxifylline equilibrates the imbalance between Prostacyclins and Thromboxanes in preeclampsia alleviating the hypercoagulable state in preeclampsia. In addition in preeclamptic patients, secretion of plasminogen activator inhibitor-1 is increased [63]. Pentoxifylline increases activity of fibrinolytic enzymes and tissue plasminogen activator; it also inhibits platelet adhesion, clot formation and decreases the risk of thrombus formation [4,99]. Thus it is hypothesized that Pentoxifylline could prevent progression of preeclampsia toward eclampsia and it could decrease the risk of thrombotic events during and after a preeclamptic gestation.

Discussion/conclusion Early prediction of preeclampsia makes it possible to plan for early interventions to reduce complications of the disease [5]. Previous studies revealed that prophylactic use of low-dose aspirin reduces the incidence of disease by only 10% in high risk pregnant women. It should be noted that the prophylaxis efficacy with low-dose aspirin is highly dependent on the time of initiation of administration [5,100]. Another study has reported that administration of low-dose aspirin after 16 weeks of gestation did not decrease risk of the disease and aspirin may decrease the risk only if administrated before 16 weeks of gestation [101]. Aspirin may prevent development of preeclampsia, possibly by improving placentation; therefore aspirin reduces the risk of placental, but not maternal, preeclampsia [102]. Pentoxifylline not only improves placentation [89] but it may also alleviate maternal factors as well, which are the leading causes of maternal preeclampsia. Thereby, Pentoxifylline could hypothetically prevent both maternal and placental preeclampsia.

Please cite this article in press as: Azimi A et al. Hypothesis: Pentoxifylline explores new horizons in treatment of preeclampsia. Med Hypotheses (2015), http://dx.doi.org/10.1016/j.mehy.2015.06.031

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