Review

Future possibilities for the treatment of septic shock with herbal components

Houli Wang MD^a,?, Tengda Xu MD^a, Matthew R. Lewin MD, PhD^b

^aDepartment of Emergency Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences,

Tsinghua University, Beijing 100730, PR China

^bDepartment of Emergency Medicine, University of California, San Francisco, CA 94143, USA

Received 1 July 2008; revised 28 July 2008; accepted 1 August 2008

Abstract The treatment of septic shock remains challenging even with the armamentarium of modern antibiotics and intensive care technologies. Reliance on antibiotics and other methods targeting modulation of the systemic inflammatory response such as steroids, hemofiltration, and cytokine antagonists has not led to reliable successful treatment for inflammation and infection-related shock. In part, this is attributable to the continuous evolution of antibacterial drug resistance. Herbal medicine has been used in treating infections and shock, worldwide, for thousands of years. The active components contained in these naturally occurring products usually have one or more of the following properties: (1) direct attack or suppression on Bacterial pathogens, (2) modulation of the host’s immune system resulting in suppression of inflammation and overproduction of Inflammatory mediators, and (3) neutralization of toxic free-radicals. In vitro and in vivo animal and human clinical studies of herbal medicines’ effectiveness in the treatment of septic shock are needed. Their pharmacological mechanisms need to be elucidated at molecular level to investigate and improve targeted therapy using heretofore unexplored uses for traditional herbal remedies. Herein, we discuss historical examples of herbal remedies used to fight infection. In addition, we discuss the use of herbal and traditional medicines as potential adjuncts in the ongoing battle against septic shock and Systemic Infections.

(C) 2009

Introduction

In China, herbal medicine has been used to treat critically ill patients for thousands of years. Doctors of Traditional Chinese Medicine have abundant experience in symptoms recognition and formulation of herbal remedies. According to the theory of traditional Chinese medicine, what we now describe as patients having “septic shock” or “severe sepsis” are patients who have “depletion syn- drome.” The characteristics of these patients as described in

* Corresponding author. Tel.: +86 10 65295326; fax: +86 10 65295327.

E-mail address: [email protected] (H. Wang).

traditional Chinese medicine are “Qi” (prostration), “Yin” (asthenia), “Yang” (impairment), and collaterals injured by concentrated toxins.

Current treatment of septic shock

Septic shock, a Severe form of host systemic inflamma- tory reaction to infections, is usually caused by bacterial infections. In the United States, it is estimated that about 215 000 persons die of septic shock per year [1,2]. In its development, uncontrolled amplification of inflammation and subsequent overproduction of inflammatory mediators

0735-6757/$ - see front matter (C) 2009 doi:10.1016/j.ajem.2008.08.003

are believed to be the main pathophysiological derangements causing diffuse endothelial damage and circulatory collapse [3,4]. Early, goal-directed antibiotic administration and anti- inflammatory modulation of the host immune response and pressure support are the Mainstays of treatment of patients with septic shock.

For a variety of reasons, septic shock continues to have a mortality rate approaching 50% despite progresses in modern medical sciences [1,2,5]. One factor contributing to the failure of therapy is antibacterial drug resistance. Although newer and safer antibiotics have been created at an increasing speed year by year, newly created or high- generation antibiotics are frequent recommendations for the treatment of patients with septic shock or patients in critical condition from infectious diseases. Under the selection pressure of antibiotics, bacteria develop drug resistance by gene mutation or plasmid transfer. The speed of bacterial resistance evolution is at least as rapid as the development of new antibiotics [6]. Common practices such as “stress” dosing of steroids do not seem to improve survival or reverse shock in hypotensive patients [7]. Meanwhile, numerous, novel strategies targeting the inflammatory response have not shown significant benefit. For example, continuous hemofiltration targeting the reduction of plasma cytokine concentrations has not yet enough evidence to recommend it as a treatment of septic shock [8]. In 2001, the Food and Drug Administration of the United States controversially approved Human Activated Protein C (drotrecogin alfa) for use in the treatment of septic shock based on phase 3, randomized clinical trials performed by the company that makes the drug. The drug has yet to be prospectively demonstrated to be effective in patient population recommended for treatment by the manufac- turer, and at least 1 clinical trial has been terminated because of bleeding risks greater than expected [9]. Numerous and redundant pathways are involved in the inflammatory response and cytokine-targeted therapy targeting single pathways have not yet been shown to improve outcomes [9-12].

Herbal medicines for infections

Long before the discovery and systematic development of antibiotics during the last century, herbal medicine was the mainstay for the treatment of infections worldwide, and it is still being generally applied in the treatment of multiple varieties of infections in the modern world. The effectiveness of some traditional herbal medicines are being examined with scientific rigor and modern technology. An interesting experiment conducted by Taniguchi and Kubo [13] tested the antimicrobial activity from the extracts of a number of plants specifically selected by East African medicine men com- pared to the antimicrobial activity of randomly selected plants from the same families. The plants collected based on

information provided by medicine men showed a much higher probability of finding active extracts than the plants collected randomly [13].

Examples of herbal medicines undergoing scientific scrutiny from China include Fructus schisandrae chinensis and Radix sophorae flavescentis, which produce the alkaloid compound matrine. These have been widely used for the treatment of chronic hepatitis B virus infection [14,15]. The antiviral activities of Herba patriniae against respiratory syncytial virus, Chaihu against Coxsackie B virus, and Prunella vulgaris against herpes simplex Virus and HIV have been reported in recent publications [16-19]. The antibacterial effect of certain herbs such as Nasturtium, horseradish root, Fructus schisandrae chinensis, and And- rographis paniculata have been tested clinically and shown varying degrees of efficacy [20-22]. Interestingly, anacardic acids extracted from cashew apples were found to have activity against methicillin-resistant Staphylococcus aureus. When combined with methicillin, the minimum inhibitory concentrations of the combinations were far lower than either one, alone. This finding suggests promise for the strategy of using some natural or herbal products to augment the antimicrobial activity of synthetic antibiotics [23]. Artemi- sinin, extracted from Artemisia annua, is the most prominent example of an herbal medicine surpassing modern, synthetic compounds for the treatment of an age-old scourge, malaria [24]. Because of the complexity of the formula and ingredients in herbal medicines, the mechanisms of herbs’ anti-infective activity can be difficult to elucidate. Currently, only a limited number of active ingredients have been identified, and the pharmacological properties of these agents are being studied.

Herbal medicines for septic shock

As described at the beginning of this article, traditional Chinese medicine patients diagnosed as having depletion syndrome have the characteristic Qi (prostration), Yin (asthenia), Yang (impairment), and collaterals injured by concentrated toxins. Traditional Chinese doctors use their judgment with the aims of the treating the “depletion syndrome,” with combinations of herbal medicine notable for strengthening the body’s resistance to infection, treating prostration, promoting blood flow, and detoxifying the body. Recently, some Chinese intensive care unit (ICU) doctors have empirically observed the utility of herbal medicine in the treatment of septic shock. In accordance with tradition, for each patient with septic shock, the formula and dosage of the prescription is individualized. At our hospital, Peking University Medical College (National Academy of Medical Sciences), about one sixth of patients with septic shock are treated with herbs in combination with modern medicines such as antibiotics and pressors (H. Wang, unpublished data 2008). In these patients, we most commonly use Panax

notoginseng, raw rhubarb, Fructus aurantii immaturus, Salvia miltiorrhiza, and Astragalus membranaceus for enteral use in the ICU. Nevertheless, the scientific under- pinnings and overall efficacy of these practices is not yet established [25].

The gut in septic shock

The gut, an important immunologically active organ, has been studied for decades regarding its role in the develop- ment of septic shock. The high-density immune cells beneath the Intestinal mucosa have enormous capacity to synthesize various inflammatory mediators [26]. Upon activation, the intrinsic immune cells amplify inflammation locally, and excessive inflammatory mediators attract polymorhyonuc- lear leukocytes and other inflammatory cells to congregate in the interstitial compartment [27]. Toxic oxygen radicals, proteolytic enzymes, and various cytokines induce the epithelial cell damage of the mucosa. The tight junctions are disrupted, and the expression of tight junction-related proteins, such as occludin and claudins, decreases [28]. Meanwhile, mucosal cells proceed to necrosis or apoptosis, intestinal mucosa integrity is disrupted, and secondary, intrinsic endotoxemia develops [29,30]. Subsequently, the translocation of viable bacteria and endotoxins into gut- associated lymphatic tissue and mesenteric lymph nodes further activate a complex interplay of mediators [26]. Finally, the amplification of a deleterious inflammatory response and the influx of cytokines into the bloodstream through microcirculation or lymphatic drainage lead to the secondary cytokines storm, which initiates the pathogenesis of septic shock and remote organ dysfunction [27,31]. In patients with septic shock, the gut is a major site where secondary infections originate and systemic inflammation amplified [32]. Thus, it is often speculated that immune modulation therapy on this organ system should have the potential to benefit patient outcomes.

Pharmacological mechanisms of herbal medi- cines on septic shock

It is generally believed that herbal medicine acts mainly through the modulation of the host’s immune system. For patients with septic shock in China, most of the herbal extractions are given enterally, and it is thought that active ingredients may exert direct effects on the immune cells beneath the gut mucosa. Based on current understandings, the pharmacological mechanisms of herbs might be supposed to have the following properties: (1) the active ingredients may exert direct toxicity or suppression of the pathogens [33], (2) some components of the herbs may have the property of modulating the host’s immune system with the beneficial effects stemming from the suppression of hitherto uncontrolled amplification of inflammation and overproduction of inflammatory mediators [33], and (3)

some active ingredients may have the property of neutraliza- tion of toxic radicals, which helps to alleviate the damage to organs via preservation of mitochondrial function [34,35]. Some active ingredients absorbed through the gut can exert systemic effects through these mechanisms.

• • 1. Rhubarb

With the development of the modern pharmacological sciences, the mechanisms by which herbs’ salutary effect on septic shock have begun to be elucidated at the molecular level (Table 1). Laboratory findings have confirmed that some kinds of herbs have the property of modulation on inflamma- tion. For example, the aqueous extract of rhubarb rhizome has been reported to have an antiplatelet aggregation activity, antioxidant activity, and vasorelaxant effects. The most active components are thought to be stilbene and anthraquinone derivatives, which can induce vascular relaxation via endothelium-dependent Nitric oxide /cGMP signaling in vitro [36-38]. The vascular relaxation may be closely related with L-type Ca²⁺ channel function [39]. Meanwhile, attenuated expression of monocyte chemoattractant protein 1 and nuclear factor-kappa B (NF-?B) in human umbilical vein Endothelial cells pretreated with the aqueous extract of rhubarb rhizome were also noticed. In addition, the expres- sion of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) was inhibited [40]. These observations suggest the active components have the potency to suppress the vascular Inflammatory process. Crude rhubarb’s effects on the amelioration of intestinal permeability and reducing the shift of intestinal bacteria has been confirmed clinically in septic patients [41,42]. This effect may be attributed to its antagonizing effect against inflammatory cytokines and components of the complement system [36]. Nevertheless, as with any pharmacologically active compound, consideration has to be given to physio- logically competing interests: Is the beneficial effect greater than the potentially adverse effects? In the case of rhubarb rhizome extracts, one naturally wonders if the suppression of inflammation supersedes the potential for loss of vascular tone. These are the types of questions needing rigorous, systematic study-there may be large differences between what is seen in vitro and clinical efficacy. When the in vitro findings do not correlate with clinical findings, clinical investigators should question the degree to which we really understand the biochemical mechanisms by which these extracts exert their clinical effects or if we are even taking the right approach to these investigations.

• • 1. Salvia miltiorrhiza

In our hospital, the extract of S miltiorrhiza has been used in combination with other traditional herbs for the treatment of patients with septic shock in the ICU. Various water- soluble and lipophilic extracts have been tested in vitro. The water-soluble compounds are mainly phenolic acid com- pounds, including single phenolic acids and poly phenolic acids. Single phenolic acids include protocatechuic aldehyde,

Table 1 Pharmacologic properties of Rheum undulatum, S miltiorrhiza, and P notoginseng

R undulatum S miltiorrhiza P notoginseng

Anti-inflammatory effects

NO ? ICAM-1 and VCAM-1 ? Neutrophil degranulation ?

MCP-1 and NF-?B ? NF-?B ? PGs & NO ?

ICAM-1 and VCAM-1 ? IL-1b, IL-6, TNF-?, IL-12, and IFN-? ? Leukotriene B4 ?

CD11b and CD18 ?

PLA2 ?

ROS production ?

Antioxidant effects Anti-lipid-peroxidation Oxygen-free radicals ? Scavenge free radicals Anti-lipid-peroxidation SOD activity ?

Anticoagulation Antiplatelet aggregation Plasma endothelin content ? Antiplatelet aggregation TXB2 ?

Antiplatelet aggregation

Others Antibacterial activity Antifungal activity

MCP-1 indicates monocyte chemoattractant protein; IFN-?, interferon-gamma; ROS, Reactive oxygen species; SOD, superoxide dismutase; TXB2, thromboxane B2.

protocatechuic acid, caffeic acid, and 3,4-dihydroxyphenyl lactic acid, whereas polyphenolic acids include rosmarinic acid, lithospermic acid, salvianolic acid A, salvianolic acid B (SalB), and other salvianolic acids. The lipophilic diterpenoid quinines extracted from S miltiorrhiza are tanshinone I (TsI), tanshinone IIA (TsIIA), tanshinone IIB, cryptotanshinone (CTs), tanshindiol C, dihydrotanshinone I (DTsI), isotanshi- none I, isotanshinone II, and other tanshinones. Based on these in vitro experiments, the therapeutic mechanisms of S miltiorrhiza‘s active components can be partially understood

-different compounds have specific activity against leuko- cyte adhesion, platelet aggregation, the release of oxygen radicals, and endothelial cell injury, among other effects associated with the pathogenesis of septic shock.

To demonstrate the extent to which S miltiorrhiza extracts have recently undergone investigation, we provide the following: protocatechuic aldehyde and SalB have inhibitory effects on VCAM-1 and ICAM-1 expression in vascular endothelium and to inhibit the activation of NF-?B in endothelial cells induced by tumor necrosis factor-alpha (TNF-?) [43,44]. 3,4-Dihydroxyphenyl lactic acid and SalB are able to ameliorate the expression of adhesion molecules CD11b and CD18 and the production of peroxides in leukocyte and to inhibit leukocyte adhesion to mesenteric venular wall in rat challenged by lipopolysaccharide [45,46]. Tanshinone I, CTs, and DTsI significantly inhibit interleukin- 12 (IL-12) and interferon-gamma production [47]. Recently, it has been found that TsIIA also strongly inhibits the production of inflammatory mediators such as IL-1b, IL-6, and TNF-?. Phospholipase A2 (PLA2) plays an important role in inflammatory and/or immunoregulatory responses, and the in vivo anti-inflammatory activity of TsI has been linked mechanistically to PLA2 inhibition. The antioxidant effects of phenolic acids include anti-lipid-peroxidation and radical scavenging. 3,4-Dihydroxyphenyl lactic acid, salvia- nolic acid A, and SalB exhibit strong activity to scavenge superoxide anion (^oO^-), hydroxyl radicals, and 1,1-diphenyl-

2

2-picrylhydrazyl potentially, and so on, in vitro [48-50]. Caffeic acid and rosmarinic acid also show free radical scavenging activity [51]. Tanshinone IIA can inhibit the association of lipid peroxidation products with DNA. In addition, it was found to decrease superoxide dismutase activity in human umbilical vein endothelial cells [52,53]. Salvianolic acid B was reported to inhibit the TNF-?- induced reactive oxygen species production in vitro [50]. The anticoagulation property of constitutes from S miltiorrhiza have been demonstrated since 1980s. Salvianolic acids can inhibit the formation of thrombosis and decrease the plasma endothelin content and the high level of thromboxane B2 [49]. Isotanshinnone IIB inhibits adenosine diphosphate and collagen-induced platelet aggregation in vitro [54]. More- over, CTs and DTsI show strong antibacterial activity against a broad range of Gram-positive bacteria. These compounds generate superoxide radicals, which are important in the antibacterial action [55]. Taken together, these results may partly explain the anti-inflammatory and antibacterial effects of S miltiorrhiza.

• • 1. Panax notoginseng

The pharmacological activity and constituents of another commonly used herbal, P notoginseng, have been studied. The principal constituents of P notoginseng are saponins (ginsenosides Rb1, Rb2, Rb3, Rc, Rd, Re, Rf, Rg1, Rh1, notoginsenosides R1, -Fa, -Fc, -Fe, -R1, gypenoside XV, and XVII, etc). These compounds reduce neutrophil degranula- tion, overproduction of prostaglandins (PGs), and the induction of nitric oxide synthase, all are thought to have key roles in the pathogenesis of septic shock. The suppression of neutrophil functions and the synthesis of PGs and NO could control inflammation. In vitro studies showed that P notoginseng can inhibit neutrophil functions, including degranulation, superoxide generation, and leukotriene B4 production. P notoginseng‘s anti-inflammatory effect was also related to the inhibition of NO and PGE2 production,

which could be due to a decreased expression of inducible NO synthase and cyclooxygenase 2 [56,57]. The antioxidant activity and anticoagulant activity of the extract of P notoginseng were also noticed in vitro studies [58,59]. Meanwhile, 2 proteins with antifungal activities were reported recently [60].

Conclusions

The scientific underpinnings of traditional medicine remain embryonic. There is a great need for rigorous, basic scientific investigations as well as Controlled clinical trials to examine the efficacy of carefully selected herbal medicines in the treatment of patients with septic shock. We suggest the possibility that the recent plateau in the survival rate of patients with septic shock treated with herbal medicines may be due to insufficient dosage of the active ingredients. Provided that the active ingredients of the herbs can be identified, purified, or synthesized and appropriately recom- bined, these formulations may provide a valuable adjunct to modern Western medicine and improved outcomes in patients with septic shock.

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