Sichuan Provincial Institute of Chinese Materia Medica

(Proceedings of TCM Conference at West China University of Medical Science
1995)

By Deng Wenlong

The term “pathogenic toxin” refers to a special pathogenic factor in the
theory of etiology of TCM, which is either included in the six exogenous
causes of disease – wind, cold, summer heat, dampness, and fire, or
dissociates itself from them. The concept of “toxin” may trace back to text
Jinguiyaolue (Synopsis of Prescriptions from the Golden Chamber), which
stated “diseases caused by Yang- toxin have the symptoms of flushed face with
brocaded veins, sore throat, vomiting, blood, and pus.” The term “pathogenic
toxin” was widely used after the time of the Jin and Yuan dynasties. Up till
now, this term has had very broad connotations, but it mainly refers to the
pathogenic factors which cause acute contagious and infectious diseases and
their complications. In this article we will attempt to show that the
characteristics of the pathogenicity of endotoxin–chemicals released into
the host from the breakdown of the cell walls of gram-negative organisms–
accords closely with that of the “pathogenic toxins” in TCM, and that TCM
treatments can improve the clinical course of febrile disease by reducing
endotoxin in infected hosts.

The TCM differentiation of endotoxic diseases are usually placed in the
category of febrile diseases caused by toxins. Endotoxic diseases not in the
category of febrile disease have the signs of toxic heat directly invading
Ying and Xue level (stages in the progression of infectious disease according
to TCM). For instance, septicemia is caused by toxic heat; acute pneumonic
failure is caused by retention of toxic heat, dampness, and blood stasis in
the lung; acute hepatic failure is caused by the movement of toxic heat and
the accumulation of damp heat in the liver; acute disseminated intravascular
coagulation is caused by excessive toxic heat invading Ying and Xue level,
etc. Abundant clinical tests show that the tendency and prognosis of the
above diseases is closely related to the content of endotoxin in the blood,
so much so that the content of endotoxin in the blood by itself can serve as
a single index for the prognosis of diseases.

We have studied the significance of endotoxins in clinical and experimental
febrile diseases systematically by using the Limulus Test to determine the
content of endotoxin in the blood of many kinds of febrile diseases (such as
high fever caused by respiratory tract infection, pulmonary infection,
biliary tract infection, septicemia, acute hepatic diseases, shock, etc.).
The results show that the content of endotoxin in blood in most of these
diseases is high. For instance, more than half of the patients suffering
from infection with gram-negative bacteria have positive test results for the
presence of endotoxin in their blood. One third of patients suffering from
infections from gram-positive bacteria and virus have endotoxin measures in
their blood of more than 50pg/ ml. Dynamic observation shows that the
patients’ clinical condition is closely related to the content of endotoxin
in their blood. This indicates that endotoxin it not only the main
pathogenic factor of infection from gram-negative bacteria, but also a factor
which causes deterioration in the state of those infected by virus and
gram-positive bacteria. In terms of infection by virus and gram-positive
bacteria, the endotoxin in the blood comes from the “endotoxin pool” in the
intestines.

W have studied the action of endotoxin in experimentally induced febrile
diseases. By applying different dosages of endotoxin to rabbits through
intravenous injection, we could duplicate the experimental febrile diseases
which have the characters of the full course of Wei, Qi, Ying, Xue phases.
Their appearances and objective tests of the animals are in full accord with
the patients suffering from febrile diseases.

Effective therapeutic methods utilizing herbs and formulas for the treatment
of febrile disease in practice have obvious curative effect, and the same
methods show similar therapeutic effect for the treatment of experimentally
induced febrile disease. For instance, using the methods of “clearing heat
and detoxification” can markedly control the syndrome of excessive heat in Qi
level manifested as high fever; using the method of “clearing heat and
detoxification,” or “cooling blood and removing blood stasis” can remarkably
improve the syndrome excessive heat at the Ying and Xue level with severe
weakness and fever.

The TCM Treatment for Endotoxic Diseases

Clearing heat and detoxifying, tonifying Qi and detoxifying, and cleansing
the viscera and purging toxins are the three main therapeutic methods
employed by TCM to prevent and treat endotoxic diseases.

Clearing Heat and Detoxifying
Research has found that many herbs that clear heat have anti- endotoxin
activity. These herbs can either inactivate endotoxin directly or antagonize
the actions of endotoxin, such as fever, inflammation etc. These herbs
include Coptis root (Huang lian) Dandelion herb (Pugongying), Pulsatilla root
(Bai tou weng), Green chiretta (Chuan xin lian), Chinese Gentian ( Long dan
cao), Forsythia fruit (Lian qiao) , Honeysuckle flower (Ji yin hua), Moutan
bark (Mudan pi), Ox gallstone (Niu huang), Scutellaria root (Huang qin),
Scrophularia (Xuanshen ), Patrinia herb ( Baijiangcao ), Isatis root
(Banlangen) , lsatis leaf (Da qing ye), etc. Applicable formulas include
White Tiger Decoction (Bai hu Tang), Antipyretic and Antitoxic Decoction
(Qing wen Bai du Yin), Pill of Six Ingredients with Magical Effects (Liu shen
Wan), Decoction of Gentian for Purging the Liver (Long dan Xie gan Tang),
Decoction for Detoxifying and Removing Blood Stasis (Jie du Hua yu Tang),
Decoction of Pulsatilla Root combination (Bai tou wen Tang), etc. According
to the heterogeneity of endotoxin and its unparalleled character of
biological activities, and according to the characteristics of traditional
Chinese herbs, we’ve designed a research system to act directly against the
action of endotoxin.

For example, after culture in vitro, we use the Limulus test or the rabbit
pyrogenic test to determine the change of the toxicity of endotoxin, and use
the lowest effective concentration of drugs as the pharmacodynamic index.
The change of the active groups of endotoxin molecules as determined by
chemical methods is taken as evidence of anti – endotoxic function. The
disappearance of the antigenicity of endotoxin under the influence of
traditional Chinese herbs serves as the counterevidence of anti-endotoxic
action. In this way the anti-endotoxic action of herbs is determined. Then
the herb’s action on the signs of fever, shock, death of rabbit or mouse
caused by the attack of endotoxin after using drugs through injection or oral
administration is used as evidence of the drug’s practical use in the clinic.
The test of the herb’s sensitive spectrum against endotoxin from various
bacteria is taken as a determinant of possible value in clinical practice.

Based on the above systematic mode, the direct anti-endotoxic function of
more than 100 traditional Chinese herbs, formulae and their chemical
components were examined. The result shows that traditional anti-endotoxin
herbs, such as Akebia (Zi cao) , Moutan bark (Mu dan pi) Honeysuckle flower
(Jin yin hua), Sophora root (Ku shen), Forsythia fruit (Lian qiao), Toad
venom ( Can su), Bear gall ( Xiong dan), Scutellaria root (Huang qin),
Formula to Clear Toxic Heat ( Redu qing), Formula to Detoxify the Viscera
(Jie du tong fi Fang) etc. are all of value.

We’ve gotten a monomer from the most effective formula by analyzing its
ingredients and chemical components. Under the influence of this monomer,
the ultrastructure of endotoxin underwent expansion, breaking and
disintegration. The toxicity and antigenicity of endotoxin then became weak
and then disappeared. The minimal concentration of the monomer to detoxify
the endotoxin from 5 kinds of bacteria sources is 0.012 – imp/ml. It has
obvious protective action when it is applied through intravenous injection or
oral administration to high fever of rabbit or death of mouse caused by
endotoxin. The above researches provide not only the experimental basis for
the method of clearing heat and detoxifying which can act directly against
the toxicity of endotoxin and inactivate the endotoxin, but also gives direct
evidence of the material basis for this therapeutic method of action against
endotoxin.

In clinical practice, the therapeutic methods of clearing heat and
detoxifying to treat acute infectious endotoxic diseases are quite good. For
instance, using a formula to clear toxic heat (Redu qing) to treat 282
patients with acute infection, the effective rate is 85.8% The Formula to
Detoxify and Remove Stasis (Jie du hua yu Fang) can obviously decrease the
concentration of endotoxin in blood of patients and improve the symptoms of
febrile diseases significantly. The Formula to Clear Heat from Ying Level
(Liang ying tou re Fang) can lower the temperature of the patients with high
fever caused by febrile diseases of the Ying level, and make the presence of
endotoxin in blood become negative. Injection of Forsythia fruit can
obviously decrease the temperature and concentration of endotoxin in blood of
the patients with high fever caused by trauma together with serious infection
and presence of endotoxin in blood.

We’ve developed a new kind of patent medicine called “Redu ping” (Medicine to
Subdue Toxic Heat) mainly used on the method of clearing heat and
detoxifying. Its anti – endotoxic function in vitro is 263 times that of
lactulose, it is similar to polymyxin B. Through oral administration it can
significantly protect against the death of mice caused by endotoxin or
aminogalactose or sensitization of actinomycin O. It can also act obviously
against the fever caused by endotoxin and tumor necrotic factor (TNF). In
clinical practice, it has been used to treat 51 patients with high fever
caused by the presence of endotoxin in blood . The therapeutic effectiveness
is quite good because it can promptly decrease the concentration of endotoxin
in blood, and let the body temperature become normal within 36.1 hours.

Tonifying Qi and Detoxifying

This method refers to increasing the ability of the body to eliminate
pathogenic toxins by using herbs and formulas that tonify Qi and strengthen
the body resistance. It originates from Niejing, which records that “The
organism is not disturbed by harmful environmental agents when vital energy
is sufficiently strong”. This aphorism sets the stage for our research on
the Qi tonifying and detoxifying herbs and formulas which can increase the
body’ s homeostasis function, especially the function of immune system in the
aspects of modern pharmacology of TCM. It seems likely that increasing the
phagocytic activity of reticuloendothelial system (RES) may increase the
ability of the body to eliminate endotoxin, because the endotoxin in blood is
mainly eliminated by the phagocytic function of mononuclear macrophages
(which are the first barrier of immune system) and ejected through the
biliary tract.

Thus, we designed the following experimental procedures to research the
function of herbs in these respects; 1) Using the ability of the herb or
herbal compound to increase the phagocytic activity of RES as the chief
condition; 2) Using a measure of the protective effects against such toxic
actions as shock or death of experimental animals caused by endotoxin as the
pharmacodynamic index; 3)Taking the non-specific function of anti -command
anti-infection as counterevidence. Practical methods included: 1) Observing
the influence on the phagocytic function of RES in swallowing three kinds of
foreign bodies (inert carbon, 32P marked staphylococcus and number 32P
chicken erythrocytic) by applying drugs to various kinds of animals such as
mice hamsters, guinea pigs and rabbits. 2) Observing the influence on the
shock and death of mice and hamsters caused by the attack of endotoxin, the
fever of guinea pigs and rabbits or the drop of temperature of hamsters
caused by endotoxin, and peripheral changes in white blood cells and diarrhea
of mice caused by endotoxin. 3) Observing the protective action against
superior mesenteric artery occlusion shock and venous infection of
gram-positive and gram -negative bacteria of mice.

We carried out systematic research on more than 200 formulas, herbs, herbal
chemical components and their derivatives based on the above research
protocols . The result shows that formulas and herbs that tonify Qi and
strengthen body resistance can significantly reinforce the phagocytic
function of RES. For instance, such herbs and formulas as Ginseng (Ren
shen), Pilose asiabell root (Dang shen), Astragalus root (Huang qi),
polysaccharidum versicolor (Yun zhi) , White Jelly Fungus (Yi ner),
Wulingshen and Pulse-activating Injection (Ginseng, Ophiopogon root,
Schizandra fruit), injection of Ginseng and Ophiopogon, injection of Ginseng
and prepared Aconite Root, Protecting Vital Qi Decoction (Bao yuan tang),
etc. all have the ability to increase the phagocytic index of RES 2-5 times,
thus accelerating the clearance of endotoxin from the blood stream. The
experimental animals to which the above medicines have been administered
showed obvious resistance against fever, change of white blood cells,
diarrhea, shock and death caused by the attack of endotoxin.

In addition, RES has strong phagocytic action against the pathogenic
microorganisms (which are the source of endotoxin) as well as the pathologic
biochemical by-products such as the by-products of coagulation and
fibrinolytics, alexinic fragments, and immunocomplexes triggered by endotoxin
inside the body. Therefore, it is clear that the herbs and herbal formulas
should have the action against non-specific infection and shock by virtue of
their reinforcement of the function of RES. This has been shown by our
experiments that demonstrate that the three medicines Pulse- activating
injection, Ginseng, and Polysaccharidum versicolor all have obvious
protective action against the death of mice caused by infection of
gram-negative and gram positive bacteria, and can prevent the rise of the
content of endotoxin in blood and can lower the death rate in the disease of
superior mesenteric artery occlusion shock of hamsters.

Moreover, the state and tendency of illness of endotoxic diseases with
deficient vital Qi is closely related to the function of the mononuclear
macrophage. For example, the recovery from various acute infections and
septicemia depends on the RES’s elimination of both the pathogenic
microorganism and its toxic by-products in the blood stream. The occurrence
and development of DIC has a close relation to the Reuse’s incomplete
elimination of the by-products of coagulation and fibrinolytics in the blood
stream, and RES failure is the cause of death in acute DIC. The occurrence
of intractable shock also is related to the failure of RES. Therefore,
resuscitating the RES is the key for intractable shock to transform into
reversible shock. Death from severe hepatitis and multiple system organ
failure( MSOF) is likewise caused by RES failure. It is thus clear that
using the formulas and herbs which tonify Qi and strengthen body resistance
to reinforce the RES activity is another main therapeutic method to treat
endotoxic diseases.

In clinic practice, Pulse Activating injection has a good therapeutic track
record in the treatment of toxic shock, such as severe pneumonic shock,
biliary shock, epidemic hemorrhagic fever and hemorrhagic shock caused by
infection. The injection can alleviate toxemia, raise the blood pressure and
improve the general condition of the patients. Using Western medicine alone
to treat shock, the death rate is 12.2 % while using the combination of
Western medicine and Pulse-activating injection, the death rate is 4.2% . In
the treatment of infectious toxic shock (52 cases) by using the injection of
Ginseng and Ophiopogon, the restoration of optimal blood pressure and the
correction rate of shock are much better than in the control group treated by
Western medicine. The injections of Ginseng and Prepared Aconite Root,
Shenfuqing, etc. all have the ingredient Ginseng, which can strongly
increase the ability of the RES to eliminate the endotoxin inside the body.
Therefore, it has obvious therapeutic effect in the treatment of various
kinds of acute, chronic hepatic injury. It is thus evident that tonifying
the Qi and Detoxifying is an effective method of TCM for treating endotoxic
diseases.

Cleansing the Viscera and Purging Toxins

There exist a large amount of gram-negative bacteria in the intestines. When
the body faces stress conditions such as high fever, blood loss, burns, or
severe trauma, it will result in serious abnormal fermentation in the
intestines, thus producing a large amount of endotoxin. The change in the
permeability of the walls of the intestine caused by lack of oxygen and blood
supply will lead to the absorption of large amounts of endotoxin into the
blood. This is not only the main reason that gram-negative infections cause
high content of endotoxin in blood, but also the most important reason for
sudden endotoxic shock in various kinds of acute abdominal and intestinal
operations.

In clinical practice, the content of endotoxin increased obviously in the
blood of patients with “Syndrome of Yang Ming Bowel Organs.” Therefore,
purgative herbs are used to get rid of the intestinal endotoxin pool, improve
blood circulation, restore the barrier action of the enteric membrane, and
reduce the absorption of enterogenous endotoxin. Experiments showed that the
herb Rhubarb and the formula Drastic Purgative Decoction (Rhubarb, Glauber’s
salt, Magnolia bark, and Immature Bitter Orange) have the above function,
because of their strong purgative and anti -bacterial action. Rhubarb and
its formulas can treat experimental fever effectively and quickly.

In clinical practice, the method of purging off the toxins of the intestines
is applied to treat acute hemorrhagic necrotic pancreatitis, intestinal
obstruction, enterogenous shock, severe hepatitis, epidemic hemorrhagic
fever, acute renal failure and acute respiratory disease (ARD) . For
instance, Decoction to Purge the Heat (Rhubarb, Glauber’s salt, Scrophularia,
Licorice), when it is used to treat adult pneumonia, can achieve full
antipyretic function within 24-72 hours, and lower the content of endotoxin
in blood. Research shows that Rhubarb doesn’t have direct anti -endotoxic
function, but it has a good therapeutic and preventive action against
enterogenous endotoxin in blood. The therapeutic mechanism is that Rhubarb
can prevent enterogenous endotoxin from entering the bloodstream. Serving as
antagonists against endotoxin, Rhubarb is completely different from
lactulose. The method of purging off toxins in the intestines to treat
enterogenous endotoxic disease therefore has a much broader meaning than the
simple laxative function as understood by modern medicine.