Papers 299
Why are Natural Plant Medicinal Products Effective in Some Patients and not in Others with the Same Disease? Yakie Niwa1' , Yoshiki Miyachi2, Koichi Is hi ynoto , and Tadashi Kanoh4 2
Niwa Institute for Immunology, 4-4 Asahimachi, Tosashimizu, Kochi-ken, 787-03, Japan Department of Dermatology, Faculty of Medicine, Kyoto University, Sakyo-ku, Kyoto 606, Japan Department of Pediatrics, Faculty of Medicine, Juntendo University, Bunkyo-ku, Tokyo 113, Japan Department of Internal Medicine, Faculty of Medicine, Kyoto University, Sakyo-ku, Kyoto 606, Japan Address for correspondence
Abstract We had previously found that the clinical efficacy of natural medicinal products was significantly enhanced by pretreatments of the natural compounds with far infrared radiation heating and brewing that effected degradation of high molecular polymers to yield free forms of low molecular monomers with anti-oxidant activity. The gastric samples from the patients were incubated with untreated or treated natural products, and the resulting materials assayed in vitro for the capacity to scavenge reactive oxygen species (fibS). The gastric
fluid of patients who had responded to the untreated natural products showed a significantly greater scavenging ability than did the patients who had not responded
Introduction Despite the impressive accomplishments of
the modern pharmaceutical industry, a large number of diseases remain for which treatment is of limited benefit. Furthermore, iatrogenic disorders have proved to be a consistent accompaniment of modern drug therapy. As a result, there is an increasing need for the development of so-
called "alternative treatment by natural medicinal prod-
ucts" and health foods, for which predictable pharmacologic activity and therapeutic efficacy can be
documented. A variety of such products have gained wide acceptance in Japan, China, and some European countries as mild nontoxic medications; however, for many products the active ingredients and mechanism of action remain to be determined.
to these agents. Similarly, the gastric fluid of patients who responded only to the treated, commercial products
We have previously investigated several
also showed a slightly greater scavenging ability than did
medicinal herbs, including some traditional Chinese herbs,
those who failed to respond to any agent, treated or untreated. Acid and pepsin contents were demonstrated in largest amounts in the gastric juice from the patients
that have been reported to be pharmacologically active when used orally. We demonstrated that the active principles of these preparations are usually low molecular an-
who had responded well to the untreated natural
medicines. Furthermore, the materials incubated with gastric fluid from the responding patients produced an
tioxidants that are liberated from repeating subunits of
bioactive low molecular compounds from repeating
higher molecular polymers by the action of gastric juice or heat treatment (1). Subsequently, we developed a procedure to potentiate the bloavailability of these low molecular antioxidants by heating and brewing the natural products from which they are derived. The resulting natural medicinal product, commercially available under the names Bioharmony or AOA (antioxidant analogs), has been shown to be effective and useffil in the treatment of several chronic inflammatory disorders (2—6), in which reactive oxygen
polymers.
species (ROS) or lipid peroxides are thought to play a
increase in the free forms of alpha-tocopherol, /3-
carotene, and flavoprotein as compared with the fluids of nonresponding patients. These findings suggest that one
of the factors determining the clinical response to
natural herbal medicinal products is the ability of the patient's digestive system to degrade the product to liberate
Key words
Natural plants, clinical response, far infrared rays, brewing, reactive oxygen species, scavenging ability, digesting capacity of gastric juice.
pathogenetic role: Raynaud's disease including cold finger
and toes, lung fibrosis observed at the end stage of PSS (progressive systemic sclerosis) or induced by bleomycin, HA (rheumatoid arthritis), especially morning stiffness, hepatitis including liver cirrhosis, nephritis (patients) required to take blood dialysis, ephelides and freckles etc, all of which are resistant to ordinary treatments (2—6). Con-
currently, these products were shown to be effective in scavenging ROS and in inhibiting lipid peroxidation both in vitro and in vivo in experimental (animals) systems (2—6).
Downloaded by: University of Arizona Library. Copyrighted material.
Received: April 30, 1990
300 Planta Med 57(1991)
The following two statements summarize the traditional wisdom with regard to the empiric use of Chinese herbs: "The same product can be effective in several different diseases with different pathogeneses," "One product may be effective in only some patients with the same disease." The first statement is explainable on the basis of multiple in aiim activities. However, the second statement has long remained an unsolved question. One possible explanation could be inferred from our recent study, in which it was demonstrated that incubation of natural herbs with gastric juice could release biologically active low molecular compounds. In this study, we have observed a correlation of the clinical response of patients to
Yukie Niwa et at
Group C: those in whom not only Chinese herb,
Unseiin, or the untreated starting materials of Bin-harmony but also ADA was ineffective.
There were 5 patients in group A (3 males, aged 35 to 51, 2 females, aged 39 and 46), 25 patients in group B (15 males, aged 33 to 50, ten females, aged 34 to 51), and nine in group C (4 males, aged 30 to 44, 5 females, aged 29 to 50). The diseases of
these patients were rheumatoid arthritis (BA) (18 patients), Raynaud's disease (5 patients), Crohn's disease (5 patients), progressive systemic sclerosis (P55) (4 patients), and abnormal pigmentation on the face (ephelides and freckles) (7 patients). Fasting gastric juice was obtained from each patient by aspiration through a gastric tube. For each patient's sample, the respective drug product was suspended at 1.6 mg/mI in
Materials and Methods ADA (antioxidant analogs) or Bin-harmony (Antioxi Brewing Company, Tosashimizu, Kochi, Japan) were used as
antioxidant drugs and health foods; ADA is the domestic name, Bio-harmony the name for international usage. Their ingredients are almost identical (2). These are produced from wheat germ, rice bran, soybean, "Hatomugi" (a kind of oriental wheat), wheat, and
sesame by being heated with continuous manual stirring at appropriate temperatures in oriental pottery vessels on a Japanese traditional oven. This method of heating emits far infrared radiation of wavelengths (ultrared ray) intermediate between visible light (A = 0.38—0.78 km) and microwaves (A> 1mm) (2). This type
of radiation heats materials without degrading the constitutive molecules of the surface and contributes to an even transfer of heat to the centre of the materials. Thereafter, each material was brewed by incubation in a humidified atmosphere with "Koji" (Aspergillas oryzae), a fungus which continuously produces large amounts ofproteases and amylases. These two procedures, heating and brewing, as previously reported, contribute to the liberation from repeating polymers within the starting vegetable materials of a variety of free low molecular compounds with antioxidant activity, including flavonoids, carotene, alpha-tocopherol, ascorbate, flavoprotein and polyphenols, including catechin, among others (2).
Standardization of ADA (2) is as follows: ADA contains 0.05 g sesame, 0.1 g sesame oil, 0.1 g wheat germs, 0.1 g
soybean, 0.D67g rice bran, 0.lg Hatomugi, 0.183g of a total of green leaf extracts, 0.3 g taste tea and 0.0003mg "Koji" per gram.
In addition to the end product of ADA, the untreated starting materials of ADA, and the Chinese herb, Unseiin (Tsumura Jyuntendo, Tokyo, Japan), which are sold commercially as anti-inflammatory drugs, were also used. These three kinds of natural products were serially administered for two month trials to thirty-nine patients with chronic inflammatory diseases for which
there is evidence that lIDS or lipid peroxides play a role in pathogenesis. All of the drugs were, in general, administered between meals. After each two month drug test, the clinical effectiveness of each drug was evaluated as recently described (2, 7, 8). After the evaluation, the patients were divided into three groups, according to clinical response to these natural drugs.
Group A: patients in whom either the Chinese
Bedfore, MA), which have a molecular mass cutoff of 3,000. Both dialysate and dialysand were neutralized with NaDH and then assayed in the fibS-generating systems, as described below.
lIDS were generated in both human neutrophil and xanthine-xanthine oxidase systems: in neutrophil systems, neutrophils were isolated from the peripheral blood of healthy vol-
unteers by a previously described technique (9—11), then suspended in Krebs-Ringer phosphate buffer (KRP) containing 5 aiM glucose and gelatin (1 mg/ml). KElP containing only glucose was
used for DEE generation assay; Hanks' solution (Nissui Pharmaceutical Co., Tokyo, Japan) containing only gelatin was used for the determination of chemiluminescence. Each lIDS was assessed by methods we have previously described (9—11). In brief, forma-
tion of D was determined by ferricytochrome c (type III, Sigma Chemical Co., St. Louis, Missouri) reduction by D produced from 4 x 106 neutrophils stimulated with 1 mg/mi opsonized zymosan (Sigma); absnrbance was measured at 550nm. Generation of H2D2 was determined by using 2.5 x 106 PMNs stimulated with 1mg/mi opsonized zymosan, 0.1 ml of 50 mmol/iiter scopoletin (Sigma) in KRP buffer, and 0.1 ml of 1 mg/ ml horseradish peroxidase (type II, Sigma). The rate of decrease in fluorescence intensity of the scopoietin within 30 mm was quanti-
tated in a fluorescence spectrophotometer (Hitachi Co., Ltd., Tokyo) set at 370 nm for excitation and 460 nm for emission.
Hydroxyl radical (DEE) was quantitated by the amount of ethylene gas formed from the reaction of a-keto-methiolbutyric acid (Sigma) with the PMN-generated DEE; 2 x 106 PMNs stimulated with 1 mg/ml opsonized zymosan and 1 mmoi a-keto-
methiolbutyric acid were used, and the total amount of ethylene
gas formed at 10, 20, and 30mm was determined on a gaschromatugraph (Hitachi). Chemiluminescence was measured in a scintillation spectrometer (Packard, Downers Grove, Illinois). Five million PMNs in 3 ml Hanks' solution containing 1 mg/mi opsonized zymno-
san, but no iuminol, were incubated in the dark. Chemiluminescence was monitored on the spectrometer, which was operated in the out-of-coincidence summation mode. lIDS generation in the xanthine-xanthine oxidase
system was performed as follows: Instead of adding neutrophils and opsonized zymosan, 0.1 ml hypoxanthine and 1.25mM EDTA
herb, Unseiin, or untreated starting materials ofADA was effective.
were diluted in a total volume of 2 ml in 5mM phosphate buffer (pH 7.2—7.4). Thereafter, approximately 0.006 U/mI dialyzed xanthine
Group B: patients in whom ADA, Unseiin, or untreated starting materials of ADA was ineffective but the ADA product itself was effective.
oxidase was added to generate D.
Previous experiments demonstrated a dose-dependent effect of each drug before and after incubation with gastric juice in the scavenging of each lIDS (1, 2). Therefore, a dose-re-
Downloaded by: University of Arizona Library. Copyrighted material.
natural products with antioxidant activity to the ability of the patients' gastric juice to liberate low molecular com- gastric juice and incubated at 37°C for 2 h, then centrifuged at pounds from polymers of repeating subunits and to the con- 2000 rpm for 10 mm. The resulting supernatants were dialyzed in tent of acid or pepsin in their gastric fluids. Immersible CX 1OTM membranes (No. PTGC ilK 25, Millipore,
Why are Natural Plant Medicinal Products Effective in Some Patients and not in Others with the Same Disease? Planta Med. 57(1991) 301
untreated AOA not incubated with gastric juice (each ROS before dialysis: P < 0.001) (Table 1). After dialysis, the more
In order to know how many free forms of low molecular antioxidants are liberated from the repeating polymer by the gastric juice from each group individuals, end products of Bio-harmony, untreated starting materials of Bio-harmony, or the Chinese herb, Unseiin were respectively incubated with gastric juice from each subject for 2 h at 37°C. Thereafter, the products were subjected to hydrolysis for 2 h at 37°C. Then, free forms of f3carotene, alpha-tocopherol, and flavoprotein (vitamin B2) were, respectively, quantified by HPLC for alpha-tocopherol and flavoprotein and by a visible absorption method for carotene. Before the incubation of the products with gastric juice, free forms ofthese products were determined, and the quantity of each free low molecular
compound was compared with that before and after incubation with gastric juice.
Further, acid and pepsin contents were determined in gastric juice from the patients of each group, and compared with the capacities for producing antioxidant activity and liberatmg free forms of low molecular antioxidants. Acid and pepsin contents were quantified according to the literature methods (12, 13). Briefly, both spontaneous and maximal acid output were quantified, and the pH, titratable activity (to neutrality with phenal red), and chloride concentration of each specimen were measured. For each specimen the acid output was expressed as: volume x titratable activity = mEq HCllper hour. Maximal acid output and pepsin output were ex-
pressed as maximal pentagastrin acid output of peak 20-minute period x 3; mEq per hour and the output stimulated by 1000 Hunt units pentagastrin, respectively. Consensus for gastric juice was obtained from each patient.
dialyzed components of untreated AOA incubated with gastric juice, compared with those before dialysis following incubation with gastric juice (O: P
Why are Natural Plant Medicinal Products Effective in Some Patients and not in Others with the Same Disease? Yakie Niwa1' , Yoshiki Miyachi2, Koichi Is hi ynoto , and Tadashi Kanoh4 2
Niwa Institute for Immunology, 4-4 Asahimachi, Tosashimizu, Kochi-ken, 787-03, Japan Department of Dermatology, Faculty of Medicine, Kyoto University, Sakyo-ku, Kyoto 606, Japan Department of Pediatrics, Faculty of Medicine, Juntendo University, Bunkyo-ku, Tokyo 113, Japan Department of Internal Medicine, Faculty of Medicine, Kyoto University, Sakyo-ku, Kyoto 606, Japan Address for correspondence
Abstract We had previously found that the clinical efficacy of natural medicinal products was significantly enhanced by pretreatments of the natural compounds with far infrared radiation heating and brewing that effected degradation of high molecular polymers to yield free forms of low molecular monomers with anti-oxidant activity. The gastric samples from the patients were incubated with untreated or treated natural products, and the resulting materials assayed in vitro for the capacity to scavenge reactive oxygen species (fibS). The gastric
fluid of patients who had responded to the untreated natural products showed a significantly greater scavenging ability than did the patients who had not responded
Introduction Despite the impressive accomplishments of
the modern pharmaceutical industry, a large number of diseases remain for which treatment is of limited benefit. Furthermore, iatrogenic disorders have proved to be a consistent accompaniment of modern drug therapy. As a result, there is an increasing need for the development of so-
called "alternative treatment by natural medicinal prod-
ucts" and health foods, for which predictable pharmacologic activity and therapeutic efficacy can be
documented. A variety of such products have gained wide acceptance in Japan, China, and some European countries as mild nontoxic medications; however, for many products the active ingredients and mechanism of action remain to be determined.
to these agents. Similarly, the gastric fluid of patients who responded only to the treated, commercial products
We have previously investigated several
also showed a slightly greater scavenging ability than did
medicinal herbs, including some traditional Chinese herbs,
those who failed to respond to any agent, treated or untreated. Acid and pepsin contents were demonstrated in largest amounts in the gastric juice from the patients
that have been reported to be pharmacologically active when used orally. We demonstrated that the active principles of these preparations are usually low molecular an-
who had responded well to the untreated natural
medicines. Furthermore, the materials incubated with gastric fluid from the responding patients produced an
tioxidants that are liberated from repeating subunits of
bioactive low molecular compounds from repeating
higher molecular polymers by the action of gastric juice or heat treatment (1). Subsequently, we developed a procedure to potentiate the bloavailability of these low molecular antioxidants by heating and brewing the natural products from which they are derived. The resulting natural medicinal product, commercially available under the names Bioharmony or AOA (antioxidant analogs), has been shown to be effective and useffil in the treatment of several chronic inflammatory disorders (2—6), in which reactive oxygen
polymers.
species (ROS) or lipid peroxides are thought to play a
increase in the free forms of alpha-tocopherol, /3-
carotene, and flavoprotein as compared with the fluids of nonresponding patients. These findings suggest that one
of the factors determining the clinical response to
natural herbal medicinal products is the ability of the patient's digestive system to degrade the product to liberate
Key words
Natural plants, clinical response, far infrared rays, brewing, reactive oxygen species, scavenging ability, digesting capacity of gastric juice.
pathogenetic role: Raynaud's disease including cold finger
and toes, lung fibrosis observed at the end stage of PSS (progressive systemic sclerosis) or induced by bleomycin, HA (rheumatoid arthritis), especially morning stiffness, hepatitis including liver cirrhosis, nephritis (patients) required to take blood dialysis, ephelides and freckles etc, all of which are resistant to ordinary treatments (2—6). Con-
currently, these products were shown to be effective in scavenging ROS and in inhibiting lipid peroxidation both in vitro and in vivo in experimental (animals) systems (2—6).
Downloaded by: University of Arizona Library. Copyrighted material.
Received: April 30, 1990
300 Planta Med 57(1991)
The following two statements summarize the traditional wisdom with regard to the empiric use of Chinese herbs: "The same product can be effective in several different diseases with different pathogeneses," "One product may be effective in only some patients with the same disease." The first statement is explainable on the basis of multiple in aiim activities. However, the second statement has long remained an unsolved question. One possible explanation could be inferred from our recent study, in which it was demonstrated that incubation of natural herbs with gastric juice could release biologically active low molecular compounds. In this study, we have observed a correlation of the clinical response of patients to
Yukie Niwa et at
Group C: those in whom not only Chinese herb,
Unseiin, or the untreated starting materials of Bin-harmony but also ADA was ineffective.
There were 5 patients in group A (3 males, aged 35 to 51, 2 females, aged 39 and 46), 25 patients in group B (15 males, aged 33 to 50, ten females, aged 34 to 51), and nine in group C (4 males, aged 30 to 44, 5 females, aged 29 to 50). The diseases of
these patients were rheumatoid arthritis (BA) (18 patients), Raynaud's disease (5 patients), Crohn's disease (5 patients), progressive systemic sclerosis (P55) (4 patients), and abnormal pigmentation on the face (ephelides and freckles) (7 patients). Fasting gastric juice was obtained from each patient by aspiration through a gastric tube. For each patient's sample, the respective drug product was suspended at 1.6 mg/mI in
Materials and Methods ADA (antioxidant analogs) or Bin-harmony (Antioxi Brewing Company, Tosashimizu, Kochi, Japan) were used as
antioxidant drugs and health foods; ADA is the domestic name, Bio-harmony the name for international usage. Their ingredients are almost identical (2). These are produced from wheat germ, rice bran, soybean, "Hatomugi" (a kind of oriental wheat), wheat, and
sesame by being heated with continuous manual stirring at appropriate temperatures in oriental pottery vessels on a Japanese traditional oven. This method of heating emits far infrared radiation of wavelengths (ultrared ray) intermediate between visible light (A = 0.38—0.78 km) and microwaves (A> 1mm) (2). This type
of radiation heats materials without degrading the constitutive molecules of the surface and contributes to an even transfer of heat to the centre of the materials. Thereafter, each material was brewed by incubation in a humidified atmosphere with "Koji" (Aspergillas oryzae), a fungus which continuously produces large amounts ofproteases and amylases. These two procedures, heating and brewing, as previously reported, contribute to the liberation from repeating polymers within the starting vegetable materials of a variety of free low molecular compounds with antioxidant activity, including flavonoids, carotene, alpha-tocopherol, ascorbate, flavoprotein and polyphenols, including catechin, among others (2).
Standardization of ADA (2) is as follows: ADA contains 0.05 g sesame, 0.1 g sesame oil, 0.1 g wheat germs, 0.1 g
soybean, 0.D67g rice bran, 0.lg Hatomugi, 0.183g of a total of green leaf extracts, 0.3 g taste tea and 0.0003mg "Koji" per gram.
In addition to the end product of ADA, the untreated starting materials of ADA, and the Chinese herb, Unseiin (Tsumura Jyuntendo, Tokyo, Japan), which are sold commercially as anti-inflammatory drugs, were also used. These three kinds of natural products were serially administered for two month trials to thirty-nine patients with chronic inflammatory diseases for which
there is evidence that lIDS or lipid peroxides play a role in pathogenesis. All of the drugs were, in general, administered between meals. After each two month drug test, the clinical effectiveness of each drug was evaluated as recently described (2, 7, 8). After the evaluation, the patients were divided into three groups, according to clinical response to these natural drugs.
Group A: patients in whom either the Chinese
Bedfore, MA), which have a molecular mass cutoff of 3,000. Both dialysate and dialysand were neutralized with NaDH and then assayed in the fibS-generating systems, as described below.
lIDS were generated in both human neutrophil and xanthine-xanthine oxidase systems: in neutrophil systems, neutrophils were isolated from the peripheral blood of healthy vol-
unteers by a previously described technique (9—11), then suspended in Krebs-Ringer phosphate buffer (KRP) containing 5 aiM glucose and gelatin (1 mg/ml). KElP containing only glucose was
used for DEE generation assay; Hanks' solution (Nissui Pharmaceutical Co., Tokyo, Japan) containing only gelatin was used for the determination of chemiluminescence. Each lIDS was assessed by methods we have previously described (9—11). In brief, forma-
tion of D was determined by ferricytochrome c (type III, Sigma Chemical Co., St. Louis, Missouri) reduction by D produced from 4 x 106 neutrophils stimulated with 1 mg/mi opsonized zymosan (Sigma); absnrbance was measured at 550nm. Generation of H2D2 was determined by using 2.5 x 106 PMNs stimulated with 1mg/mi opsonized zymosan, 0.1 ml of 50 mmol/iiter scopoletin (Sigma) in KRP buffer, and 0.1 ml of 1 mg/ ml horseradish peroxidase (type II, Sigma). The rate of decrease in fluorescence intensity of the scopoietin within 30 mm was quanti-
tated in a fluorescence spectrophotometer (Hitachi Co., Ltd., Tokyo) set at 370 nm for excitation and 460 nm for emission.
Hydroxyl radical (DEE) was quantitated by the amount of ethylene gas formed from the reaction of a-keto-methiolbutyric acid (Sigma) with the PMN-generated DEE; 2 x 106 PMNs stimulated with 1 mg/ml opsonized zymosan and 1 mmoi a-keto-
methiolbutyric acid were used, and the total amount of ethylene
gas formed at 10, 20, and 30mm was determined on a gaschromatugraph (Hitachi). Chemiluminescence was measured in a scintillation spectrometer (Packard, Downers Grove, Illinois). Five million PMNs in 3 ml Hanks' solution containing 1 mg/mi opsonized zymno-
san, but no iuminol, were incubated in the dark. Chemiluminescence was monitored on the spectrometer, which was operated in the out-of-coincidence summation mode. lIDS generation in the xanthine-xanthine oxidase
system was performed as follows: Instead of adding neutrophils and opsonized zymosan, 0.1 ml hypoxanthine and 1.25mM EDTA
herb, Unseiin, or untreated starting materials ofADA was effective.
were diluted in a total volume of 2 ml in 5mM phosphate buffer (pH 7.2—7.4). Thereafter, approximately 0.006 U/mI dialyzed xanthine
Group B: patients in whom ADA, Unseiin, or untreated starting materials of ADA was ineffective but the ADA product itself was effective.
oxidase was added to generate D.
Previous experiments demonstrated a dose-dependent effect of each drug before and after incubation with gastric juice in the scavenging of each lIDS (1, 2). Therefore, a dose-re-
Downloaded by: University of Arizona Library. Copyrighted material.
natural products with antioxidant activity to the ability of the patients' gastric juice to liberate low molecular com- gastric juice and incubated at 37°C for 2 h, then centrifuged at pounds from polymers of repeating subunits and to the con- 2000 rpm for 10 mm. The resulting supernatants were dialyzed in tent of acid or pepsin in their gastric fluids. Immersible CX 1OTM membranes (No. PTGC ilK 25, Millipore,
Why are Natural Plant Medicinal Products Effective in Some Patients and not in Others with the Same Disease? Planta Med. 57(1991) 301
untreated AOA not incubated with gastric juice (each ROS before dialysis: P < 0.001) (Table 1). After dialysis, the more
In order to know how many free forms of low molecular antioxidants are liberated from the repeating polymer by the gastric juice from each group individuals, end products of Bio-harmony, untreated starting materials of Bio-harmony, or the Chinese herb, Unseiin were respectively incubated with gastric juice from each subject for 2 h at 37°C. Thereafter, the products were subjected to hydrolysis for 2 h at 37°C. Then, free forms of f3carotene, alpha-tocopherol, and flavoprotein (vitamin B2) were, respectively, quantified by HPLC for alpha-tocopherol and flavoprotein and by a visible absorption method for carotene. Before the incubation of the products with gastric juice, free forms ofthese products were determined, and the quantity of each free low molecular
compound was compared with that before and after incubation with gastric juice.
Further, acid and pepsin contents were determined in gastric juice from the patients of each group, and compared with the capacities for producing antioxidant activity and liberatmg free forms of low molecular antioxidants. Acid and pepsin contents were quantified according to the literature methods (12, 13). Briefly, both spontaneous and maximal acid output were quantified, and the pH, titratable activity (to neutrality with phenal red), and chloride concentration of each specimen were measured. For each specimen the acid output was expressed as: volume x titratable activity = mEq HCllper hour. Maximal acid output and pepsin output were ex-
pressed as maximal pentagastrin acid output of peak 20-minute period x 3; mEq per hour and the output stimulated by 1000 Hunt units pentagastrin, respectively. Consensus for gastric juice was obtained from each patient.
dialyzed components of untreated AOA incubated with gastric juice, compared with those before dialysis following incubation with gastric juice (O: P
