A study on the usefulness of eppikajutsuto for cellulitis

Cellulitis is a skin and soft‐tissue infection that is primarily treated with antimicrobial therapy, with the assumption that an organism is the causative agent. Eppikajutsuto (EPTJ) is generally used to alleviate inflammatory swelling, pain, and warmth in joints owing to its heat™1‐clearing and fluid™1‐regulating properties. This study is a retrospective analysis of the efficacy and safety of EPTJ in the treatment of cellulitis.


INTRODUCTION
Cellulitis is a soft-tissue infection characterized by inflammation of the dermis and subcutaneous adipose tissue.It results from microbial invasion due to impairment of the skin barrier function.Primary symptoms include heat, swelling, erythema, and tenderness.The extremities are the sites of predilection for cellulitis, and the incidence of cellulitis in the lower extremities is approximately 200 per 100,000 individuals [1].The mainstay of treatment for cellulitis is antimicrobial therapy based on the assumed causative organism.However, there are cases in which the infection spreads deep into the skin or cellulitis recurs even with standard treatment.

METHODS
This retrospective observational study used an opt-out approach and was approved by the ethics committee of the Akita Medical Association (approval no.54).A total of 103 patients (49 men and 54 women) with cellulitis were treated with EPTJ at the Minamiakita Orthopedic Clinic and Igarashi Memorial Hospital between April 1, 2014, and November 30, 2023.Of the 103 patients, 99 patients (48 men and 51 women) were included in the study, and four patients who used steroids or nonsteroidal anti-inflammatory drugs (NSAIDs) from the start of EPTJ treatment were excluded (Figure 1).Cases of necrotizing fasciitis determined based on computed tomography (CT) and magnetic resonance imaging (MRI) and clinical symptoms were excluded.
All patients were administered granular type EPTJ extract (TJ-28; Tsumura & Co., Tokyo, Japan) before meals at a dose of 5.0-7.5 g/day depending on the body weight of the patient.Doses of 7.5 g/day were administered to patients weighing 50 kg or more, and 5.0 g/day to patients weighing less than 50 kg.Every 7.5 g of EPTJ extract granule contained 3.25 g of dried extract of the following mixed crude drugs: Japanese Pharmacopeia (JP) gypsum (8.0 g), Ephedra herb (6.0 g), JP Atractylodes lancea rhizome (4.0 g), JP jujube (3.0 g), JP Glycyrrhiza (2.0 g), and JP ginger (1.0 g) [9].EPTJ was used for inflammatory swelling (heat™ 1 impediment) of the joints or limbs caused by cellulitis.
Efficacy was judged as "effective" when symptoms improved with EPTJ (including concomitant use of Kampo prescriptions), and "ineffective" when EPTJ was changed to another drug.Adverse events were also recorded.
Each parameter is expressed as a median (IQR) value.The Mann-Whitney U-test was used for comparisons between the two groups.Fisher's exact test was used for statistical analysis.Values of p < 0.05 were regarded as statistically significant.

Analysis of all cases
The median patient age was 70 years (range: 55-83 years).The median age of the 48 male patients was 61 years (51-74 years), and the median age of the 51 female patients was 80 years (61-87 years), with no significant difference between the sexes (p = 0.4161).The median dosage of EPTJ was 7.5 g (7.5-7.5 g).The median duration of EPTJ treatment was seven days (5-7 days).
The median white blood cell (WBC) count before EPTJ administration was 7600/mm 3 (6200-10,350/ mm 3 ).The median C-reactive protein (CRP) levels of patients before EPTJ administration was 3.53 mg/dL (0.70-8.48 mg/dL).Treatment was determined to be effective in 94 patients (94.9%) and ineffective in the remaining five patients.No adverse events were observed.

Comparison of effective and ineffective groups
The median age in the effective group was 70 years (56-83 years), and 63 years (43-96 years) in the ineffective group, with no significant difference in age between the groups ( p = 0.5256).The median dosage of EPTJ in the effective group was 7.5 g (7.5-7.5 g) and 7.5 g (7.5-7.5 g) in the ineffective group, with no significant difference between the two groups ( p = 0.5839).The duration of treatment in the effective group was seven days (7-9 days) and four days (3-7 days) in the ineffective group, which was significantly shorter than that in the effective group ( p = 0.0221).
The WBC count before EPTJ administration in the effective group was 7500/mm 3 (6200-10,350/mm 3 ) and that in the ineffective group was 8900/mm 3 (7525-19,650/mm 3 ), with no significant difference between the two groups (p = 0.3489).The CRP level before EPTJ administration in the effective group was 3.53 mg/dL (0.88-8.53 mg/dL) and that in the ineffective group was 2.97 mg/dL (0.63-5.85 mg/dL), with no significant difference between the two groups ( p = 0.5285).
There were no significant differences in the effectiveness between the infected areas (p = 0.3123).There were no significant differences in effectiveness between patients with concomitant use of antimicrobial agents and those without concomitant use of antimicrobial agents ( p = 0.1955).Effective treatments included cefdinir (22 patients), minocycline (17 patients), cefazolin (three patients), levofloxacin (one patient), amoxicillin (one patient), clavulanate-amoxicillin (one patient), and doripenem (one patient).Antibiotics in the ineffective group included minocycline (four patients) (Table 1).In the ineffective group, two patients were switched to NSAIDs, one to NSAIDs and prednisolone, one to continued antibiotics alone, and one to pregabalin (Table 2).

Comparison with and without concomitant use of antimicrobial agents
There were 48 patients (23 men, 25 women) in the group with concomitant use of antimicrobial agents (antibiotic group) and 51 patients (25 men, 26 women) in the group without the concomitant use of antimicrobial  agents (non-antibiotic group).The median age in the antibiotic group was 73 years (60-83 years) and 64 years (50-81 years) in the non-antibiotic group, with no significant differences between the age groups (p = 0.1657).The median dosage of EPTJ in the antibiotic group was 7.5 g (7.5-7.5 g) and 7.5 g (7.5-7.5 g) in the non-antibiotic group, with no significant difference between the two groups (p = 0.5559).The duration of treatment in the antibiotic group was seven days (range, 5-10 days) and that in the non-antibiotic group was seven days (range, 5-7 days), with no significant difference between the two groups (p = 0.3382).The WBC count before EPTJ administration in the antibiotic group was 8300/mm 3 (6500-10,500/mm 3 ), and that in the nonantibiotic group was 6800/mm 3 (5800-9400/mm 3 ), with no significant difference between the two groups (p = 0.1146).The CRP level before EPTJ administration in the antibiotic group was 5.28 mg/dL (1.33-10.24mg/ dL) and that in the non-antibiotic group was 0.75 mg/dL (0.11-2.11 mg/dL), with no significant difference between the two groups (p = 0.0993).There were no significant differences in effectiveness in the infected areas ( p = 0.7397).There were 44 effective cases in the antibiotic group (efficacy rate, 91.7%) and 50 cases in the non-antibiotic group (efficacy rate, 98.0%), with no significant difference between the two groups (p = 0.1955) (Table 3).

DISCUSSION
Eppikajutsuto was first described by Jin Gui Yao Lue in Chapter 5 on Wind Stroke and Joint Diseases-Pulses, Patterns, and Treatment.Jin Gui Yao Lue states that "EPTJ recorded in the Qian Jin Yao Fang can be used to treat muscle fatigue and weakness due to severe loss of body fluids from profuse sweating (caused by exuberant internal heat™ 1 ) coupled with an exposure to wind upon sweating."In Chapter 14: Water Qi Retention-Pulses, Patterns, and Treatment, the authors further stated that "patients with skin water may present with severe body swelling, deep pulses, and dysuria, which in turn result in water retention.Thirst with normal urination is not a water qi disorder but is caused by insufficient body fluids.Water qi disorders should be treated with EPTJ" [2].
Because gypsum exhibits a heat™ 1 -clearing (cooling) effect, it can alleviate redness and heat.The Atractylodes lancea rhizome and Ephedra herb exert fluid™ 1 -regulating effects, and can alleviate swelling.These compounds exhibit analgesic effects.The combination of Ephedra herb with gypsum results in the absorption of fluid™ 1 which drains into the urine, resulting in an enhanced anti-inflammatory effect.Glycyrrhiza also inhibits prostaglandin production and exerts analgesic effects [10].Thus, EPTJ alleviates the four T A B L E 3 Comparison of the antibiotic and non-antibiotic groups.cardinal signs of inflammation (Figure 2).In addition, Ephedra herb and ginger cause sweating and release excess fluid™ 1 .

Variables
Cellulitis is usually caused by Streptococcus bacteria and sometimes by Staphylococcus aureus.Therefore, first-generation cephem antibiotics are the mainstay of treatment.Cefdinir and faropenem were administered only in mild cases.A combination of cefoperazone-sulbactam and meropenem was administered in moderate and severe cases, respectively.Clindamycin, minocycline, and sulfamethoxazoletrimethoprim (ST) combinations have also been used in patients with a history of beta-lactam antimicrobial allergies.Katayama et al. reported that EPTJ inhibits the growth of exfoliative toxin-positive S. aureus [11].In this study, antimicrobial agents were used in 48.5% of the patients; however, there was no significant difference in therapeutic efficacy depending on whether concomitant antimicrobial agents were used.Furthermore, 53.2% of the effective group did not receive concomitant antimicrobials and 80.0% of the ineffective group received concomitant antimicrobials; therefore, it may be possible to treat cellulitis with EPTJ alone.
Non-steroidal anti-inflammatory drugs are believed to relieve the symptoms of cellulitis.In this study, 94.9% of patients improved without the concomitant use of NSAIDs, and the concomitant use of NSAIDs was considered unnecessary in the initial treatment phase.However, because 80.0% of the patients in the ineffective group required additional analgesics, it may be necessary to use a small amount of concomitant NSAIDs in actual clinical practice or to use them as an adjunct.Treatment duration was significantly shorter in the ineffective group than in the effective group.Four men patients were switched to analgesics.Whether men have a lower pain threshold requires further investigation [12,13].Furthermore, it remains to be investigated whether NSAIDs should be added when the analgesic effect of EPTJ alone is insufficient or whether the first choice of antimicrobial agents should be changed.
Ephedrine is extracted from Ephedra herbs and should be administered with caution to patients with cardiac disease because of its side effects, such as increased heart rate and blood pressure [14].Glycyrrhiza may also cause elevated blood pressure, edema, and hypokalemia owing to pseudohyperaldosteronism [15].The study included 21.2% hypertension cases and 5.1% arrhythmia cases; however, none of these cases were problematic.The short median dosing duration (seven days) may have contributed to this finding.It is important to discontinue the use of EPTJ as soon as symptoms improve rather than use it prophylactically.
Hainosankyuto was created in Japan by Yoshimatsu Todo, who combined hainosan and hainoto.It is used to treat carbuncles, furuncles, whitlows, and other pyogenic conditions in which the affected area is red, swollen, and painful [2].In obstetrics and gynecology, lymphedema often leads to repeated cellulitis triggered by infection, for which HNST has been used [16].In this study, only one case of combined use of EPTJ and HNST was reported; however, we should consider whether the use of antibacterial agents or NSAIDs is unnecessary when EPTJ is used in combination with HNST.As this was a single-arm study without a control group, future multicenter studies with a control group are necessary to confirm whether EPTJ is effective for treating cellulitis.
The EPTJ extract granules for ethical use indicate that "EPTJ is indicated for alleviating the following symptoms in patients experiencing edema, diaphoresis, and difficulty in micturition.Intended uses include alleviation of swelling, pain, or a sensation of burning in the joints or limbs."[17] Cellulitis is often associated with inflammatory swelling of skin and around the joints or limbs, and EPTJ can be expected to alleviate these symptoms.

CONCLUSIONS
The efficacy rate of EPTJ for cellulitis was 94.9% and no adverse events were observed.Thus, EPTJ may be a safe and effective treatment option for cellulitis.Although antimicrobial agents were used in 48.5% of the patients, there was no difference in their use of antimicrobial agents between the effective and ineffective groups.Further studies are needed to determine whether the concomitant use of antimicrobials is mandatory, or whether NSAIDs should be administered concomitantly.

T A B L E 1
Comparison of the effective and ineffective groups.VariablesEffective group (n = 94) Ineffective group (n = 5)

T A B L E 2
Patient profile of the ineffective treatment group.

F I G U R E 2
Action of eppikajutsuto on the four cardinal signs of inflammation.