The main purpose of this study is to assess the treatment effect of DBT in moderate to severe acute diverticulitis. The secondary aim of this study is to investigate the preventive effect of DBT on colonic diverticulitis. Patients with a history of diverticulitis are advised to consume a high-fiber diet or ingest fiber supplements, minimize red meat consumption, avoid non-aspirin non-steroidal anti-inflammatory drugs, stop smoking, maintain or achieve a healthy body weight, and exercise regularly [6]. Although multiple studies have investigated the methods of colonic diverticulitis prevention, the existing results are not supported by high-quality evidence. In this study, we will investigate differences between treatment with DBT combined with antibiotics, relative to treatment with placebo.
Diverticula can occur at any site in the colon. However, they occur primarily in the sigmoid colon in Western countries; in contrast, the right side or bilateral colon is more commonly involved in Japan. The standard treatment for acute uncomplicated diverticulitis has been bowel rest (i.e., fasting), intravenous fluids, and intravenous antibiotics. There will be a diverse assortment of antibiotics used for patients in this study, based on variability in the antibiotics used in clinical practice among centers in the study. Additionally, while many trials have focused on surgical treatment of acute diverticulitis, there have been few studies dedicated to medical treatment of this condition. A review of the published data revealed that there is no standardization regarding the medical treatment of uncomplicated acute diverticulitis [11]. In this study, we will not limit the types of antibiotics; all antibiotics will be noted in the case report forms.
In Kampo medicine, internal abscesses generally comprise abscesses of the lungs and intestines. Similar to external abscesses, they are attributed to heat and constraint, which allow the formation of toxins and secondarily lead to the formation of pus. The appropriate strategy is to discharge the toxin, eliminate the phlegm, clear the heat, and open the constraint. If clumping of heat with stasis and stagnation is also present, herbs such as Rhei Radix et Rhizoma (da hung大黄) and Moutan Cortex (mu dan pi牡丹皮) can be added to drain heat and dispel stasis [8]. In this context, DBT is one of the most suitable formulas for treatment of acute diverticulitis. DBT might have preventive effects on the recurrence of diverticulitis, although the prognosis of patients was not reported in a prior study [9].
Most herbal medicine is orally administered, and many components of these medicines come into contact with the intestinal microflora in the alimentary tract. Some are modified by intestinal bacteria before their absorption into the bloodstream from the gastrointestinal tract [12]. Although administration of intravenous antibiotics may influence intestinal microflora and the effect of DBT might be altered, compared with classical therapy, our previous study showed that both intravenous antibiotics and DBT could be used at the same time [9].
DBT consists of five crude drugs: Rhei Rhizoma, Natrium sulfuricum, Moutan Cortex, Persicae Semen, and Benincasae Semen. Of these, Rhei Rhizoma or rhubarb is one of the most important traditional herbal medicines, widely used in Kampo and traditional Chinese medicines for thousands of years, especially as a purgative. It might prevent bowel retention, overgrowth of toxic bacteria in patients with acute diverticulitis, and enable resolution of acute inflammation.
Studies regarding other functions of rhubarb in modern medical research in both clinical and basic science settings have revealed that rhubarb has multiple effects, including defervescence and anti-inflammatory actions, as well as the expulsion of a variety of harmful materials (e.g., endogenous and exogenous toxins) from the bowel and the body.
It is shown that rhubarb protects against acute lung injury induced by lipopolysaccharide, and that rhubarb administration improves respiratory function of the body. Its effect is related to the regulation of the production of nitric oxide as well as phospholipase A, and platelet-activating factor activities [14]. These effects may be related to the improvement of inflammation in diverticulitis.
Moutan Cortex, the root cortex of Paeonia suffraticosa, is an herbal medicine widely used as an analgesic, antispasmodic, and anti-inflammatory agent. Moutan Cortex reportedly inhibits the secretions of interleukin-8, a major mediator of acute neutrophil-mediated inflammation, and macrophage chemoattractant protein-1, a potent mediator of chronic macrophage-mediated inflammation in human monocytic U937 cells [15]. Recently, Moutan Cortex was shown to protect against sepsis induced by lipopolysaccharide/ D-galactosamine [16]. The known chemical components of Moutan Cortex include paeonol, paeonoside, paeonolide, paeoniflorin, benzoylpaeoniflorin, oxypaeoniflorin, benzoyloxy-paeoniflorin, and apiopaeonoside.
Moutan Cortex inhibited the lipopolysaccharide + interferon-g -induced expression of inducible nitric oxide synthase and tumor necrosis factor-a release. The lipopolysaccharide + interferon-g-induced activation of nuclear factor-kB was almost entirely blocked by Moutan Cortex [16].
Persicae Semen or Prunus persica, is also well-known as a traditional medicine in Japan, China, and other Asian countries. They are frequently used as ingredients in a variety of Kampo and Chinese medicine formulas, particularly those used to treat women’s diseases. The chemical constituents of the herb include cyanogenic glycosides, amygdalin and prunasin as major components, along with glycerides, sterols, and emulsion. Amygdalin is abundant in the seeds of bitter almond and apricots of the Prunus genus, and other rosaceous plants. Persicae Semen has anti-edema, anti-writhing, and anti-inflammation activities.
Each of these crude drugs has some anti-inflammatory effects, and the combination of these crude drugs may produce the synergy of Kampo medicine.
Moreover, we are considering to do sub-groups analysis as following: Correlation between diverticulitis incidence and BMI, gender, ages, seasons, and correlation between success rate of diverticulitis treatment and antibiotics, BMI, gender, ages, seasons.
In conclusion, this study protocol may contribute to the development of an effective treatment to help relieve acute diverticulitis. It may also provide evidence on the efficacy and safety of DBT in acute diverticulitis patients.
Trial status
Recruitment began in January 2018, and is expected to be completed in March 2020.
The latest protocol is Ver2.0, approved by ethical committee on July 25th, 2019.