Elsevier

Phytomedicine

Volume 60, July 2019, 152987
Phytomedicine

Original Article
The standardized herbal combination BNO 2103 contained in Canephron® N alleviates inflammatory pain in experimental cystitis and prostatitis

https://doi.org/10.1016/j.phymed.2019.152987Get rights and content

Abstract

Background

Urinary tract infections are among the most common types of infections and give rise to inflammation with pain as one of the main symptoms. The herbal medicinal product Canephron® N contains BNO 2103, a defined mixture of pulverized rosemary leaves, centaury herb, and lovage root, and has been used in the treatment of urinary tract infections for more than 25 years.

Purpose

To test the hypothesis that BNO 2103 reduces pain in cystitis and prostatitis by virtue of anti-inflammatory properties, and to reveal potential mechanisms underlying the anti-inflammatory features.

Study design

BNO 2103 was studied for anti-inflammatory and analgesic properties in three animal models in vivo, and the mode of action underlying the anti-inflammatory features was investigated in human leukocytes and cell-free assays in vitro.

Methods

To assess the anti-inflammatory and analgesic efficacy of BNO 2103 we employed cyclophosphamide-induced cystitis and carrageenan-induced prostatitis in rats, and zymosan-induced peritonitis in mice. Human neutrophils and monocytes as well as isolated human 5-lipoxygenase and microsomal prostaglandin E2 synthase-1-containing microsomes were utilized to assess inhibition of leukotriene and/or prostaglandin E2 production by HPLC and/or ELISA.

Results

When given orally, BNO 2103 reduced inflammation and hyperalgesia in experimental cystitis in rats, while individual components of BNO 2103 also reduced hyperalgesia. Furthermore, BNO 2103 reduced hyperalgesia in rats with carrageenan-induced prostatitis. Cell-based and cell-free studies implicate inhibition of prostaglandin E2 and leukotriene B4 biosynthesis as potential mechanisms underlying the analgesic and anti-inflammatory effects.

Conclusion

Our data support the hypothesis that BNO 2103 reduces pain by virtue of its anti-inflammatory properties, possibly related to suppression of prostaglandin E2 and leukotriene B4 formation, and suggest that this combination has the potential to treat clinical symptoms such as inflammatory pain. Thus BNO 2103 may represent an alternative to reduce the use of antibiotics in urinary tract infections.

Introduction

Urinary tract infections (UTIs) are among the most common bacterial infections, affecting 150 million people each year worldwide (Flores-Mireles et al., 2015, Geerlings, 2016). While women are preferentially at risk for UTI, with 50–60% of women experiencing at least one UTI in their lifetime, UTIs can affect men and women at all ages causing significant morbidity in infants, older men, and females at all ages (Flores-Mireles et al., 2015). Clinically, UTIs are considered uncomplicated in otherwise healthy individuals with no structural or neurological urinary tract abnormalities. While a variety of microorganisms can cause UTIs, infections with E. coli are most common (Asadi Karam et al., 2019).

The most bothersome symptom of acute uncomplicated UTIs is pain, which is part of inflammation associated with the immune response (Kidd and Urban, 2001). Depending on the site, these can be urethritis, cystitis, pyelonephritis, or prostatitis in males. For uncomplicated UTIs, treatment with antibiotics is recommended (Grabe et al., 2015). However, recent guidelines indicate non-antibiotic treatment (e.g., non-steroidal anti-inflammatory drugs, NSAIDs) as option for patients with mild to moderate symptoms in order to avoid fostering antibiotic resistance development (AWMF, 2017).

Canephron® N has a long-standing use for the treatment and prophylaxis of uncomplicated UTIs and of urinary stones (Naber, 2013). It is an herbal medicine containing BNO 2103, a standardized mixture of pulverized rosemary leaves, centaury herb, and lovage root. BNO 2103 is proposed as an attractive alternative to antibiotics due to its efficacy in the treatment of pain and inflammation associated with UTIs, its good safety and tolerability (Naber, 2013), and its intrinsic ability to avoid problems associated with bacterial antibiotic resistance.

To test the hypothesis that BNO 2103 reduces pain by suppressing inflammation, we employed cyclophosphamide (cycP)-induced cystitis in female rats and carrageenan-induced prostatitis in male rats. In addition, we investigated biosynthesis of prostaglandin E2 (PGE2) and leukotrienes (LTs), which promote inflammation and inflammatory pain, as possible points of attack.

Section snippets

Test item

Canephron® N contains BNO 2103, a 1:1:1 (w:w:w) mixture of pulverized rosemary leaves (Rosmarinus officinalis Linné), centaury herb (Centaurium erythraea Rafn), and lovage root (Levisticum officinale Koch) as active pharmaceutical ingredient. BNO 2103 was produced, controlled for quality, and provided by Bionorica SE (Neumarkt, Germany). An UPLC-based fingerprint (UV detection) at a wavelength of 205 nm of the aqueous ethanolic extract of BNO 2103 can be found as Supplemental material.

For in

BNO 2103 reduces nociception in experimental cystitis

Since pain is a prominent symptom of cystitis, we studied whether BNO 2103 could reduce pain in cycP-induced cystitis in female rats. CycP-treated animals displayed pronounced hyperalgesia as evidenced by reduced nociceptive threshold (4.1 ± 0.60 g) compared to sham animals (16.4 ± 2.6 g). Animals pretreated with BNO 2103 exhibited a dose-dependent reduction in nociceptive responses (Fig. 1A and B). For comparison, the area under the curve (AUC) was calculated for each treatment (Fig. 1B):

Discussion

UTIs are among the most common types of infections (Geerlings, 2016) and the body responds with pronounced inflammation (Wu et al., 2017). Acute inflammation is initiated by the release of various mediators, e.g., PGs, LTs, and cytokines (Funk, 2001, Newton and Dixit, 2012). The cardinal signs of inflammation are redness, heat, and swelling, as well as pain and reduced function, and PGs and LTs markedly contribute to the development of these signs (Funk, 2001). For patients with lower UTIs, the

Conclusion

Our data highlight the efficacy of BNO 2103 in reducing hyperalgesia and inflammation in experimental inflammation models in vivo and in vitro. These results suggest that Canephron® N, which contains BNO 2103, has the potential to alleviate one of the most bothersome symptoms of UTIs, i.e., inflammatory pain. Thus, it presents a valuable alternative treatment option to antibiotics in uncomplicated cases of UTI and thereby facilitates antibiotic stewardship.

Conflict of interest

BN and GK are employees of Bionorica SE; other authors declare no conflicts of interest.

Acknowledgments

We thank Philippe Lluel and Endre Mikus for their experimental expertise; and Marietta Kaszkin-Bettag and Sean O'Shea for help with editing.

This work was supported by Bionorica SE.

BN, GK, OW planned and designed experiments; AK, SP, HP, AR conducted experiments, collected and analyzed data; BN, GK prepared figures; BN, GK, OW drafted and all authors reviewed, revised and approved the manuscript.

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