Original ArticleThe standardized herbal combination BNO 2103 contained in Canephron® N alleviates inflammatory pain in experimental cystitis and prostatitis
Graphical abstract
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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