Nocturia is a very inconvinient lower urinary tract symptom. Nocturia is hard to cure clinically because the cause is multifactorial and is associated with disturbance of day–night differences in urine production and bladder capacity [1]. The objective of our study was to evaluate the efficacy of a mixture of nobiletin and tangeretin (NoT) in the treatment of nocturia and to confirm the safety of NoT in older adults. NoT are flavonoids, which are a class of polyphenol derived from the peel of Citrus depressa, a type of lemon that is native to Okinawa in Japan and is also found in Taiwan. There is emerging evidence that NoT modulate the circadian rhythm [2]. Therfore, we conducted a randomized clinical trial to investigate the efficacy of NoT in treating nocturia.

This randomized, placebo-controlled, double-blind, two-sequence two-period crossover study included 40 patients with nocturia (Figure 1). Both men and women aged ≥50 years with nocturia were recruited, and each patient was confirmed to have a nighttime frequency ≥2 voids on a frequency volume chart (FVC). Included patients had an Eastern Cooperative Oncology Group performance status of 0-2 and were required to undergo regular checkups at our hospital. Patients were excluded if they had (1) global polyuria ≥40 ml/kg/24h, (2) postvoid residual ≥200 ml, (3) severe benign prostatic hyperplasia, overactive bladder, neurogenic bladder, or conditions considered unsuitable for inclusion in this study. Patients were allocated to AP (sequence 1, S1) or PA (sequence 2, S2) in a double-blind manner with stratified block randomization (A=active, NoT, P=placebo). Patients allocated to S1 group were orally administered a mixture of 50 mg of NoT (including 30 mg nobiletin + 15 mg tangeretin) once daily after dinner for 6 weeks. After a washout period of more than 2 weeks, the placebo was orally administered once daily after dinner for 6 weeks. The order of the NoT mixture and the placebo were reversed for the S2 group.

The primary endpoint was the change in nocturnal functional bladder capacity measured by the FVC. Secondary endpoints included: (1) change in the International Prostate Symptom Score (IPSS), (2) sleep quality measured with the Pittsburgh Sleep Quality Index (PSQI), (3) changes in items on the FVC (nighttime frequency, 24-hour urine volume, nocturnal polyuria index).

Data were presented as the mean ± standard deviation and statistical significance was determined by a paired t-test. Assuming a difference in mean bladder capacity change between the two groups of 20 and a standard deviation of 20, 16 patients were required for each group, based on a power of 80% to detect a significant difference at a two-sided level of 5%. A total of 40 patients were planned to be recruited to allow for dropouts.

A total of 40 patients (27 men and 13 women) with a mean age of 73.5 years were randomized (Table 1A) and 36 patients were completed the trial while 4 patients withdrew. The reasons for withdrawal were admission into a diabetes mellitus (DM) educational program, urinary tract infection, cancer of unknown primary, and poor drug compliance. No adverse events directly related to this study were observed.

The primary endpoint measure, mean changes in nocturnal bladder capacity were 6.2±38.6 ml on NoT and 0.5±47.9 ml on the placebo (difference: 5.7 ml, P=0.61, not significant) (Table 1B). The secondary endpoints for FVC variables revealed that the mean change in nighttime frequency on NoT significantly decreased compared with that on placebo. The mean changes were −0.49±0.86 times on NoT and 0.01±0.82 times on placebo (difference: −0.50 times, P=0.040). Other secondary endpoints did not differ significantly between NoT and placebo. The changes in the nocturnal polyuria index were −2.8±8.1% on NoT and −0.2±11.6% on the placebo (difference: −2.6%, P=0.30, not significant). However, the change in the nocturnal polyuria index from baseline to the end of NoT administration significantly decreased from 42.7% to 39.9% (before–after difference: −2.8%, P=0.048).

In patients with nocturia, NoT did not result in a significant change in the nocturnal bladder capacity compared with placebo. In contrast, NoT resulted in a significant decrease in the nighttime frequency. NoT appeared to influence the nighttime frequency by decreasing the nocturnal polyuria index. Further research is needed to elucidate the mechanism of action. 

To our knowledge, this is the first study to show that NoT are effective for older adults (mean age 73.5 years) with nocturia. In addition, the present study is the first randomized, placebo-controlled, double-blind trial of NoT for nocturia patients as far as we know. Although the sample size was small, we believe that this randomized design provides a high level of evidence.

The present study demonstrated that NoT were well tolerated and resulted in a mild but significant improvement in the nighttime frequency of older adults with nocturia. The results suggest that NoT warrant further investigation in larger trials over longer periods of time.

Negoro H, Kanematsu A, Yoshimura K, Ogawa O. Chronobiology of micturition: putative role of the circadian clock, J Urol. 19(2013) 843-84https://doi.org/10.1016/j.juro.2013.02.024.
Mileykovskaya E, Yoo SH, Dowhan W, Chen Z, Nobiletin: Targeting the Circadian Network to Promote Bioenergetics and Healthy Aging, Biochemistry (Mosc). 8(2020) 1554-155https://doi.org/10.1134/S000629792012007X.

Continence 2S2 (2022) 100327
DOI: 10.1016/j.cont.2022.100327