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      Dihydroartemisinin attenuates benign prostatic hyperplasia in rats by inhibiting prostatic epithelial cell proliferation

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          Abstract

          Background

          Benign prostatic hyperplasia (BPH) is a common urological condition in aging men. While dihydroartemisinin (DHA) exhibits a wide range of pharmacological activities, to date, there have been no studies examining the effects of DHA on BPH.

          Methods

          An in vivo BPH model was constructed in rats via daily subcutaneous injection of testosterone propionate (TP) for 28 consecutive days. Rats were randomly distributed into four groups and treated as follows: (I) control; (II) TP treatment; (III) TP and finasteride treatment (positive control); and (IV) TP and DHA treatment. At the end of the experiment, rats were sacrificed and the prostate weight, prostate index, thickness of the epithelium, collagen deposition, serum dihydrotestosterone (DHT) levels, 5α-reductase 2 (5AR-2) expression, and proliferating cell nuclear antigen (PCNA) levels in the prostate were examined. Normal human prostatic epithelial RWPE-1 cells were used in in vitro experiments to further investigate the anti-proliferative effects of DHA.

          Results

          TP increased the prostate weight and prostate index in rats, and this effect was reduced with DHA treatment. In addition, DHA attenuated the morphological changes and collagen deposition in the prostate tissue induced by TP. Furthermore, DHA reduced the expression of PCNA, serum DHT, and prostatic 5AR-2 in rats with TP-induced BPH. In vitro analysis revealed that DHA significantly inhibited the proliferation of TP-treated RWPE-1 cells.

          Conclusions

          DHA significantly inhibited the development of BPH by suppressing serum DHT levels, prostatic 5AR-2 expression, and the proliferation of benign prostatic epithelial cells. Thus, DHA is a novel medicinal agent with potential therapeutic efficacy in the treatment of patients with BPH.

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          Benign prostatic hyperplasia.

          Dominique Dana Marie Thomas, Leanna Laor, Tania Hossack … (2016)
          Benign prostatic hyperplasia (BPH), which causes lower urinary tract symptoms (LUTS), is a common diagnosis among the ageing male population with increasing prevalence. Many risks factors, both modifiable and non-modifiable, can increase the risk of development and progression of BPH and LUTS. The symptoms can be obstructive (resulting in urinary hesitancy, weak stream, straining or prolonged voiding) or irritative (resulting in increased urinary frequency and urgency, nocturia, urge incontinence and reduced voiding volumes), or can affect the patient after micturition (for example, postvoid dribble or incomplete emptying). BPH occurs when both stromal and epithelial cells of the prostate in the transitional zone proliferate by processes that are thought to be influenced by inflammation and sex hormones, causing prostate enlargement. Patients with LUTS undergo several key diagnostic investigations before being diagnosed with BPH. Treatment options for men with BPH start at watchful waiting and progress through medical to surgical interventions. For the majority of patients, the starting point on the treatment pathway will be dictated by their symptoms and degree of bother.
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            Review of the clinical pharmacokinetics of artesunate and its active metabolite dihydroartemisinin following intravenous, intramuscular, oral or rectal administration

            Carrie A Morris, Stephan Duparc, Isabelle Borghini-Fuhrer … (2011)
            Artesunate (AS) is a clinically versatile artemisinin derivative utilized for the treatment of mild to severe malaria infection. Given the therapeutic significance of AS and the necessity of appropriate AS dosing, substantial research has been performed investigating the pharmacokinetics of AS and its active metabolite dihydroartemisinin (DHA). In this article, a comprehensive review is presented of AS clinical pharmacokinetics following administration of AS by the intravenous (IV), intramuscular (IM), oral or rectal routes. Intravenous AS is associated with high initial AS concentrations which subsequently decline rapidly, with typical AS half-life estimates of less than 15 minutes. AS clearance and volume estimates average 2 - 3 L/kg/hr and 0.1 - 0.3 L/kg, respectively. DHA concentrations peak within 25 minutes post-dose, and DHA is eliminated with a half-life of 30 - 60 minutes. DHA clearance and volume average between 0.5 - 1.5 L/kg/hr and 0.5 - 1.0 L/kg, respectively. Compared to IV administration, IM administration produces lower peaks, longer half-life values, and higher volumes of distribution for AS, as well as delayed peaks for DHA; other parameters are generally similar due to the high bioavailability, assessed by exposure to DHA, associated with IM AS administration (> 86%). Similarly high bioavailability of DHA (> 80%) is associated with oral administration. Following oral AS, peak AS concentrations (Cmax) are achieved within one hour, and AS is eliminated with a half-life of 20 - 45 minutes. DHA Cmax values are observed within two hours post-dose; DHA half-life values average 0.5 - 1.5 hours. AUC values reported for AS are often substantially lower than those reported for DHA following oral AS administration. Rectal AS administration yields pharmacokinetic results similar to those obtained from oral administration, with the exceptions of delayed AS Cmax and longer AS half-life. Drug interaction studies conducted with oral AS suggest that AS does not appreciably alter the pharmacokinetics of atovaquone/proguanil, chlorproguanil/dapsone, or sulphadoxine/pyrimethamine, and mefloquine and pyronaridine do not alter the pharmacokinetics of DHA. Finally, there is evidence suggesting that the pharmacokinetics of AS and/or DHA following AS administration may be altered by pregnancy and by acute malaria infection, but further investigation would be required to define those alterations precisely.
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              The role of chronic prostatic inflammation in the pathogenesis and progression of benign prostatic hyperplasia (BPH).

              Alberto Briganti, G Gandaglia, Andrea Salonia … (2013)
              Several different stimuli may induce chronic prostatic inflammation, which in turn would lead to tissue damage and continuous wound healing, thus contributing to prostatic enlargement. Patients with chronic inflammation and benign prostatic hyperplasia (BPH) have been shown to have larger prostate volumes, more severe lower urinary tract symptoms (LUTS) and a higher probability of acute urinary retention than their counterparts without inflammation. Chronic inflammation could be a predictor of poor response to BPH medical treatment. Thus, the ability to identify patients with chronic inflammation would be crucial to prevent BPH progression and develop target therapies. Although the histological examination of prostatic tissue remains the only available method to diagnose chronic inflammation, different parameters, such as prostatic calcifications, prostate volume, LUTS severity, storage and prostatitis-like symptoms, poor response to medical therapies and urinary biomarkers, have been shown to be correlated with chronic inflammation. The identification of patients with BPH and chronic inflammation might be crucial in order to develop target therapies to prevent BPH progression. In this context, clinical, imaging and laboratory parameters might be used alone or in combination to identify patients that harbour chronic prostatic inflammation. © 2013 BJU International.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Ann Transl Med
                Journal ID (iso-abbrev): Ann Transl Med
                Journal ID (publisher-id): ATM
                Title: Annals of Translational Medicine
                Publisher: AME Publishing Company
                ISSN (Print): 2305-5839
                ISSN (Electronic): 2305-5847
                Publication date (Print and electronic): August 2021
                Publication date (Print): August 2021
                Volume: 9
                Issue: 15
                Electronic Location Identifier: 1246
                Affiliations
                [1]deptDepartment of Urology, Xiangya Hospital , Central South University , Changsha, China
                Author notes

                Contributions: (I) Conception and design: B Zhang, Y He; (II) Administrative support: None; (III) Provision of study materials or patients: X Chen, Y He; (IV) Collection and assembly of data: B Zhang, Y He, G Yu, BS Li, KN Wang; (V) Data analysis and interpretation: B Zhang, Y He; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.

                Correspondence to: Yao He. Department of Urology, Xiangya Hospital, Central South University, Xiangya Road 88, Changsha 410008, China. Email: heyao1984@ 123456163.com .
                Article
                Publisher ID: atm-09-15-1246
                DOI: 10.21037/atm-21-3296
                PMC ID: 8421977
                PubMed ID: 34532383
                SO-VID: 2d9b807d-a9f0-4034-9016-deea925c42c7
                Copyright © 2021 Annals of Translational Medicine. All rights reserved.
                License:

                Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0.

                History
                Date received : 04 June 2021
                Date accepted : 23 July 2021
                Categories
                Subject: Original Article

                Keywords: benign prostatic hyperplasia (bph),testosterone propionate (tp),dihydroartemisinin (dha),proliferation
                Data availability:
                Keywords: benign prostatic hyperplasia (bph), testosterone propionate (tp), dihydroartemisinin (dha), proliferation

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