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Biochemical Pharmacology Oct 2023Trypanosoma cruzi is the causative agent of Chagas' disease, an endemic and neglected disease. The treatment is limited to only two drugs, benznidazole (BZL) and...
Trypanosoma cruzi is the causative agent of Chagas' disease, an endemic and neglected disease. The treatment is limited to only two drugs, benznidazole (BZL) and nifurtimox (NFX), introduced more than fifty years ago and no new advances have been made since then. Nucleoside diphosphate kinases (NDPK) are key metabolic enzymes which have gained interest as drug targets of pathogen organisms. Taking advantage of the computer-assisted drug repurposing approaches, in the present work we initiate a search of potential T. cruzi nucleoside diphosphate kinase 1 (TcNDPK1) inhibitors over an ∼ 12,000 compound structures database to find drugs targeted to this enzyme with trypanocidal activity. Four medicines were selected and evaluated in vitro, ketorolac (KET, an anti-inflamatory), dutasteride (DUT, used to treat benign prostatic hyperplasia), nebivolol and telmisartan (NEB and TEL, used to treat high blood pressure). The four compounds were weak inhibitors and presented different trypanocidal effect on epimastigotes, trypomastigotes and intracellular stages. NEB and TEL were the most active drugs with increased effect on intracellular stages, (IC = 2.25 µM and 13.21 µM respectively), and selectivity indexes of 13.01 and 8.59 respectively, showing comparable effect to BZL, the first line drug for Chagas' disease treatment. In addition, both presented positive interactions when combined with BZL. Finally, transgenic epimastigotes with increased expression of TcNDPK1 were more resistant to TEL and NEB, suggesting that TcNDPK1 is at least one of the molecular targets. In view of the results, NEB and TEL could be repurposed medicines for Chagas' disease therapy.
PubMed: 37634596
DOI: 10.1016/j.bcp.2023.115766 -
International Journal of Molecular... Aug 2023Prostate-specific membrane antigen (PSMA)-based imaging improved the detection of primary, recurrent and metastatic prostate cancer. However, in certain patients, a low...
Prostate-specific membrane antigen (PSMA)-based imaging improved the detection of primary, recurrent and metastatic prostate cancer. However, in certain patients, a low PSMA surface expression can be a limitation for this promising diagnostic tool. Pharmacological induction of PSMA might be useful to further improve the detection rate of PSMA-based imaging. To achieve this, we tested dutasteride (Duta)-generally used for treatment of benign prostatic enlargement-and lovastatin (Lova)-a compound used to reduce blood lipid concentrations. We aimed to compare the individual effects of Duta and Lova on cell proliferation as well as PSMA expression. In addition, we tested if a combination treatment using lower concentrations of Duta and Lova can further induce PSMA expression. Our results show that a treatment with ≤1 μM Duta and ≥1 μM Lova lead to a significant upregulation of whole and cell surface PSMA expression in LNCaP, C4-2 and VCaP cells. Lower concentrations of Duta and Lova in combination (0.5 μM Duta + 0.5 μM Lova or 0.5 μM Duta + 1 μM Lova) were further capable of enhancing PSMA protein expression compared to a single compound treatment using higher concentrations in all tested cell lines (LNCaP, C4-2 and VCaP).
Topics: Male; Humans; Dutasteride; Prostate; Lovastatin; Glutamate Carboxypeptidase II; Antigens, Surface; Prostatic Neoplasms; Prostate-Specific Antigen; Cell Line, Tumor
PubMed: 37569712
DOI: 10.3390/ijms241512338 -
The Journal of Dermatological Treatment Dec 2023Mesotherapy is a technique by which lower doses of therapeutic agents and bioactive substances are administered by intradermal injections to the skin. Through... (Review)
Review
Mesotherapy is a technique by which lower doses of therapeutic agents and bioactive substances are administered by intradermal injections to the skin. Through intradermal injections, mesotherapy can increase the residence time of therapeutic agents in the affected area, thus allowing for the use of lower doses and longer intervals between sessions which may in turn improve the treatment outcome and patient compliance. This systematic review aims to summarize the current literature that evaluates the efficacy of this technique for the treatment of hair loss and provides an overview of the results observed. Of the 416 records identified, 27 articles met the inclusion criteria. To date, mesotherapy using 6 classes of agents and their combinations have been studied; this includes dutasteride, minoxidil, growth factors or autologous suspension, botulinum toxin A, stem cells, and mesh solutions/multivitamins. While several studies report statistically significant improvements in hair growth after treatment, there is currently a lack of standardized regimens. The emergence of adverse effects after mesotherapy has been reported. Further large-scale and controlled clinical trials are warranted to evaluate the utility of mesotherapy for hair loss disorders.
Topics: Humans; Mesotherapy; Alopecia; Minoxidil; Treatment Outcome; Injections, Intradermal
PubMed: 37558233
DOI: 10.1080/09546634.2023.2245084 -
CNS Drugs Aug 2023Premenstrual dysphoric disorder (PMDD) is characterized by the predictable onset of mood and physical symptoms secondary to gonadal steroid fluctuation during the luteal... (Review)
Review
Premenstrual dysphoric disorder (PMDD) is characterized by the predictable onset of mood and physical symptoms secondary to gonadal steroid fluctuation during the luteal phase of the menstrual cycle. Although menstrual-related affective dysfunction is responsible for considerable functional impairment and reduction in quality of life worldwide, currently approved treatments for PMDD are suboptimal in their effectiveness. Research over the past two decades has suggested that the interaction between allopregnanolone, a neurosteroid derivative of progesterone, and the gamma-aminobutyric acid (GABA) system represents an important relationship underlying symptom genesis in reproductive-related mood disorders, including PMDD. The objective of this narrative review is to discuss the plausible link between changes in GABAergic transmission secondary to the fluctuation of allopregnanolone during the luteal phase and mood impairment in susceptible individuals. As part of this discussion, we explore promising findings from early clinical trials of several compounds that stabilize allopregnanolone signaling during the luteal phase, including dutasteride, a 5-alpha reductase inhibitor; isoallopregnanolone, a GABA-A modulating steroid antagonist; and ulipristal acetate, a selective progesterone receptor modulator. We then reflect on the implications of these therapeutic advances, including how they may promote our knowledge of affective regulation more generally. We conclude that these and other studies of PMDD may yield critical insight into the etiopathogenesis of affective disorders, considering that (1) symptoms in PMDD have a predictable onset and offset, allowing for examination of affective state kinetics, and (2) GABAergic interventions in PMDD can be used to better understand the relationship between mood states, network regulation, and the balance between excitatory and inhibitory signaling in the brain.
Topics: Female; Humans; Premenstrual Dysphoric Disorder; Pregnanolone; Quality of Life; Menstrual Cycle; Luteal Phase; GABA Modulators; gamma-Aminobutyric Acid; Premenstrual Syndrome
PubMed: 37542704
DOI: 10.1007/s40263-023-01030-7 -
Dermatology and Therapy Aug 2023Finasteride and dutasteride are 5-alpha reductase selective inhibitors (5ARIs). They were introduced as therapeutic agents for the treatment of benign prostatic... (Review)
Review
Finasteride and dutasteride are 5-alpha reductase selective inhibitors (5ARIs). They were introduced as therapeutic agents for the treatment of benign prostatic hyperplasia in 1992 and 2002, respectively; finasteride has also been approved for the treatment of androgenetic alopecia since early 2000. These agents inhibit the conversion of testosterone (T) to 5α-dihydrotestosterone (5α-DHT), limiting steroidogenesis and playing a crucial role in the physiological function of the neuroendocrine system. Therefore, it has been proposed that blocking androgen synthesis with the use of 5ARIs would be beneficial in the treatment of various diseases related to states of hyperandrogenism. This review describes the dermatological pathologies in which 5ARIs have been used as part of the treatment, evaluation of the efficacy, and knowledge of the safety profile. Specifically, we discuss the application of 5ARIs in androgenetic alopecia, acne, frontal fibrosing alopecia, hirsutism, and the implications of adverse events associated with its use to inform about the applications of 5ARIs in general dermatology practice.
PubMed: 37432644
DOI: 10.1007/s13555-023-00974-4 -
The Lancet Regional Health. Europe Aug 2023Prostatic artery embolisation (PAE) is a minimally invasive treatment of symptomatic benign prostatic hyperplasia (BPH). Our aim was to compare patient's symptoms...
Prostatic artery embolisation versus medical treatment in patients with benign prostatic hyperplasia (PARTEM): a randomised, multicentre, open-label, phase 3, superiority trial.
BACKGROUND
Prostatic artery embolisation (PAE) is a minimally invasive treatment of symptomatic benign prostatic hyperplasia (BPH). Our aim was to compare patient's symptoms improvement after PAE and medical treatment.
METHODS
A randomised, open-label, superiority trial was set in 10 French hospitals. Patients with bothersome lower urinary tract symptoms (LUTS) defined by International Prostatic Symptom Score (IPSS) > 11 and quality of life (QoL) > 3, and BPH ≥50 ml resistant to alpha-blocker monotherapy were randomly assigned (1:1) to PAE or Combined Therapy ([CT], oral dutasteride 0.5 mg/tamsulosin hydrochloride 0.4 mg per day). Randomisation was stratified by centre, IPSS and prostate volume with a minimisation procedure. The primary outcome was the 9-month IPSS change. Primary and safety analysis were done according to the intention-to-treat (ITT) principle among patients with an evaluable primary outcome. ClinicalTrials.gov Identifier: NCT02869971.
FINDINGS
Ninety patients were randomised from September 2016 to February 2020, and 44 and 43 patients assessed for primary endpoint in PAE and CT groups, respectively. The 9-month change of IPSS was -10.0 (95% confidence interval [CI]: -11.8 to -8.3) and -5.7 (95% CI: -7.5 to -3.8) in the PAE and CT groups, respectively. This reduction was significantly greater in the PAE group than in the CT group (-4.4 [95% CI: -6.9 to -1.9], p = 0.0008). The IIEF-15 score change was 8.2 (95% CI: 2.9-13.5) and -2.8 (95% CI: -8.4 to 2.8) in the PAE and CT groups, respectively. No treatment-related AE or hospitalisation was noticed. After 9 months, 5 and 18 patients had invasive prostate re-treatment in the PAE and CT group, respectively.
INTERPRETATION
In patients with BPH ≥50 ml and bothersome LUTS resistant to alpha-blocker monotherapy, PAE provides more urinary and sexual symptoms benefit than CT up to 24 months.
FUNDING
French Ministry of Health and a complementary grant from Merit Medical.
PubMed: 37415648
DOI: 10.1016/j.lanepe.2023.100672 -
JAAD International Sep 2023
PubMed: 37404245
DOI: 10.1016/j.jdin.2023.04.011 -
Dermatologic Surgery : Official... Sep 2023Mesotherapy, a technique of transdermal microinjections of specific preparations, is increasingly used in fields such as dermatology and specifically for alopecia...
BACKGROUND
Mesotherapy, a technique of transdermal microinjections of specific preparations, is increasingly used in fields such as dermatology and specifically for alopecia treatment. Its popularity stems from its ability to deliver drugs in a targeted manner while minimizing systemic side effects.
OBJECTIVE
To assess and review current knowledge regarding the use of mesotherapy to deliver alopecia medications and highlight future directions for research.
MATERIALS AND METHODS
The authors used research databases including PubMed and Google Scholar to identify current literature on mesotherapy and alopecia. The following search terms were used among other terms: "Mesotherapy" or "Intradermal" AND "Alopecia".
RESULTS
Recent studies are promising for the intradermal delivery of dutasteride and minoxidil in the treatment of androgenetic alopecia.
CONCLUSION
Although limitations exist with dutasteride and minoxidil therapies, further research regarding the preparation, delivery, and maintenance of these drugs is warranted as mesotherapy could establish this technique as a safe, effective, and viable treatment option for androgenetic alopecia.
Topics: Humans; Dutasteride; Minoxidil; Alopecia; Mesotherapy; Drug-Related Side Effects and Adverse Reactions; Treatment Outcome
PubMed: 37387642
DOI: 10.1097/DSS.0000000000003866 -
Journal of Cosmetic Dermatology Jan 2024Minoxidil and the 5-alpha reductase inhibitors (5-ARIs), specifically, dutasteride and finasteride, are usually used to treat pattern hair loss (PHL), but evidence on... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Minoxidil and the 5-alpha reductase inhibitors (5-ARIs), specifically, dutasteride and finasteride, are usually used to treat pattern hair loss (PHL), but evidence on the relative effectiveness of these drugs is far less for women than men.
AIMS
We performed an age-adjusted network meta-analysis (NMA) to determine the comparative efficacy of monotherapy with the three agents-in any dosage and administrative route-on PHL in adult women.
METHODS
The peer-reviewed literature was systematically reviewed to obtain data for our NMA. The outcome measure for our NMA was "change in total hair density." We referred to "regimen" as an "agent and its dosage;" our Bayesian NMA estimated regimens' surface under the cumulative ranking curve (SUCRA) values and pairwise relative effects.
RESULTS
Our NMA used data from 13 trials-across which the following 10 regimens were identified (in decreasing order of SUCRA): 5 mg/day finasteride for 24 weeks (SUCRA = 95.7%), 5% topical minoxidil solution twice daily for 24 weeks (SUCRA = 89.5%), 1 mg/day minoxidil for 24 weeks (SUCRA = 78.1%), 5% topical minoxidil foam 1 half capful/day for 24 weeks (SUCRA = 66.5%), 3% topical minoxidil solution 1 mL twice daily for 24 weeks (SUCRA = 45.1%), 2% topical minoxidil solution 1 mL twice daily for 24 weeks (SUCRA = 44.6%), 5% topical minoxidil solution 1 mL/day for 24 weeks (SUCRA = 41.7%), 0.25 mg/day minoxidil for 24 weeks (SUCRA = 35.5%), 1.25 mg/day finasteride for 24 weeks (SUCRA = 24.8%) and 1 mg/day finasteride for 24 weeks (SUCRA = 4.3%).
CONCLUSION
Our findings can improve clinical guidelines and help dermatologists manage female PHL more optimally with the available options.
Topics: Male; Adult; Female; Humans; Minoxidil; 5-alpha Reductase Inhibitors; Finasteride; Network Meta-Analysis; Bayes Theorem; Treatment Outcome; Alopecia
PubMed: 37386777
DOI: 10.1111/jocd.15910 -
Clinica Chimica Acta; International... Jul 2023Androgenetic alopecia (AGA) is treated by 5α-reductase inhibitors (5ARI) such as finasteride and dutasteride, which are widely used as therapeutic agents. However,...
BACKGROUND
Androgenetic alopecia (AGA) is treated by 5α-reductase inhibitors (5ARI) such as finasteride and dutasteride, which are widely used as therapeutic agents. However, their pharmacokinetics in target organs (scalp and hair follicles) have not yet been investigated.
PURPOSE
To confirm the effective action of finasteride and dutasteride in the hair follicle tissues, we developed a method to measure these concentrations in hair.
RESULTS
Compared to the non-detection (N.D.) group, the dihydrotestosterone (DHT) concentrations decreased significantly in both the finasteride and dutasteride groups. The dutasteride group showed significantly lower DHT concentrations among all groups.
CONCLUSIONS
Measurement of finasteride, dutasteride, and DHT concentrations in hair would aid in evaluating the drug pharmacokinetics and its therapeutic effects on AGA patients.
Topics: Humans; Finasteride; Dutasteride; Dihydrotestosterone; Alopecia; Hair
PubMed: 37385468
DOI: 10.1016/j.cca.2023.117456