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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 -
Journal of Cosmetic Dermatology May 2024The evidence base pertaining to the efficacy of monotherapies for androgenetic alopecia (AGA), the most common form of hair loss, is ever expanding-and this warrants a...
BACKGROUND
The evidence base pertaining to the efficacy of monotherapies for androgenetic alopecia (AGA), the most common form of hair loss, is ever expanding-and this warrants a formal comparison therapies' effect on a frequent basis.
AIMS
The objective of the current study was to determine the comparative effect of relevant monotherapies for male AGA.
PATIENTS/METHODS
Our aim was achieved by conducting Bayesian network meta-analysis (NMA), under a random effects model, for two outcomes: 6-month change in (1) total and (2) terminal hair density in adult (i.e., aged 18 years and above) men with AGA; these analyses were preceded by a systematic search of the peer-reviewed literature for suitable data. Interventions' surface under the cumulative ranking curve (SUCRA) and pairwise relative effects (quantified as mean differences) were estimated through the NMAs.
RESULTS
We determined the comparative effect of 20 active comparators and a control (i.e., placebo/vehicle). "Dutasteride 0.5 mg once daily for 24 weeks" was ranked the most effective in terms of 6-month change in (1) total hair density (SUCRA = 87%) and terminal hair density (SUCRA = 98%). Our results showed that interventions' effectiveness can be dose dependent.
CONCLUSIONS
Our updated analyses of the up-to-date evidence regarding monotherapies for male AGA showed that the oral form of 5-alpha reductase inhibitors are more effective than oral minoxidil and other newer agents like Botox, microneedling, and photobiomodulation. Our findings can better inform clinical decision making and design of future research studies.
PubMed: 38725143
DOI: 10.1111/jocd.16362 -
The World Journal of Men's Health May 2024Finasteride and dutasteride are used to treat benign prostatic hyperplasia (BPH) and reduce the risk of developing prostate cancer. Finasteride blocks only the type 2...
PURPOSE
Finasteride and dutasteride are used to treat benign prostatic hyperplasia (BPH) and reduce the risk of developing prostate cancer. Finasteride blocks only the type 2 form of 5-alpha-reductase, whereas dutasteride blocks both type 1 and 2 forms of the enzyme. Previous studies suggest the possibility that dutasteride may be superior to finasteride in preventing prostate cancer. We directly compared the effects of finasteride and dutasteride on the risk of prostate cancer in patients with BPH using a pooled analysis of 15 real-world databases.
MATERIALS AND METHODS
We conducted a multicenter, cohort study of new-users of finasteride and dutasteride. We include patients who were prescribed 5 mg finasteride or dutasteride for the first time to treat BPH and had at least 180 days of prescription. We excluded patients with a history of prostate cancer or a prostate-specific antigen level ≥ 4 ng/mL before the study drug prescription. Cox regression analysis was performed to examine the hazard ratio (HR) for prostate cancer after propensity score (PS) matching.
RESULTS
A total of 8,284 patients of new-users of finasteride and 8,670 patients of new-users of dutasteride were included across the 15 databases. In the overall population, compared to dutasteride, finasteride was associated with a lower risk of prostate cancer in both on-treatment and intent-to-treat time-at-risk periods. After 1:1 PS matching, 4,897 patients using finasteride and 4,897 patients using dutasteride were enrolled in the present study. No significant differences were observed for risk of prostate cancer between finasteride and dutasteride both on-treatment (HR=0.66, 95% confidence interval [CI]: 0.44-1.00; p=0.051) and intent-to-treat time-at-risk periods (HR=0.87, 95% CI: 0.67-1.14; p=0.310).
CONCLUSIONS
Using real-world databases, the present study demonstrated that dutasteride was not associated with a lower risk of prostate cancer than finasteride in patients with BPH.
PubMed: 38772542
DOI: 10.5534/wjmh.230327 -
Journal of Clinical PsychopharmacologyPrior studies indicate that neuroactive steroids mediate some of alcohol's effects. Dutasteride, widely used to treat benign prostatic hypertrophy, is an inhibitor of... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Prior studies indicate that neuroactive steroids mediate some of alcohol's effects. Dutasteride, widely used to treat benign prostatic hypertrophy, is an inhibitor of 5-alpha reductase enzymes, which play a central role in the production of 5α-reduced neuroactive steroids. The purpose of this study was to test dutasteride's tolerability and efficacy for reducing drinking.
METHODS
Men (n = 142) with heavy drinking (>24 drinks per week) and a goal to either stop or reduce drinking to nonhazardous levels were randomized to placebo or 1 mg dutasteride daily for 12 weeks. We hypothesized that dutasteride-treated patients would be more successful in reducing drinking.
RESULTS
Generalized linear mixed models that included baseline drinking, treatment, time and their 2-way interaction identified significant interactions of treatment-time, such that dutasteride treatment reduced drinking more than placebo. During the last month of treatment, 25% of dutasteride-treated participants had no hazardous drinking (no heavy drinking days and not more than 14 drinks per week) compared with 6% of placebo-treated participants (P = 0.006; NNT = 6). Sensitivity analysis identified baseline drinking to cope as a factor associated with larger reductions in drinking for dutasteride compared with placebo-treated participants. Dutasteride was well tolerated. Adverse events more common in the dutasteride group were stomach discomfort and reduced libido.
CONCLUSION
Dutasteride 1 mg daily was efficacious in reducing the number of heavy drinking days and drinks per week in treatment-seeking men. The benefit of dutasteride compared with placebo was greatest for participants with elevated baseline drinking to cope motives.
Topics: Humans; Dutasteride; Male; 5-alpha Reductase Inhibitors; Middle Aged; Alcohol Drinking; Adult; Double-Blind Method; Treatment Outcome; Aged; Azasteroids
PubMed: 38684046
DOI: 10.1097/JCP.0000000000001849 -
Medicina (Kaunas, Lithuania) Sep 2023: Androgenetic alopecia (AGA) and alopecia areata (AA) are the most common types of non-cicatricial alopecia. Both diseases have limited effective therapeutic options...
: Androgenetic alopecia (AGA) and alopecia areata (AA) are the most common types of non-cicatricial alopecia. Both diseases have limited effective therapeutic options and affect patient quality of life. Pharmacogenetic tests can help predict the most appropriate treatment option by evaluating the single nucleotide polymorphisms (SNPs) corresponding to genes related to alopecia. The objective of the study was to evaluate and compare selected SNPs and genes in AA and AGA patients from Romania and Brazil. : We performed a retrospective study regarding the associations between AA and AGA and 45 tag SNPs of 15 genes in 287 Romanian and 882 Brazilian patients. The DNA samples were collected from oral mucosa using a swab. The SNPs were determined by the qPCR technique. Each genetic test displays the subject's genotype of the selected gene and the prediction of a successful treatment (e.g., genotype AA of the GR-alpha gene is related to a predisposition to normal sensibility to topical glucocorticoid, and, therefore, glucocorticoids should be effective). : The , , , and genes were statistically significantly different in Brazil compared to Romania. The activity that predicts the response to minoxidil treatment showed in our analysis that minoxidil is recommended in half of the cases of AGA and AA. Patients with AGA and a high expression of or -2 may benefit from Dutasteride or Latanoprost treatment, respectively. Most of the studied genes showed no differences between the two populations. : The DNA analysis of the patients with alopecia may contribute to a successful treatment.
PubMed: 37763773
DOI: 10.3390/medicina59091654 -
Urology Aug 2023Testosterone and dihydrotestosterone are significant drivers of male external genital development, and therefore teratogens that alter these hormone profiles have been...
Testosterone and dihydrotestosterone are significant drivers of male external genital development, and therefore teratogens that alter these hormone profiles have been hypothesized to cause aberrations in development. Here, we present the first case report of genitalia anomalies after prenatal exposure to spironolactone and dutasteride through 8-weeks of gestation. The patient was born with abnormal male external genitalia which was surgically managed. Long-term outcomes such as gender identity, sexual function, hormonal maturation through puberty, and fertility remain unknown. These numerous considerations necessitate multi-disciplinary management with close follow-up to address sexual, psychological, and anatomic concerns.
Topics: Pregnancy; Humans; Male; Female; Cholestenone 5 alpha-Reductase; Gender Identity; 3-Oxo-5-alpha-Steroid 4-Dehydrogenase; Testosterone; Dihydrotestosterone; Disorders of Sex Development
PubMed: 37178876
DOI: 10.1016/j.urology.2023.05.001 -
Journal of Cosmetic Dermatology Jun 2024Oral finasteride and topical minoxidil formulations are the only FDA-approved drug therapies for androgenetic alopecia (AGA). Research into dutasteride, topical...
BACKGROUND
Oral finasteride and topical minoxidil formulations are the only FDA-approved drug therapies for androgenetic alopecia (AGA). Research into dutasteride, topical finasteride, and nontopical minoxidil (low-dose oral and sublingual) formulations in the treatment of AGA has spiked within recent years. Early findings show that these alternative drug therapies may have similar to improved efficacy and safety profiles relative to the conventional treatment options.
AIMS
Conducting a bibliometric analysis, compare trends in publications on these alternative drug therapies, identify key contributors, evaluate major findings from top-cited articles, and elucidate gaps in evidence.
METHODS
A search was conducted on the Web of Science database for publications on the use of alternative drug therapies in the treatment of AGA. A total of 95 publications, published between January 2003-March 2024, and their citation metadata were included in the analysis.
RESULTS
Dutasteride showed the greatest (n = 37) and longest (20+ years) history of publications, as well as the highest cumulative citations (n = 914); however, nontopical minoxidil showed a burst in research activity within the last 5 years (n = 33 publications since 2019). A relatively low number of randomized control trials (n = 3) for nontopical minoxidil suggests a need for higher-quality evidence.
CONCLUSIONS
Our analysis reveals major trends, contributors, and gaps in evidence for alternative drug therapies for AGA, which can help inform researchers on their future projects in this growing field of study. There is enthusiasm for exploring off-label formulations: nontopical forms of minoxidil (oral and sublingual), topical finasteride, and mesotherapy.
PubMed: 38873787
DOI: 10.1111/jocd.16427 -
International Journal of Pharmaceutical... 2024Alopecia is a chronic dermatological disorder affecting men and women worldwide. Given the high incidence and significant impact on patients' well-being, options for...
BACKGROUND
Alopecia is a chronic dermatological disorder affecting men and women worldwide. Given the high incidence and significant impact on patients' well-being, options for managing and treating alopecia are essential. Topical available options remain limited and oral products may result in adverse effects. TrichoFoam™ is a ready-to-use foaming vehicle developed for compounding pharmacies and formulated with gentle, non-irritating, and sensory-pleasant ingredients.
OBJECTIVE
The purpose of this study was to assess topical foams' physicochemical and microbiological stabilities of formulations compounded with TrichoFoam™ as the ready-touse vehicle.
METHODS
HPLC analyses were conducted in a bracketed study covering concentrations of 0.1% to 2.0% of caffeine, 0.01% to 0.1% of clobetasol propionate, 0.1% to 0.25% of dutasteride, 0.25% to 0.50% of nicotinamide, and 0.25% to 2.5% of progesterone compounded with TrichoFoam™. Antimicrobial Effectiveness Testing was conducted at the beginning and end of the studies.
RESULTS
Most formulations presented a beyond-use date of at least 90-180 days, except for clobetasol propionate, which showed compatibility for 14 days, and dutasteride 0.25%, which showed a BUD of 30 days.
CONCLUSION
This validates the stability of the active pharmaceutical ingredients from different pharmacological classes with TrichoFoam™, suggesting that this ready-to-use vehicle can be an excellent alternative for personalized alopecia treatment.
Topics: Male; Humans; Female; Clobetasol; Anti-Inflammatory Agents; Dutasteride; Progesterone; Caffeine; Administration, Topical; Hair; Alopecia
PubMed: 38604144
DOI: No ID Found -
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 -
Journal of the American Academy of... Jul 2024
Topics: Humans; 5-alpha Reductase Inhibitors; Alopecia; Retrospective Studies; Male; Propensity Score; Adult; Middle Aged; Female; Sexual Dysfunction, Physiological; Finasteride; Dutasteride
PubMed: 38552905
DOI: 10.1016/j.jaad.2024.03.019