Current Pharmaceutical Design - Volume 27, Issue 23, 2021

Background: Reactive Oxygen Species (ROS) are required for intact spermatogenesis and sperm function, but excessive levels will cause oxidative stress, impairing sperms and sperm function due to membrane damage and DNA fragmentation. Objective: Theoretically, antioxidant supplementation may act as a protection system against free radicals. Since infertile males have higher levels of ROS, nutritional supplements are widely used for protecting sperms. In the recent review, the authors summarize the most recent data regarding the effect of antioxidant treatment and draw the attention of the limitations of antioxidant use in male infertility. Methods: The recent review gives an update of antioxidant treatment in male infertility. Results: Improvement of sperm parameters was reported in the majority of studies. Comparing different antioxidants versus placebo showed low certainty of evidence with a serious risk of bias, and there is a lack regarding certain doses, pregnancy rate, and live birth rate outcomes. Various clinical studies and randomized control trials reported negative outcomes. Conflicting findings lead the attention to the study of biochemical features of the oxidant vs. antioxidant equilibrium. Higher exposure to antioxidants will result in “reductive stress”, which has harmful effects on sperm function, moreover can negatively influence embryo development. Reductive stress is as dangerous as oxidative stress and may act as a cause of different human pathologies. Conclusion: An intact balance of oxidant and antioxidant systems is required for normal sperm function. No guideline exists for the antioxidant dose regimen and treatment duration. Overdosing can result in reductive stress, which is also harmful to fertility and can cause several diseases. Assessment of the pre-treatment redox status can be recommended before the administration of exogenous antioxidants.

Leydig and Sertoli cells are essential for the testicular homeostasis. Clinically, the testicular homeostasis is impaired in hypogonadal and subfertile men. Therapeutically, the selective oestrogen receptor modulator clomiphene citrate (CC) is frequently used to treat these patients. In men, the mechanism of action of CC has long been thought to be limited to inhibition of the retro-control by oestrogen on the pituitary gland. However, oestrogen receptors are also expressed in the testis. Therefore, we will explore in this review the systemic effects as well as its action on reproductive function. We will describe in particular the possible effects of CC on the secretory functions of Leydig and Sertoli cells and their implication on the testicular microenvironment. CC is a costeffective and relatively safe off-label treatment for young hypogonadal men actively trying for a child or subfertile men with low testosterone with a positive effect on sperm concentration. Nevertheless, its effects on the oestrogen receptors and other signalling pathways at the testicular level remain poorly investigated. Further research, including combined treatment, could allow improving sperm morphology and sperm motility which do not seem to be significantly enhanced by CC alone.

Tamoxifen is a selective oestrogen receptor modulator (SERM). SERMs act on oestrogen receptors to inhibit oestradiol mediated negative feedback on the hypothalamic-pituitary-gonadal (HPG) axis, thereby upregulating gonadotrophin secretion and release from the pituitary. Hence, Tamoxifen is used to upregulate activation of the HPG axis in the treatment of male-factor infertility. However, due to a lack of robust evidence, Tamoxifen has not been FDA approved for use in male-factor infertility and so its use is currently off-label. In this study, we performed a literature search of the OVID medline database and identified 37 studies describing the effects of tamoxifen which we then reviewed. Evidence suggests Tamoxifen effectively increases androgen levels and sperm concentrations in males with idiopathic oligozoospermia. Evidence for increased motility and pregnancy rates in these patients is less conclusive. Further randomised control trials are needed to elucidate the safety of Tamoxifen combination therapies and their efficacy in improving pregnancy rates.

Background: To date, no randomized and controlled study has demonstrated the effect of adjuvant medical therapy on testicular sperm production before the sperm retrieval procedures in men with non-obstructive azoospermia (NOA). Objectives: To present the available data on the administration of pharmaceutical agents prior to testicular sperm extraction (TESE) procedures in order to obtain better sperm retrieval results in men with NOA. Methods and Results: Various pharmaceutical agents were used empirically to induce spermatogenesis in the treatment of NOA. The rationale for adjuvant hormonal treatment has been to increase intratesticular testosterone levels with different dosages of gonadotropins, anti-estrogen agents, or aromatase inhibitors. Conclusion: Based on the published studies, in the presence of a normal range of peripheral serum total testosterone levels, no medical treatment is advised, and TESE procedures should be performed directly in men with NOA. Further well-designed and randomized, placebo-controlled trials are needed to support the potential benefit of pretreatment prior to TESE procedures.

The therapeutic range of cyclic nucleotide phosphodiesterase 5 inhibitors (PDE5) inhibitors is getting wider in the last years. This review study focuses on the potential employment of PDE5 inhibitors as an adjunct tool for the therapeutic management of male infertility. The literature tends to suggest a beneficial effect of PDE5 inhibitors on Leydig and Sertoli cells secretory function. It also appears that PDE5 inhibitors play a role in the regulation of the contractility of the testicular tunica albuginea and the epididymis. Moreover, scientific data suggest that PDE5 inhibitors enhance the prostatic secretory function leading to an improvement in sperm motility. Other studies additionally demonstrate the role of PDE5 inhibitors in the regulation of the sperm capacitation process. Placebo-controlled, randomized, blind studies are necessary to unambiguously incorporate PDE5 inhibitors as an adjunct tool for the pharmaceutical treatment of semen disorders and male infertility.

In heart failure (HF) patients, current European Society of Cardiology (ESC) guidelines recommend the use of three loop diuretics (furosemide, torasemide, bumetanide) in order to not only reduce HF hospitalizations but also improve symptoms and exercise capacity in patients with signs and/or symptoms of congestion. In addition, for the first time in hypertensive patients, European Society of Hypertension (ESH) guidelines recommend the use of torasemide. This review aimed to summarize the mode of action of loop diuretics, to present their pharmacokinetic characteristics, and to discuss their place in the management of arterial hypertension and heart failure, with special emphasis however on torasemide.

Background: Long non-coding RNAs (lncRNA) have been identified as novel molecular regulators in cancers. LncRNA ADAMTS9-AS2 can mediate the occurrence and development of cancer through various ways, such as regulating miRNAs, activating the classical signaling pathways in cancer, and so on, which have been studied by many scholars. In this review, we summarize the molecular mechanisms of ADAMTS9-AS2 in different human cancers. Methods: Through a systematic search of PubMed, lncRNA ADAMTS9-AS2 mediated molecular mechanisms in cancer are summarized inductively. Results: ADAMTS9-AS2 aberrantly expression in different cancers is closely related to cancer proliferation, invasion, migration, and inhibition of apoptosis. The involvement of ADAMTS9-AS2 in DNA methylation, mediating PI3K / Akt / mTOR signaling pathways, and regulating miRNAs and proteins, shows its significant potential as a therapeutic cancer target. Conclusion: LncRNA ADAMTS9-AS2 can become a promising biomolecular marker and a therapeutic target for human cancer.

Drug-drug interactions may occur when combining two or more drugs may cause some adverse events such as cardiotoxicity, central neurotoxicity, hepatotoxicity, etc. However, a large number of researchers who are proficient in pharmacokinetics and pharmacodynamics have been engaged in drug assays and trying to find out the side effects of all kinds of drug combinations. However, at the same time, the number of new drugs is increasing dramatically, and the drug assay is an expensive and time-consuming process. It is impossible to find all the adverse reactions through drug experiments. Therefore, new attempts have been made in using computational techniques to deal with this problem. In this review, we conduct a review of the literature on applying the computational method for predicting drug-drug interactions. We first briefly introduce the widely used data sets. After that, we elaborate on the existing state-of-art deep learning models for drug-drug interactions prediction. We also discussed the challenges and opportunities of applying the computational method in drug-drug interactions prediction.

Background and Aims: Alcohol use disorders (AUD) are among the most prevalent mental disorders around the world, yet still remain the most undertreated. Many studies report the low rate of treatment uptake, less than 20%, among people with AUD. Among those accessing care, a large majority only approach their GP for help. Therefore, primary care is a strategic setting for the identification and the management of AUD. International recommendations stress AUD pharmacotherapy for withdrawal and craving management, but very few studies have shown interest in the management of AUDs in primary care. The main objective of this study was to analyse pharmacotherapy in AUD management in primary care by means of a systematic literature review. Methods: A systematic literature review (PRISMA) was carried out. 5 databases were screened: PUBMED via MEDLINE, LiSSa, the SUDOC catalogue, PASCAL and EMBASE. Search algorithms were used integrating the concepts of pharmacotherapy management, alcohol use disorders and primary care, only in the English language. Results: 296 studies were selected and 10 were included. One was a follow-up study on the national prescription database, while four were cross-sectional studies with an auto-questionnaire survey. Of the 10 studies included, two were conducted in Europe, five in North America, two in Australia and one in South Africa. These pharmacotherapy studies were concerned with the anti-craving treatment, and 3 types of medications were used: Disulfiram, Acamprosate and Naltrexone. Factors identified as limiting or facilitating prescriptions concerned cost, indications, efficacy, training and adjuncts to pharmacotherapy. Conclusion: Knowledge and prescription of pharmacotherapy for AUD, more specifically, anti-craving treatment, is insufficient in primary care. There is a lack of data and studies on the efficacy of anti-craving treatment in primary care. Guidelines for AUD management, including psychological and medical management and pharmacotherapy, do exist but have not been adapted to primary care practice. Barriers and facilitators of pharmacotherapy prescription in AUD in primary care were identified in this study.