Treatment preferences of patients with erectile dysfunction: a systematic review of randomized controlled trials.

INTRODUCTION: Patients' treatment preferences (PTP) depend on the complex interaction of numerous patient- and treatment-related factors; their assessment can guide therapy and promote compliance of patients with erectile dysfunction (ED). We aimed to systematically describe the literature evaluating the treatment preferences of patients with ED, published in the last 25 years. EVIDENCE ACQUISITION: A comprehensive bibliographic search of multiple databases was conducted in June, 2023. The literature search was limited to the articles published since 1998. Articles were deemed eligible if they described male patients with ED (P) undergoing treatment for this condition (I) compared with other treatments, placebo or sham therapy (C), and reported PTP (O). Only randomized controlled trials (RCTs) and post-hoc analyses of RCTs were selected (S). The data were presented in a narrative fashion. The risk of bias (RoB) was evaluated using the RoB 2 tool and the Mulhall-Montorsi model. EVIDENCE SYNTHESIS: A total 14 RCTs evaluating 6,841 patients and 4 post-hoc analyses of RCTs were included. All RCTs were considered to be at high RoB. No validated tool was used to investigate PTP. Sildenafil was the most frequently evaluated ED treatment (9 RCTs). Sildenafil was chosen over placebo by 78-100% of subjects and over ICI in 70% of patients due to its easier route of administration. No significant difference in patient preference was recorded between Sildenafil tablets and orodispersible (53% vs. 47%, P>0.05). Tadalafil was preferred over Sildenafil by 66-73% of patients (P<0.05), mainly because it allowed an erection long after taking the drug (55-67%). Tadalafil as-needed was chosen over Tadalafil 3 times/week by 57-59% of the patients (P<0.05). CONCLUSIONS: The available RCTs support the preference of ED patients for Sildenafil over ICI, Tadalafil over Sildenafil, and Tadalafil as-needed over Tadalafil 3 times/week. However, these findings should be considered at high RoB.

Repurposing Lansoprazole and Posaconazole to treat leishmaniasis: Integration of in vitro testing, pharmacological corroboration, and mechanisms of action.

Leishmaniasis remains a serious public health problem in many tropical regions of the world. Among neglected tropical diseases, the mortality rate of leishmaniasis is second only to malaria. All currently approved therapeutics have toxic side effects and face rapidly increasing resistance. To identify existing drugs with antileishmanial activity and predict the mechanism of action, we designed a drug-discovery pipeline utilizing both in-silico and in-vitro methods. First, we screened compounds from the Selleckchem Bio-Active Compound Library containing ~1622 FDA-approved drugs and narrowed these down to 96 candidates based on data mining for possible anti-parasitic properties. Next, we completed preliminary in-vitro testing of compounds against Leishmania amastigotes and selected the most promising active compounds, Lansoprazole and Posaconazole. We identified possible Leishmania drug targets of Lansoprazole and Posaconazole using several available servers. Our in-silico screen identified likely Lansoprazole targets as the closely related calcium-transporting ATPases (LdBPK_352080.1, LdBPK_040010.1, and LdBPK_170660.1), and the Posaconazole target as lanosterol 14-alpha-demethylase (LdBPK_111100.1). Further validation showed LdBPK_352080.1 to be the most plausible target based on induced-fit docking followed by long (100ns) MD simulations to confirm the stability of the docked complexes. We present a likely ion channel-based mechanism of action of Lansoprazole against Leishmania calcium-transporting ATPases, which are essential for parasite metabolism and infectivity. The LdBPK_111100.1 interaction with Posaconazole is very similar to the known fungal orthologue. Herein, we present two novel anti-leishmanial agents, Posaconazole and Lansoprazole, already approved by the FDA for different indications and propose plausible mechanisms of action for their antileishmanial activity.

The emerging paradigm of calcium homeostasis as a new therapeutic target for protozoan parasites.

Calcium channels (CCs), a group of ubiquitously expressed membrane proteins, are involved in many pathophysiological processes of protozoan parasites. Our understanding of CCs in cell signaling, organelle function, cellular homeostasis, and cell cycle control has led to improved insights into their structure and functions. In this article, we discuss CCs characteristics of five major protozoan parasites Plasmodium, Leishmania, Toxoplasma, Trypanosoma, and Cryptosporidium. We provide a comprehensive review of current antiparasitic drugs and the potential of using CCs as new therapeutic targets. Interestingly, previous studies have demonstrated that human CC modulators can kill or sensitize parasites to antiparasitic drugs. Still, none of the parasite CCs, pumps, or transporters has been validated as drug targets. Information for this review draws from extensive data mining of genome sequences, chemical library screenings, and drug design studies. Parasitic resistance to currently approved therapeutics is a serious and emerging threat to both disease control and management efforts. In this article, we suggest that the disruption of calcium homeostasis may be an effective approach to develop new anti-parasite drug candidates and reduce parasite resistance.

Bisindolylmaleimide IX: A novel anti-SARS-CoV2 agent targeting viral main protease 3CLpro demonstrated by virtual screening pipeline and in-vitro validation assays.

SARS-CoV-2, the virus that causes COVID-19 consists of several enzymes with essential functions within its proteome. Here, we focused on repurposing approved and investigational drugs/compounds. We targeted seven proteins with enzymatic activities known to be essential at different stages of the viral cycle including PLpro, 3CLpro, RdRP, Helicase, ExoN, NendoU, and 2'-O-MT. For virtual screening, energy minimization of a crystal structure of the modeled protein was carried out using the Protein Preparation Wizard (Schrodinger LLC 2020-1). Following active site selection based on data mining and COACH predictions, we performed a high-throughput virtual screen of drugs and investigational molecules (n = 5903). The screening was performed against viral targets using three sequential docking modes (i.e., HTVS, SP, and XP). Virtual screening identified ∼290 potential inhibitors based on the criteria of energy, docking parameters, ligand, and binding site strain and score. Drugs specific to each target protein were further analyzed for binding free energy perturbation by molecular mechanics (prime MM-GBSA) and pruning the hits to the top 32 candidates. The top lead from each target pool was further subjected to molecular dynamics simulation using the Desmond module. The resulting top eight hits were tested for their SARS-CoV-2 anti-viral activity in-vitro. Among these, a known inhibitor of protein kinase C isoforms, Bisindolylmaleimide IX (BIM IX), was found to be a potent inhibitor of SARS-CoV-2. Further, target validation through enzymatic assays confirmed 3CLpro to be the target. This is the first study that has showcased BIM IX as a COVID-19 inhibitor thereby validating our pipeline.

Multistage antiplasmodial activity of hydroxyethylamine compounds, in vitro and in vivo evaluations.

Malaria, a global threat to the human population, remains a challenge partly due to the fast-growing drug-resistant strains of Plasmodium species. New therapeutics acting against the pathogenic asexual and sexual stages, including liver-stage malarial infection, have now attained more attention in achieving malaria eradication efforts. In this paper, two previously identified potent antiplasmodial hydroxyethylamine (HEA) compounds were investigated for their activity against the malaria parasite's multiple life stages. The compounds exhibited notable activity against the artemisinin-resistant strain of P. falciparum blood-stage culture with 50% inhibitory concentrations (IC50) in the low micromolar range. The compounds' cytotoxicity on HEK293, HepG2 and Huh-7 cells exhibited selective killing activity with IC50 values > 170 µM. The in vivo efficacy was studied in mice infected with P. berghei NK65, which showed a significant reduction in the blood parasite load. Notably, the compounds were active against liver-stage infection, mainly compound 1 with an IC50 value of 1.89 µM. Mice infected with P. berghei sporozoites treated with compound 1 at 50 mg kg-1 dose had markedly reduced liver stage infection. Moreover, both compounds prevented ookinete maturation and affected the developmental progression of gametocytes. Further, systematic in silico studies suggested both the compounds have a high affinity towards plasmepsin II with favorable pharmacological properties. Overall, the findings demonstrated that HEA and piperidine possessing compounds have immense potential in treating malarial infection by acting as multistage inhibitors.

Novel parallelized quadrupole/linear ion trap/Orbitrap tribrid mass spectrometer improving proteome coverage and peptide identification rates.

Proteome coverage and peptide identification rates have historically advanced in line with improvements to the detection limits and acquisition rate of the mass spectrometer. For a linear ion trap/Orbitrap hybrid, the acquisition rate has been limited primarily by the duration of the ion accumulation and analysis steps. It is shown here that the spectral acquisition rate can be significantly improved through extensive parallelization of the acquisition process using a novel mass spectrometer incorporating quadrupole, Orbitrap, and linear trap analyzers. Further, these improvements to the acquisition rate continue to enhance proteome coverage and general experimental throughput.

Artifacts in Fourier transform mass spectrometry.

Recent work on a new, higher sensitivity preamplifier design for Fourier transform ion cyclotron resonance mass spectrometry (FTICRMS) revealed a number of artifact peaks (spectral features) which do not contain useful chemical information. In order to determine the cause of these artifacts and eliminate them, these severely distorted spectra were compared with similarly distorted signal models. The source of several common signal processing artifacts was thereby determined and correlated to radio-frequency interference (RFI) noise and saturation of the amplifier and/or the digitizer. Under such conditions, the fast Fourier transform (FFT) generates spectral artifact peaks corresponding to harmonics and mixing frequencies of the real signal peaks and RFI frequencies. While this study was done using FTICRMS data, it is important to stress that these artifacts are inherent to the digitization and FFT process and thus are relevant to any FT-based MS instrument, including the orbitrap and FT ion trap.

The spontaneous loss of coherence catastrophe in Fourier transform ion cyclotron resonance mass spectrometry.

The spontaneous loss of coherence catastrophe (SLCC) is a frequently observed, yet poorly studied, space-charge related effect in Fourier-transform ion cyclotron resonance mass spectrometry (FTICR-MS). This manuscript presents an application of the filter diagonalization method (FDM) in the analysis of this phenomenon. The temporal frequency behavior reproduced by frequency shift analysis using the FDM shows the complex nature of the SLCC, which can be explained by a combination of factors occurring concurrently, governed by electrostatics and ion packet trajectories inside the ICR cell.

A low-noise, wideband preamplifier for a Fourier-transform ion cyclotron resonance mass spectrometer.

FTMS performance parameters such as limits of detection, dynamic range, sensitivity, and even mass accuracy and resolution can be greatly improved by enhancing its detection circuit. An extended investigation of significant design considerations for optimal signal-to-noise ratio in an FTMS detection circuit are presented. A low noise amplifier for an FTMS is developed based on the discussed design rules. The amplifier has a gain of approximately 3500 and a bandwidth of 10 kHz to 1 MHz corresponding to m/z range of 100 Da to 10 kDa (at 7 Tesla). The performance of the amplifier was tested on a MALDI-FTMS, and has demonstrated a 25-fold reduction in noise in a mass spectrum of C(60) compared with that of a commercial amplifier.

First signal on the cryogenic Fourier-transform ion cyclotron resonance mass spectrometer.

The construction and achievement of the first signal on a cryogenic Fourier-transform ion cyclotron resonance mass spectrometer (FTICR-MS) are reported here, demonstrating proof-of-concept of this new instrument design. Building the FTICR cell into the cold bore of a superconducting magnet provided advantages over conventional warm bore design. At 4.2 K, the vacuum system cryopumps itself, thus removing the requirement for a large bore to achieve the desired pumping speed for maintaining base pressure. Furthermore, because the bore diameter has been reduced, the amount of magnet wire needed to achieve high field and homogeneity was also reduced, greatly decreasing the cost/Tesla of the magnet. The current instrument implements an actively shielded 14-Tesla magnet of vertical design with an external matrix-assisted laser desorption/ionization (MALDI) source. The first signal was obtained by detecting the laser desorbed/ionized (LDI) C(60)(+*) ions, with the magnet at 7 Tesla, unshimmed, and the preamplifier mounted outside of the vacuum chamber at room temperature. A subsequent experiment done with the magnet at 14 Tesla and properly shimmed produced a C(60) spectrum showing approximately 350,000 resolving power at m/z approximately 720. Increased magnetic field strength improves many FTMS performance parameters simultaneously, particularly mass resolving power and accuracy.