RNA Polymerase Inhibitor Enisamium for Treatment of Moderate COVID-19 Patients: A Randomized, Placebo-Controlled, Multicenter, Double-Blind Phase 3 Clinical Trial.

Enisamium is an orally available therapeutic that inhibits influenza A virus and SARS-CoV-2 replication. We evaluated the clinical efficacy of enisamium treatment combined with standard care in adult, hospitalized patients with moderate COVID-19 requiring external oxygen. Hospitalized patients with laboratory-confirmed SARS-CoV-2 infection were randomly assigned to receive either enisamium (500 mg per dose, four times a day) or a placebo.

Male Reproduction in Spinal Muscular Atrophy (SMA) and the Potential Impact of Oral Survival of Motor Neuron 2 (SMN2) Pre-mRNA Splicing Modifiers.

Spinal muscular atrophy (SMA) is a neuromuscular disease caused by deletions or mutations in the survival of motor neuron 1 (SMN1) gene resulting in reduced levels of SMN protein. SMN protein is produced by cells throughout the body, and evidence suggests that low SMN protein can have systemic implications, including in male reproductive organs. However, a paucity of research exists on this important topic.

Luciferase Expressing Preclinical Model Systems Representing the Different Molecular Subtypes of Colorectal Cancer.

Colorectal cancer (CRC) is a heterogeneous disease. More insight into the biological diversity of CRC is needed to improve therapeutic outcomes. Established CRC cell lines are frequently used and were shown to be representative models of the main subtypes of CRC at the genomic and transcriptomic level.

Differential CMS-Related Expression of Cell Surface Carbonic Anhydrases IX and XII in Colorectal Cancer Models-Implications for Therapy.

Tumor-associated carbonic anhydrases IX (CAIX) and XII (CAXII) have long been in the spotlight as potential new targets for anti-cancer therapy. Recently, CAIX/CAXII specific inhibitor SLC-0111 has passed clinical phase I study and showed differential response among patients with colorectal cancer (CRC). CRC can be classified into four different consensus molecular subgroups (CMS) showing unique expression patterns and molecular traits.

Reproductive findings in male animals exposed to selective survival of motor neuron 2 (SMN2) gene splicing-modifying agents.

Risdiplam is a daily, orally dosed, survival of motor neuron 2 (SMN2) mRNA splicing-modifying agent approved for the treatment of spinal muscular atrophy (SMA). RG7800 is a closely related SMN2 mRNA-splicing compound. Effects on secondary mRNA splice targets such as Forkhead Box M1 (FOXM1) and MAP kinase-activating death domain protein (MADD), which have been implicated in cell-cycle regulation, were observed in non-clinical studies with both risdiplam and RG7800.

Addressing Today's Absorption, Distribution, Metabolism, and Excretion (ADME) Challenges in the Translation of In Vitro ADME Characteristics to Humans: A Case Study of the mRNA Splicing Modifier Risdiplam.

Small molecules that present complex absorption, distribution, metabolism, and elimination (ADME) properties can be challenging to investigate as potential therapeutics. Acquiring data through standard methods can yield results that are insufficient to describe the in vivo situation, which can affect downstream development decisions. Implementing in vitro-in vivo-in silico strategies throughout the drug development process is effective in identifying and mitigating risks while speeding up their development.

Enisamium is an inhibitor of the SARS-CoV-2 RNA polymerase and shows improvement of recovery in COVID-19 patients in an interim analysis of a clinical trial.

Pandemic SARS-CoV-2 causes a mild to severe respiratory disease called Coronavirus Disease 2019 (COVID-19). Control of SARS-CoV-2 spread will depend on vaccine-induced or naturally acquired protective herd immunity. Until then, antiviral strategies are needed to manage COVID-19, but approved antiviral treatments, such as remdesivir, can only be delivered intravenously.

Risdiplam treatment has not led to retinal toxicity in patients with spinal muscular atrophy.

Objective: Evaluation of ophthalmologic safety with focus on retinal safety in patients with spinal muscular atrophy (SMA) treated with risdiplam (EVRYSDI®), a survival of motor neuron 2 splicing modifier associated with retinal toxicity in monkeys. Risdiplam was approved recently for the treatment of patients with SMA, aged ≥ 2 months in the United States, and is currently under Health Authority review in the EU.

Methods: Subjects included patients with SMA aged 2 months-60 years enrolled in the FIREFISH, SUNFISH, and JEWELFISH clinical trials for risdiplam.

Rewriting the (tran)script: Application to spinal muscular atrophy.

Targeting RNA drastically expands our target space to therapeutically modulate numerous cellular processes implicated in human diseases. Of particular interest, drugging pre-mRNA splicing appears a very viable strategy; to control levels of splicing product by promoting the inclusion or exclusion of exons. After describing the concept of "splicing modulation", this chapter will cover the outstanding progress achieved in this field, by highlighting the breakthrough accomplished recently for the treatment of spinal muscular atrophy using two therapeutic modalities: splice switching oligonucleotides and small molecules.

Risdiplam distributes and increases SMN protein in both the central nervous system and peripheral organs.

Spinal muscular atrophy (SMA) is a rare, inherited neuromuscular disease caused by deletion and/or mutation of the Survival of Motor Neuron 1 ( gene. A second gene, , produces low levels of functional SMN protein that are insufficient to fully compensate for the lack of . Risdiplam (RG7916; RO7034067) is an orally administered, small-molecule pre-mRNA splicing modifier that distributes into the central nervous system (CNS) and peripheral tissues.

Discovery of Risdiplam, a Selective Survival of Motor Neuron-2 ( SMN2) Gene Splicing Modifier for the Treatment of Spinal Muscular Atrophy (SMA).

SMA is an inherited disease that leads to loss of motor function and ambulation and a reduced life expectancy. We have been working to develop orally administrated, systemically distributed small molecules to increase levels of functional SMN protein. Compound 2 was the first SMN2 splicing modifier tested in clinical trials in healthy volunteers and SMA patients.

In Vitro Bioavailability Study of an Antiviral Compound Enisamium Iodide.

An investigation into the biopharmaceutics classification and a study of the in vitro bioavailability (permeability and solubility) of the antiviral compound enisamium iodide (4-(benzylcarbamoyl)-1-methylpyridinium iodide) were carried out. The solubility of enisamium iodide was determined in four different buffers. Apparent intestinal permeability () of enisamium iodide was assessed using human colon carcinoma (Caco-2) cells at three concentrations.

Radiostereometric migration measurement of an uncemented Cerafit® femoral stem: 26 patients followed for 10 years.

Radiostereometric analysis (RSA) is the gold standard for evaluating micromotions of orthopaedic implants. The method is applied for identifying novel design weaknesses in endoprostheses. Current research frequently assesses relatively short time periods.

Specific Correction of Alternative Survival Motor Neuron 2 Splicing by Small Molecules: Discovery of a Potential Novel Medicine To Treat Spinal Muscular Atrophy.

Spinal muscular atrophy (SMA) is the leading genetic cause of infant and toddler mortality, and there is currently no approved therapy available. SMA is caused by mutation or deletion of the survival motor neuron 1 (SMN1) gene. These mutations or deletions result in low levels of functional SMN protein.

Analysis of direct clinical consequences of MLC positional errors in volumetric-modulated arc therapy using 3D dosimetry system.

In advanced, intensity-modulated external radiotherapy facility, the multileaf collimator has a decisive role in the beam modulation by creating multiple segments or dynamically varying field shapes to deliver a uniform dose distribution to the target with maximum sparing of normal tissues. The position of each MLC leaf has become more critical for intensity-modulated delivery (step-and-shoot IMRT, dynamic IMRT, and VMAT) compared to 3D CRT, where it defines only field boundaries. We analyzed the impact of the MLC positional errors on the dose distribution for volumetric-modulated arc therapy, using a 3D dosimetry system.

Cryopreservation does not alter main characteristics of Good Manufacturing Process-grade human multipotent mesenchymal stromal cells including immunomodulating potential and lack of malignant transformation.

Background Aims: The immunomodulating capacity of multipotent mesenchymal stromal cells (MSCs) qualifies them as a therapeutic tool in several diseases. However, repeated transplantation with products of reproducible characteristics may be required. This could be achieved with cryopreserved aliquots of Good Manufacturing Practice (GMP)-grade MSCs.

Radiostereometric migration analysis of the Lubinus SP II hip stem: 59 hips followed for 2 years.

The aim of this prospective study was to analyze the migration pattern of the Lubinus SP II hip stem and to evaluate the clinical results. Fifty-nine patients were followed for 2 years. Translational and rotational micromotion of the implant was measured by radiostereometric analysis (RSA) and the Harris hip score (HHS), and the Charnley classification was used to assess the clinical outcome.

Monitoring of xenograft tumor growth and response to chemotherapy by non-invasive in vivo multispectral fluorescence imaging.

A continuous monitoring of the whole tumor burden of individuals in orthotopic tumor models is a desirable aim and requires non-invasive imaging methods. Here we investigated whether quantification of a xenograft tumor intrinsic fluorescence signal can be used to evaluate tumor growth and response to chemotherapy. Stably fluorescence protein (FP) expressing cell clones of colorectal carcinoma and germ cell tumor lines were generated by lentiviral transduction using the FPs eGFP, dsRed2, TurboFP635, and mPlum.

Stress-related femoral cortical and cancellous bone density loss after collum femoris preserving uncemented total hip arthroplasty: a prospective 7-year follow-up with quantitative computed tomography.

Purpose: Bone loss around uncemented femoral components is suspected to precede implant loosening and contribute to problems in revision surgery. Short-stemmed cementless femoral components are designed to preserve proximal femoral bone stock and ultimately the longevity of the prosthesis.

Methods: With quantitative computed tomography-assisted osteodensitometry, we prospectively analyzed femoral cortical and cancellous bone density (BD) and contact area changes of an uncemented collum femoris preserving stem (n = 38) 10 days, 1, 3 and 7 years post-operatively.

Periacetabular cortical and cancellous bone mineral density loss after press-fit cup fixation: a prospective 7-year follow-up.

The impact of total hip arthroplasty on strain adaptive bone remodeling has been extensively analyzed by dual-energy x-ray absorptiometry. In this study, we present a prospective computed tomography-assisted study of periacetabular cortical and cancellous bone mineral density (in milligrams of calcium hydroxyapatite [CaHA] per milliliter, or mgCaHA/mL) changes 10 days and 1, 3, and 7 years after press-fit cup implantation for 38 hips in vivo. Cancellous bone mineral density decreased by Ø -63% ventral and Ø -85% dorsal to the cup; cortical bone mineral density, by Ø -22% ventral and Ø -18% dorsal to the cup.

Comparison of cortical and cancellous bone remodeling of the pelvis after press-fit cup total hip arthroplasty dependent on patient and prosthesis-specific characteristics: a computed tomography-assisted osteodensitometry study in vivo.

Even though periprosthetic bone loss is common after total hip arthroplasty, there is no scientific evidence whether it compromises the survival of the prosthesis. Using quantitative computed tomography-assisted osteodensitometry, we determined the pattern of periacetabular bone density (BD) changes of two different press-fit cups (54 hips) 10 days, 1 year and 3 years post-operatively. We measured cortical and cancellous BD at three points of time and evaluated the effects of patient-specific characteristics [age, gender, body mass index (BMI)], clinical function, and BD at index operation.

Quantitative computed tomography-assisted osteodensitometry of the pelvis after press-fit cup fixation: a prospective ten-year follow-up.

Background: As a follow-up of a previously reported three-year study, we analyzed the periprosthetic acetabular cortical and cancellous bone density changes at ten years after implantation of a press-fit cup.

Methods: Prospective clinical, radiographic, and quantitative computed tomography examinations were performed within ten days and at mean periods of one, three, and ten years after total hip arthroplasty with a press-fit cup, a femoral stem with a tapered design, and alumina-alumina pairing. Periacetabular cortical and cancellous bone density (mg CaHA/mL) in the cranial, ventral, and dorsal regions about the cup were measured for twenty-four hips in vivo.

Excellent results with cementless total hip arthroplasty and alumina-on-alumina pairing: minimum ten-year follow-up.

Ceramic-on-ceramic coupling is thought to be a durable alternative to metal- or alumina-on-polyethylene pairing. No evidence exists suggesting superior clinical and radiological results for hydroxyapatite-coated stems versus uncoated stems. The aim of this study is to report the performance of an alumina-on-alumina bearing cementless total hip arthroplasty and to compare stems with a tapered design with and without hydroxyapatite coating.

Use of orthoses and orthopaedic technical devices in proximal spinal muscular atrophy. Results of survey in 194 SMA patients.

Purpose: The purpose of this study is to determine the use of orthopaedic and assistive devices for Spinal muscular atrophy (SMA) patients, following a survey of 194 patients.

Method: The use of wheelchairs, corsets and orthoses was evaluated in 194 SMA patients whose mean age was 12.6 (SD 7.