New clinical insight in amyotrophic lateral sclerosis and innovative clinical development from the non-profit repurposing trial of the old drug guanabenz

Drug repurposing is considered a valid approach to accelerate therapeutic solutions for rare diseases. However, it is not as widely applied as it could be, due to several barriers that discourage both industry and academic institutions from pursuing this path. Herein we present the case of an academic multicentre study that considered the repurposing of the old drug guanabenz as a therapeutic strategy in amyotrophic lateral sclerosis. The difficulties encountered are discussed as an example of the barriers that academics involved in this type of study may face. Although further development of the drug for this target population was hampered for several reasons, the study was successful in many ways. Firstly, because the hypothesis tested was confirmed in a sub-population, leading to alternative innovative solutions that are now under clinical investigation. In addition, the study was informative and provided new insights into the disease, which are now giving new impetus to laboratory research. The message from this example is that even a repurposing study with an old product has the potential to generate innovation and interest from industry partners, provided it is based on a sound rationale, the study design is adequate to ensure meaningful results, and the investigators keep the full clinical development picture in mind

DRUDIT: web-based DRUgs DIscovery Tools to design small molecules as modulators of biological targets.

Abstract Motivation New in silico tools to predict biological affinities for input structures are presented. The tools are implemented in the DRUDIT (DRUgs DIscovery Tools) web service. The DRUDIT biological finder module is based on molecular descriptors that are calculated by the MOLDESTO (MOLecular DEScriptors TOol) software module developed by the same authors, which is able to calculate more than one thousand molecular descriptors. At this stage, DRUDIT includes 250 biological targets, but new external targets can be added. This feature extends the application scope of DRUDIT to several fields. Moreover, two more functions are implemented: the multi- and on/off-target tasks. These tools applied to input structures allow for predicting the polypharmacology and evaluating the collateral effects. Results The applications described in the article show that DRUDIT is able to predict a single biological target, to identify similarities among biological targets, and to discriminate different target isoforms. The main advantages of DRUDIT for the scientific community lie in its ease of use by worldwide scientists and the possibility to be used also without specific, and often expensive, hardware and software. In fact, it is fully accessible through the WWW from any device to perform calculations. Just a click or a tap can start tasks to predict biological properties for new compounds or repurpose drugs, lead compounds, or unsuccessful compounds. To date, DRUDIT is supported by four servers each able to execute 8 jobs simultaneously. Availability and implementation The web service is accessible at the www.drudit.com URL and its use is free of charge. Supplementary information Supplementary data are available at Bioinformatics online

Smoothing of Slug Tests for Laboratory Scale Aquifer Assessment—A Comparison Among Different Porous Media

A filtering analysis of hydraulic head data deduced from slug tests injected in a confined aquifer with different porous media is proposed. Experimental laboratory tests were conducted in a large-scale physical model developed at the University of Calabria. The hydraulic head data were deduced from the records of a pressure sensor arranged in the injection well and subjected to a processing operation to filter the high-frequency noise. The involved smoothing techniques are the Fourier transform and two types of wavelet transform. The performances of the filtered hydraulic heads were examined for different slug volumes and four model layouts in terms of optimal fitting of the Cooper’s analytical solution. The hydraulic head variations in the confined aquifer were analyzed using wavelet transform in order to discover their energy contributions and frequency oscillations. Finally, the raw and smoothed hydraulic heads were adopted to calculate the hydraulic conductivity of the aquifer

The effect of zoledronic acid on serum osteoprotegerin in early stage multiple myeloma

We evaluated the effect of zoledronic acid (ZA) on serum levels of osteoprotegerin (OPG) and the ligand for receptor activator of nuclear factor kappaB (RANKL) in patients with smoldering myeloma. In treated subjects we found an increase of OPG accounting for an effect of ZA on osteoblast and/or bone marrow stromal cells together with the direct effect on osteoclasts

Protective effects of melatonin in inflamed intestinal epithelium are associated with reduced NF-κB activation and changes in DNA methylation status

Melatonin is the main product of the pineal gland but is also released in the gastrointestinal tract (GIT). Production of melatonin at GIT is independent of the photoperiod and contributes almost completely to plasma melatonin concentration during daylight hours. The physiological role of melatonin at GIT is poorly characterized but recently anti-inflammatory effects have been reported. In this study, we evaluated the effect of Melatonin in intestinal epithelial cells (IEC) stimulated by Interleukin-1β. Our results clearly show that melatonin at micromolar concentrations inhibits the inflammatory response in IEC. The protective effect is expressed through a marked decrease in release and expression of inflammatory mediators, inhibition of DNA damage, and reduced activation of the NF-κB. Moreover, our results provide evidence that local inhibitor effect of Melatonin can involve an epigenetic mechanism also. In conclusion, our findings suggest that the intake of small amounts of melatonin, comparable with those found in pharmaceutical preparations used for sleep disorders, can also exert beneficial effects to the gastrointestinal physiology

Prone Positioning and Intravenous Zanamivir may Represent Effective Alternatives for Patients with Severe ARDS Virus A (H1N1) Related Pneumonia in Hospitals with no Access to ECMO

The first patient with influenza A/H1N1-related pneumonia was admitted to an Italian ICU at the end of August 2009. Until then, despite the international alarm, the level of awareness was low and very few Italian hospitals were equipped with ECMOs. Moreover the PCR test for A H1N1 virus was sporadically available and the emergency departments of even the largest institutions could rely only on the rapid test for the urgent screening of patients with pneumonia and respiratory failure. On September 5th, a young and “apparently” previously healthy man, was admitted to our ICU because of a severe ARDS caused by influenza A H1N1 virus. As there was no ECMO available, he was treated with prolonged cycles of prone positioning ventilation. Antiviral treatment was started with Oseltamivir, but as enteral absorption was impaired by paralytic ileus and tube feeding intolerance, Oseltamivir had to be discontinued. Intravenous Zanamivir 1200 mg/day for ten days was therefore prescribed as “off label” antiviral therapy. A bone marrow biopsy allowed the diagnosis of an initial stage of “hairy cells leukaemia.” ARDS related to A/H1N1 influenza was the first sign of the disease in our patient. He did well with complete clearance of the infection from the BAL after 10 days of Zanamivir, although the nasopharyngeal swabs remained positive for ten more days. Prone positioning ventilation may be a life-saver strategy in patients with severe ARDS when ECMO is not immediately available. However, prone positioning ventilation is often associated with severe impairment of the absorption of drugs that require enteral administration via the nasogastric tube. In these cases, intravenous Zanamivir may be an effective alternative strategy

Short‐ and intermediate‐term efficacy of buprenorphine TDS in chronic painful neuropathies

Abstract  Buprenorphine is a potent opioid available as a transdermal delivery system (TDS) formulation. This open‐label study investigated its safety, tolerability, and efficacy in 30 patients with chronic painful neuropathy. Subjects with visual analogue scale (VAS) score ≥5 under stable analgesic treatment were entered. The starting dosage of 35 μg/h was increased up to 70.0 μg/h in case of unsatisfactory pain control as assessed by fortnightly visits. The primary endpoint was the number of patients achieving at least 30% pain relief at day 42 visit. Treatment was safe over the study period. Nine patients dropped out for side effects, mostly nausea and daily sleepiness. Buprenorphine TDS was well tolerated in 21 patients. Thirteen patients achieved >30% of pain relief at day 42 visit. Five patients needed to increase the dosage to 52.5 μg/h. Eight patients did not meet the primary outcome, but none allowed increasing the dosage to 70 μg/h, and four patients withdrew consent to continue the study before day 42 visit because of a 'fear to become addicted,' although 40% had obtained VAS reduction. In our study, which needs to be confirmed by a controlled trial, buprenorphine TDS induced clinically meaningful pain relief in about 40% of patients with chronic painful neuropathy, suggesting its use as a third‐line treatment