Summary Discovering the unintended “off-targets” that predict adverse drug reactions (ADRs) is daunting by empirical methods alone. Drugs can act on multiple protein targets, some of which can be unrelated by traditional molecular metrics, and hundreds of proteins have been implicated in side effects. We therefore explored a computational strategy to predict the activity of 656 marketed drugs on 73 unintended “side effect” targets. Approximately half of the predictions were confirmed, either from proprietary databases unknown to the method or by new experimental assays. Affinities for these new off-targets ranged from 1 nM to 30 μM. To explore relevance, we developed an association metric to prioritize those new off-targets that explained side effects better than any known target of a given drug, creating a Drug-Target-ADR network. Among these new associations was the prediction that the abdominal pain side effect of the synthetic estrogen chlorotrianisene was mediated through its newly discovered inhibition of the enzyme COX-1. The clinical relevance of this inhibition was borne-out in whole human blood platelet aggregation assays. This approach may have wide application to de-risking toxicological liabilities in drug discovery.

BackgroundCachexia, a >10% loss of body-weight, is one factor determining the poor prognosis of pancreatic cancer. Deficiency of L-Carnitine has been proposed to cause cancer cachexia.FindingsWe screened 152 and enrolled 72 patients suffering from advanced pancreatic cancer in a prospective, multi-centre, placebo-controlled, randomized and double-blinded trial to receive oral L-Carnitine (4 g) or placebo for 12 weeks. At entry patients reported a mean weight loss of 12 ± 2,5 (SEM) kg. During treatment body-mass-index increased by 3,4 ± 1,4% under L-Carnitine and decreased (−1,5 ± 1,4%) in controls (p < 0,05). Moreover, nutritional status (body cell mass, body fat) and quality-of-life parameters improved under L-Carnitine. There was a trend towards an increased overall survival in the L-Carnitine group (median 519 ± 50 d versus 399 ± 43 d, not significant) and towards a reduced hospital-stay (36 ± 4d versus 41 ± 9d,n.s.).ConclusionWhile these data are preliminary and need confirmation they indicate that patients with pancreatic cancer may have a clinically relevant benefit from the inexpensive and well tolerated oral supplementation of L-Carnitine.

Hydrogels that provide mechanical support and sustainedly release therapeutics have been used to treat tendon injuries. However, most hydrogels are insufficiently tough, release drugs in bursts, and require cell infiltration or suturing to integrate with surrounding tissue. Here, we report that a hydrogel serving as a high-capacity drug depot and combining a dissipative tough matrix on one side and a chitosan adhesive surface on the other side supports tendon gliding and strong adhesion (larger than 1,000 J/m2) to tendon on opposite surfaces of the hydrogel, as we show with porcine and human tendon preparations during cyclic-friction loadings. The hydrogel is biocompatible, strongly adheres to patellar, supraspinatus and Achilles tendons of live rats, boosted healing and reduced scar formation in a rat model of Achilles-tendon rupture, and sustainedly released the corticosteroid triamcinolone acetonide in a rat model of patellar tendon injury, reducing inflammation, modulating chemokine secretion, recruiting tendon stem and progenitor cells, and promoting macrophage polarization to the M2 phenotype. Hydrogels with ‘Janus’ surfaces and sustained-drug-release functionality could be designed for a range of biomedical applications.

1. Using a Ussing chamber and neuronal retrograde tracing with 1,1fi-didodecyl-3,3,3fi,3fi-tetramethylindocarbocyanine perchlorate (DiI) we characterized the afferent and efferent neuronal pathways which mediated distension-evoked secretion in the guinea-pig distal colon.2. Acute capsaicin application (10 µM) to the serosal site of the Ussing chamber evoked a secretory response which was blocked by tetrodotoxin (1 µM), the combined application of the NK1 and NK3 receptor antagonists CP-99,994-1 and SR 142801 (1 µM), and by combined application of atropine (10 µM) and the VIP receptor antagonist VIP(6-28) (10 µM). Functional desensitization of extrinsic primary afferents by long-term application of capsaicin significantly diminished distension-evoked secretion by 46 %.3. After functional desensitization by capsaicin, serosal application of gadolinium (100 µM) inhibited the distension-evoked chloride secretion by 54 %; the L-type Ca 2+ channel blocker nifedipine (1 µM) and the 5-HT 1P receptor antagonist renzapride (1 µM) had no effect. The combination of atropine and VIP(6-28) or the combination of NK1 and NK3 receptor antagonists almost abolished distension-evoked secretion.4. The secretory response evoked by electrical field stimulation, carbachol (1 µM) or VIP (1 µM) was not attenuated by gadolinium. Field stimulation-evoked chloride secretion was not affected by blockade of NK1 and NK3 receptors.5. Twelve per cent of DiI-labelled submucosal neurones with projections to the mucosa were immunoreactive for choline acetyltransferase, substance P and calbindin and very probably represented intrinsic primary afferent neurones.6. Distension-evoked chloride secretion was mediated by capsaicin-sensitive extrinsic primary afferents and by stretch-sensitive intrinsic primary afferent neurones. Both the extrinsic and intrinsic afferents converge on common efferent pathways. These pathways consist of VIPergic and cholinergic secretomotor neurones that are activated via NK1 and NK3 receptors.

We were not able to demonstrate a difference in postprandial abdominal pain or in the length of hospital stay. Patients with self-selected eating, however, were able to restart eating 1 day earlier, and this difference was found to be significant. Our data suggest that normalization of serum lipase is not obligatory for enteral nutrition in mild acute pancreatitis.