Catch Your Breath, Take It Bitter
The chronic constrictive airway diseases – asthma and chronic obstructive pulmonary disease (COPD) – together affect 300 million individuals worldwide. Bronchodilators (corticosteroids, long-acting beta2 agonists and muscarinic antagonists, adenosine agonists, phosphodiesterase-4 inhibitors), mostly administered as inhaled drugs in fixed combinations, are the obvious and well-established therapeutic option. But now, in WO/2012/021291(Univ. of Maryland [US]; Feb. 16, 2012) the inventors claim that bitter tastants of the most diverse structure could achieve the same effect because they increase calcium influx in human airway smooth muscle cells. Studies were performed with cultured primary ASM cells loaded with a fluorophore and responses to 1.0 mM of aristocholic acid, chloroquine, colchicine, denatonium, quinine, saccharin, salicin, strychnine and yohimbine were recorded. Chloroquine and quinine relax intact mouse airway tracheas contracted by 1.0 mM serotonin. Finally, bitter taste receptor agonists relieved bronchoconstriction in a mouse model of asthma. This patent application, crammed with many more experimental data than we can hint at here, moves on ground also explored by others (PubMed).
Hypertension, Glucose Control – And Now ALS
The potassium channel opener diazoxide(a benzothiadiazine) acts as a vasodilator in hypertensive crises (PubMed), and although its mechanism in diabetes was published over 40 years ago (PubMed) it is still considered a lead structure for antidiabetic drug development (PubMed). Given the fact that impaired neuronal potassium channel function has been described in several CNS conditions diazoxide was investigated here too, but the doses required to manage post-ischemic cognitive deficiencies or bupivacaine-induced convulsions in animal models were quite high. In WO/2012/022730(Neurotec Pharma [ES]; Feb. 23, 2012) the inventors show that to treat amyotrophic lateral sclerosis where neuronal potassium channels also play a key role (paper), much lower doses are sufficient — to be exact, doses ranging from 0.15 mg/m2/day to 13.00 mg/m2/day which do not induce hyperglycemia in a transgenic mouse model of ALS although they do delay disease onset and improve nerve conduction. – Also note WO/2004/082582from the French C.N.R.S. claiming diazoxide for retinal ischemia.
The “Flunomides” Offer Hope in Spinal Cord Injury
LeflunomideN-(4-trifluoromethylphenyl)-5-methylisoxazol-4-carboxamide), a disease-modifying antirheumatic drug, is marketed by Sanofi as Arava(TM). It exerts its immunomodulatory effects through inhibition of the mitochondrial enzyme dihydroorotate dehydrogenase, interfering selectively with the cell cycle of activated and autoimmune lymphocytes. This intrinsic ability to spare (in a relative sense) resting lymphocytes leaves a lot of possibilities open. WO/2012/025217(Algiax Pharmaceuticals GmbH [DE]; March 1, 2012) has found a new use in CNS trauma: rats with severe spinal cord contusion injury showed faster improvement of locomotor and voiding functions when given leflunomide (20 mg/kg/day) in vehicle by gavage for 7 days. The activity actually comes from an active primary metabolite teriflunomide, a malononitrilamide (PubMed) which was shown to be directly active in this patent application at the same dosages as the parent compound. The same was found for HR325 (laflunimus). – Note that leflunomide has recently been reported as being effective in the treatment of complex cytomegalovirus syndromes (PubMed).
A Host Cell Target Modulator For Preventing Influenza
The vacuolar adenosine triphosphatase (V-ATPase) is almost ubiquitously present in organelle membanes; like its cousins, its is a transmembrane proton pump. Because of its involvement in a large number of cellular functions, inhibitors (e.g., plecomacrolides) have been discussed for a number of different therapies, including also as antivirals including influenza drugs (PubMed). However, because of the seemingly inherent, high cytotoxicity of treatments targeting v-ATPases, most applications have been abandoned, and the focus switched to their cytotoxic effects as antitumor drugs (PubMed). The inventors of WO/2012/028732(Centre de Recherche Public de la Santé [LU]; March 8, 2012)have shown that saliphenylhalamide (also an anticancer candidate; see paper) and its derivatives have a surprisingly good selectivity index in comparison to the plecomacrolides bafilomycin and concanymcin. Benzolactone enamide v-ATPase inhibitors have antiviral activity against influenza A virus in vitro at concentrations about 10 to 50 times below the 50% cytotoxic concentrations of the drugs. In various experimental paradigms they protected against pandemic H1N1 (A/Hamburg/01/2009), oseltamivir resistant H1N1 (A/Luxembourg/572/2008) and also against highly pathogenic avian influenza virus H5N1 (A/Chicken/Nigera/BA211/2006). In animal studies (mice) the v-ATPase inhibitors tested protected 62.5% of the animals against a lethal challenge of a mouse adapted influenza virus.