Bis-Quinolinium Cyclophane Blockers of SK Potassium Channels Are Antagonists of M3 Muscarinic Acetylcholine Receptors.

Dequalinium is used as an antimicrobial compound for oral health and other microbial infections. Derivatives of dequalinium, the bis-quinolinium cyclophanes UCL 1684 and UCL 1848, are high affinity SK potassium channel antagonists. Here we investigated these compounds as M3 muscarinic receptor (mACHR) antagonists. We used the R-CEPIAer endoplasmic reticulum calcium reporter to functionally assay for Gq-coupled receptor signaling, and investigated the bis-quinolinium cyclophanes as antagonists of M3 mACHR activation in transfected CHO cells. Given mACHR roles in airway smooth muscle (ASM) contractility, we also tested the ability of UCL 1684 to relax ASM. We find that these compounds antagonized M3 mACHRs with an IC50 of 0.27 µM for dequalinium chloride, 1.5 µM for UCL 1684 and 1.0 µM for UCL 1848. UCL 1684 also antagonized M1 (IC50 0.12 µM) and M5 (IC50 0.52 µM) mACHR responses. UCL 1684 was determined to be a competitive antagonist at M3 receptors as it increased the EC50 for carbachol without a reduction in the maximum response. The Ki for UCL1684 determined from competition binding experiments was 909 nM. UCL 1684 reduced carbachol-evoked ASM contractions (>90%, IC50 0.43 µM), and calcium mobilization in rodent and human lung ASM cells. We conclude that dequalinium and bis-quinolinium cyclophanes antagonized M3 mACHR activation at sub- to low micromolar concentrations, with UCL 1684 acting as an ASM relaxant. Caution should be taken when using these compounds to block SK potassium channels, as inhibition of mACHRs may be a side-effect if excessive concentrations are used.

The neurologist's dilemma: a comprehensive clinical review of Bell's palsy, with emphasis on current management trends.

BACKGROUND: Recent advances in Bell's palsy (BP) were reviewed to assess the current trends in its management and prognosis. MATERIAL/METHODS: We retrieved the literature on BP using the Cochrane Database of Systematic Reviews, PubMed, and Google Scholar. Key words and phrases used during the search included 'Bell's palsy', 'Bell's phenomenon', 'facial palsy', and 'idiopathic facial paralysis'. Emphasis was placed on articles and randomized controlled trails (RCTs) published within the last 5 years. RESULTS: BP is currently considered the leading disorder affecting the facial nerve. The literature is replete with theories of its etiology, but the reactivation of herpes simplex virus isoform 1 (HSV-1) and/or herpes zoster virus (HZV) from the geniculate ganglia is now the most strongly suspected cause. Despite the advancements in neuroimaging techniques, the diagnosis of BP remains one of exclusion. In addition, most patients with BP recover spontaneously within 3 weeks. CONCLUSIONS: Corticosteroids are currently the drug of choice when medical therapy is needed. Antivirals, in contrast, are not superior to placebo according to most reliable studies. At the time of publication, there is no consensus as to the benefit of acupuncture or surgical decompression of the facial nerve. Long-term therapeutic agents and adjuvant medications for BP are necessary due to recurrence and intractable cases. In the future, large RCTs will be required to determine whether BP is associated with an increased risk of stroke.

Inhibitors of fatty acid synthesis in prokaryotes and eukaryotes as anti-infective, anticancer and anti-obesity drugs.

There is a large range of diseases, such diabetes and cancer, which are connected to abnormal fatty acid metabolism in human cells. Therefore, inhibitors of human fatty acid synthase have great potential to manage or treat these diseases. In prokaryotes, fatty acid synthesis is important for signaling, as well as providing starting materials for the synthesis of phospholipids, which are required for the formation of the cell membrane. Recently, there has been renewed interest in the development of new molecules that target bacterial fatty acid synthases for the treatment of bacterial diseases. In this review, we look at the differences and similarities between fatty acid synthesis in humans and bacteria and highlight various small molecules that have been shown to inhibit either the mammalian or bacterial fatty acid synthase or both.

A friend to the airways: a review of the emerging clinical importance of the bronchial arterial circulation.

Lungs receive the bulk of their blood supply through the pulmonary arteries. The bronchial arteries, on the other hand, vascularize the bronchi and their surroundings. These two arteries anastomose near the alveolar ducts. Contrary to the pulmonary circulation which is fairly well studied, the bronchial arteries have been appreciated more by their absence, and in some cases, by an interruption in the pulmonary arterial flow. Therefore, a more accurate anatomical and functional knowledge of these atherosclerosis-resistant vessels is needed to help surgeons and clinicians to avoid iatrogenic injuries during pulmonary interventions. In this review, we have revisited the anatomy and pathophysiology of the bronchial arteries in humans, considering the recent advances in imaging techniques. We have also elaborated on the known clinical applications of these arteries in both the pathogenesis and management of common pulmonary conditions.

Inhaled antibiotics for gram-negative respiratory infections.

Several disease states create conditions that lead to opportunistic Gram-negative respiratory infections. Inhalation is the most direct and, until recently, underutilized means of antimicrobial drug targeting for respiratory tract infections. All approved antimicrobial agents for administration by inhalation are indicated for Pseudomonas aeruginosa infections in patients with cystic fibrosis. These inhaled therapies have directly contributed to a significant reduction in exacerbations and hospitalizations in this patient population over the last few decades. The relentless adaptation of pathogenic organisms to current treatment options demands that the pharmaceutical industry continue designing next-generation antimicrobial agents over 70 years after they were first introduced. Recent technological advances in inhalation devices and drug formulation techniques have broadened the scope of antimicrobial structural classes that can be investigated by inhalation; however, there is an urgent need to discover novel compounds with improved resistance profiles relative to those drugs that are already marketed.