dextrorphan and Neoplasms

Increasing the affinity of diamidines for AT-rich regions of DNA has long been an important goal of medicinal chemists who wanted to improve the antiparasitic and antifungal properties of that class of derivatives. In recent years it was demonstrated that diamidines could interfere with many other biomolecular targets including ion channels as well as enzymes and modulate some RNA-protein, DNA-protein, and protein-protein interactions. It is therefore not surprising that diamidines now emerge as novel potential drug candidates for the treatment of various diseases, i.a. neurodegenerative disorders, acidosis-related pathological conditions, hypertension, thrombosis, type 2 diabetes, myotonic dystrophy, and cancers. A summary of the most striking results obtained to date in those domains is presented is this review.

Topics: Amidines; Animals; Diabetes Mellitus, Type 2; DNA; Enzymes; Humans; Hypertension; Ion Channels; Myotonic Dystrophy; Neoplasms; Neurodegenerative Diseases; Proteins; RNA; Thrombosis

This review has covered the five potential causes for opioid poorly responsive pain, namely (a) a loss of opioid receptors on the spinal terminals of C-fibres as a result of peripheral nerve damage, (b) an accumulation of morphine-3-glucuronide, (c) changes in the non-opioid peptides, F8Fa or CCK, either spinally or supraspinally, (d) actions of the opioid peptide dynorphin and (e) spinally generated hypersensitive states via activation of the NMDA receptor. The loss of opioid receptors is likely to be important where peripheral nerve pathology or compression occurs, but the evidence suggests that increasing the dose will overcome the reduced opioid response. Morphine-3-glucuronide is unlikely to be a factor, nor is dynorphin, but the endogenous peptides CCK and F8Fa may be important. Finally, there is an association between the NMDA receptor and hyperalgesia/allodynia and reduced opioid sensitivity. Dextrorphan and ketamine reduce NMDA mediated events and so are available to test this hypothesis.

Topics: Analgesics, Opioid; Animals; Central Nervous System; Clonidine; Dextromethorphan; Dextrorphan; Dynorphins; Humans; Morphine; N-Methylaspartate; Neoplasms; Neurophysiology; Neuroprotective Agents; Pain; Rats; Receptors, N-Methyl-D-Aspartate; Receptors, Opioid; Sympatholytics

Panobinostat is a potent oral pan-deacetylase inhibitor with promising clinical activity in hematologic malignancies. Panobinostat was shown to inhibit CYP2D6 activity in vitro; thus understanding the magnitude of the potential clinical inhibition of panobinostat on co-medications that are CYP2D6 substrates becomes important.. This study evaluated the effects of co-administration of panobinostat with a sensitive CYP2D6 substrate, dextromethorphan (DM), in patients with advanced cancer who have functional CYP2D6 genes. Patients received 60 mg DM alone on day 1, panobinostat at 20 mg alone on days 3 and 5, and both agents on day 8. Plasma concentrations of DM and its metabolite dextrorphan (DX) were determined by liquid chromatography-tandem mass spectrometry following serial blood collections on day 1 (DM alone) and day 8 (in combination with panobinostat).. Panobinostat increased DM exposure by 64 % [geometric mean ratio (GMR), 1.64 (90 % confidence interval (CI), 1.17-2.31)] and DX exposure by 29 % (GMR, 1.29 [90 % CI, 1.10-1.51]). These results indicated that panobinostat weakly inhibited a sensitive CYP2D6 substrate in cancer patients by increasing DM exposure by less than twofold.. Safety monitoring of sensitive CYP2D6 substrates with narrow therapeutic index is recommended when co-administering with panobinostat in future clinical practice.

Topics: Aged; Antineoplastic Agents; Chromatography, Liquid; Cytochrome P-450 CYP2D6; Cytochrome P-450 CYP2D6 Inhibitors; Dextromethorphan; Dextrorphan; Drug Interactions; Female; Humans; Hydroxamic Acids; Indoles; Male; Middle Aged; Neoplasms; Panobinostat; Tandem Mass Spectrometry