Dextrorphan (tartrate)

Dextrorphan binds to opioid receptors in guinea-pig brain membranes and is an antagonist at opioid receptors in myenteric plexus

Dextrorphan (+)-tartrate, purified by repeated crystallization to remove all traces of the enantiomer levorphanol, binds to mu, delta, and kappa sites on guinea-pig brain membranes with lower affinities (by a factor of 400-3200) than levorphanol. In the guinea-pig ileum myenteric plexus longitudinal muscle preparation (GPI), dextrorphan, at 100-200 microM, inhibits the electrically stimulated twitch, but this action is not blocked or reversed by naloxone; both (+)- and (-)-naloxone produce similar non-opioid twitch inhibition at comparable concentrations. At 10-20 microM, dextrorphan blocks and reverses the twitch inhibition due to mu and kappa agonists, but the blockade can be overcome only partially by increasing the agonist concentration. We conclude that dextrorphan is an opioid ligand with low affinity and with antagonist effect on opioid receptors in the GPI.

Identification of Additional Anti-Persister Activity against Borrelia burgdorferi from an FDA Drug Library

Lyme disease is a leading vector-borne disease in the United States. Although the majority of Lyme patients can be cured with standard 2-4 week antibiotic treatment, 10%-20% of patients continue to suffer from prolonged post-treatment Lyme disease syndrome (PTLDS). While the cause for this is unclear, persisting organisms not killed by current Lyme antibiotics may be involved. In our previous study, we screened an FDA drug library and reported 27 top hits that showed high activity against Borrelia persisters. In this study, we present the results of an additional 113 active hits that have higher activity against the stationary phase B. burgdorferi than the currently used Lyme antibiotics. Many antimicrobial agents (antibiotics, antivirals, antifungals, anthelmintics or antiparasitics) used for treating other infections were found to have better activity than the current Lyme antibiotics. These include antibacterials such as rifamycins (3-formal-rifamycin, rifaximin, rifamycin SV), thiostrepton, quinolone drugs (sarafloxacin, clinafloxacin, tosufloxacin), and cell wall inhibitors carbenicillin, tazobactam, aztreonam; antifungal agents such as fluconazole, mepartricin, bifonazole, climbazole, oxiconazole, nystatin; antiviral agents zanamivir, nevirapine, tilorone; antimalarial agents artemisinin, methylene blue, and quidaldine blue; antihelmintic and antiparasitic agents toltrazuril, tartar emetic, potassium antimonyl tartrate trihydrate, oxantel, closantel, hycanthone, pyrimethamine, and tetramisole. Interestingly, drugs used for treating other non-infectious conditions including verteporfin, oltipraz, pyroglutamic acid, pidolic acid, and dextrorphan tartrate, that act on the glutathione/γ-glutamyl pathway involved in protection against free radical damage, and also the antidepressant drug indatraline, were found to have high activity against stationary phase B. burgdorferi. Among the active hits, agents that affect cell membranes, energy production, and reactive oxygen species production are more active against the B. burgdorferi persisters than the commonly used antibiotics that inhibit macromolecule biosynthesis. Future studies are needed to evaluate and optimize the promising active hits in drug combination studies in vitro and also in vivo in animal models. These studies may have implications for developing more effective treatments of Lyme disease.

Drug reinforcement studied by the use of place conditioning in rat

Rats display a preference for an environment in which they previously received morphine. The present report provides behavioral and pharmacological data for this simple model of reinforcement produced by opiates and describes an aversion in rats for an environment in which they previously received naloxone. Preferences were produced with intravenous (i.v.) morphine sulfate at doses of 0.08-15 mg/kg and durations of the pairing between environment and morphine of 10 min to 1.5 h. Preferences were also seen with other opiate agonists (etorphine-HCl and levorphanol-tartrate), another route of drug administration (subcutaneous), and after 1-4 administrations of morphine. Cocaine-HCl (i.v.), a non-narcotic drug, known to be self-administered by humans, also produced a place preference. Lithium chloride (i.v.), an agent found to be a punishing stimulus in other situations, produced a place aversion. There was no appreciable preference for an environment paired with dextrorphan-tartrate and naloxone-HCl (2 mg/kg, i.p.) blocked the production of the preference produced by i.v. morphine. In contrast to the effect produced by morphine, aversions were produced with (-)-naloxone-HCl alone at doses of 0.1-45 mg/kg (i.v.). The aversion was not produced at (+)-naloxone. Implantation of rats with a 75 mg morphine pellet 3 days prior to place conditioning potentiated the aversive effect of naloxone. It was concluded that place conditioning produced by morphine and naloxone is mediated by specific opiate receptors and that stimulating and decreasing activity of the endogenous opioid peptide system with systemically administered drugs is positively reinforcing and aversive, respectively. The discussion emphasizes application of the simple and sensitive place conditioning model to drug reinforcement research, including analyses of reinforcement produced by microinjection of opiates into the brain.

Pharmacology of the allodynia in rats evoked by high dose intrathecal morphine

Morphine sulfate in doses of 90 to 150 micrograms/3 microliters evoke a prominent behavioral syndrome characterized by 1) periodic bouts of spontaneous agitation during which the rat scratches and bites at the skin of the caudal dermatomes and 2) vigorous agitation, vocalization and coordinated efforts to bite and escape evoked by a light tactile stimulus applied to the flank, suggestive of a pain state (allodynia). The phenomenon is not reversed by naltrexone or is it subject to tolerance. The ordering of activity of an opioid alkaloid related agent in producing this touch-evoked agitation is: noroxymorphone-3-glucuronide, morphine-3-glucuronide, morphine-3-ethereal sulfate, dihydromorphine, noroxymorphone dihydrate, hydromorphone, dihydrocodeine tartrate, morphine sulfate, dihydroisomorphine, morphine-HCl, 6-acetylmorphine, N-normorphine-HCl and (+)-morphine. The following agents were essentially without effect at the highest doses examined: 3,6-diacetylmorphine, N-normeperidine-HCl, nalorphine-HCl, alfentanil, sufentanil, naloxone, naltrexone, methadone, dextrorphan tartrate, meperidine-HCl, oxycodone, levorphanol, oxymorphone, codeine phosphate, thebaine, nalbuphine and naltrexone-3-glucuronide. The observations that the sulfated and conjugated metabolites are 10 to 50 times more potent than their unmetabolized precursor suggest the possibility that, in high concentrations certain phenanthrene opioid alkaloids with a free 3-OH position, an ether bridge and no N-methyl extension will be subject to conjugation and this metabolite will alter the processing of otherwise innocuous tactile stimuli. The fact that the phenomenon appeared at least partially stereospecific may reflect upon the fact that other laboratories have shown that glucuronyl transferase may preferentially convert (-)-morphine to the 3-glucuronide and (+)-morphine to the 6-glucuronide which may be less active.(ABSTRACT TRUNCATED AT 250 WORDS)

A sensitive assay of metoprolol and its major metabolite alpha-hydroxy metoprolol in human plasma and determination of dextromethorphan and its metabolite dextrorphan in urine with high performance liquid chromatography and fluorometric detection

A reverse-phase High Performance Liquid Chromatographic (HPLC) method was developed for the analysis of metoprolol in the large number of human plasma samples obtained in in vitro-in vivo correlations (IVIVC) and bioavailability studies of extended release formulations of metoprolol tartrate. The metabolite, alpha-hydroxy metoprolol (OH-met), could also be quantified. The analytes were extracted from the plasma using solid phase columns, separated on a C-4 analytical column followed by fluorimetric detection. The linearity, precision, accuracy, stability, selectivity and ruggedness were validated for the concentration ranges of 1-400 ng ml-1 for metoprolol and 0.5-200 ng ml-1 for OH-met. The same chromatographic conditions were slightly modified to quantify dextromethorphan and its metabolite dextrorphan in urine in the concentration range 0.052-0.05 microgram ml-1 as a method for screening for fast metabolizers.