PubMed · 15387046
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Jack J Hirschfeld. 2004. Codeine use.. https://doi.org/10.14219/jada.archive.2004.0356
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Recent evidence suggests that injection drug users who abuse heroin are at increased risk of CNS complications from human immunodeficiency virus (HIV) infection. Opiate drugs may intrinsically alter the pathogenesis of HIV by directly modulating immune function and by directly modifying the CNS response to HIV. Despite this, the mechanisms by which opiates increase the neuropathogenesis of HIV are uncertain. In the present study, we describe the effect of morphine and the HIV-1 protein toxin Tat(1-72) on astroglial function in cultures derived from ICR mice. Astroglia maintain the blood-brain barrier and influence inflammatory signaling in the CNS. Astrocytes can express mu-opioid receptors, and are likely targets for abused opiates, which preferentially activate mu-opioid receptors. While Tat alone disrupts astrocyte function, when combined with morphine, Tat causes synergistic increases in [Ca(2+)](i). Moreover, astrocyte cultures treated with morphine and Tat showed exaggerated increases in chemokine release, including monocyte chemoattractant protein-1 (MCP-1) and regulated on activation, normal T cell expressed and secreted (RANTES), as well as interleukin-6 (IL-6). Morphine-Tat interactions were prevented by the mu-opioid receptor antagonist beta-funaltrexamine, or by immunoneutralizing Tat(1-72) or substituting a nontoxic, deletion mutant (Tat(Delta31-61)). Our findings suggest that opiates may increase the vulnerability of the CNS to viral entry (via recruitment of monocytes/macrophages) and ensuing HIV encephalitis by synergistically increasing MCP-1 and RANTES release by astrocytes. The results further suggest that astrocytes are key intermediaries in opiate-HIV interactions and disruptions in astroglial function and inflammatory signaling may contribute to an accelerated neuropathogenesis in HIV-infected individuals who abuse opiates.
An HPLC system using a new, simple and rapid liquid-liquid extraction and high-performance liquid chromatography-diode array detector method (HPLC-DAD) detection was validated to determine tramadol concentration in rabbit plasma. The method described was applied to a pharmacokinetic study of intravenous tramadol injections in rabbits. The extraction with ethylacetate yielded good response. The recovery of tramadol from plasma averaged 90.40%. Serial plasma samples were obtained prior to, during and after completion of the infusion for determination of tramadol concentrations. Tramadol concentrations were measured using reverse-phase high-performance liquid chromatography and pharmacokinetic application with intravenous tramadol in rabbits revealed that tramadol followed one-compartment open model. Maximum plasma concentration (C(max)) and area under the plasma concentration-time curve (AUC) for tramadol were 14.3 microg mL(-1) and 42.2 microg h mL(-1), respectively. The method developed was successfully applied to a simple, rapid, specific, sensitive and accurate HPLC method for investigation of the pharmacokinetics of tramadol in rabbit plasma.
Opioids depress respiration and decrease chest wall compliance. A previous study in this laboratory showed that dopamine-D(1) receptor (D(1)R) agonists restored phrenic nerve activity after arrest by fentanyl in immobilized, mechanically ventilated cats. The reinstated phrenic nerve rhythm was slower than control, so it was not known whether D(1)R agonists can restore spontaneous breathing to levels that provide favorable alveolar gas exchange and blood oxygenation. It was also not known whether the agonists counteract opioid analgesia. In the present study, anesthetized, spontaneously breathing cats were given intravenous doses of fentanyl (18.0 +/- 3.4 microg/kg) that severely depressed depth and rate of respiration, lowered arterial hemoglobin oxygenation (HbO(2)), elevated end-tidal carbon dioxide (ETCO(2)), and abolished the nociceptive hind limb crossed-extensor reflex. Fentanyl (30 microg/kg) also evoked tonic discharges of caudal medullary expiratory neurons in paralyzed mechanically ventilated cats, which might explain decreased chest compliance. The selective D(1)R agonists 6-chloro APB (3 mg/kg) or dihydrexidine (DHD, 1 mg/kg) increased depth and rate of spontaneous breathing after opioid depression and returned HbO(2) and ETCO(2) to control levels. Opioid arrest of the nociceptive reflex remained intact. Pretreatment with DHD prevented significant depression of spontaneous breathing by fentanyl (17.5 +/- 4.3 microg/kg). Tonic firing evoked by fentanyl in expiratory neurons was converted to rhythmic respiratory discharges by DHD (1 mg/kg). The results suggest that D(1)R agonists might be therapeutically useful for the treatment of opioid disturbances of breathing without impeding analgesia.