Drug Delivery across Barriers to the Middle and Inner Ear

The prevalence of ear disorders has spurred efforts to develop drug delivery systems to treat these conditions. Here, recent advances in drug delivery systems that access the ear through the tympanic membrane (TM) are reviewed. Such methods are either non-invasive (placed on the surface of the TM), or invasive (placed in the middle ear, ideally on the round window [RW]). The major hurdles to otic drug delivery are identified and highlighted the representative examples of drug delivery systems used for drug delivery across the TM to the middle and (crossing the RW also) inner ear.     

LOUIS KAHN'S THEORY OF ‘INSPIRED RITUAL’ AND ARCHITECTURAL SPACE

In his drawing from 1971, titled The Room, Louis Kahn depicts two people within an interior that derives its shape from ancient Roman buildings. He was indebted to Frank Brown, the historian at the American Academy in Rome, who argued that the Romans fashioned rituals as the basis for constructing architectural spaces. I will show that Kahn developed a related theory of design founded on an ‘inspired ritual,’ illustrating this in The Room, which is an appropriate setting for the two figures involved in a conversation.     

Vanilloid receptor agonists potentiate the in vivo local anesthetic activity of percutaneously injected site 1 sodium channel blockers

BACKGROUND: Capsaicin, the pungent ingredient in chili peppers, is a vanilloid with noxious and analgesic effects that inhibits tetrodotoxin-resistant sodium currents. Because tetrodotoxin-resistant currents are found primarily in small-diameter nociceptor afferents of the peripheral nerves, their inhibition may lead to selective analgesia. Therefore, the authors evaluated the interactions between tetrodotoxin, a site 1 sodium channel blocker, and capsaicin on nerve blockade in vivo. METHODS: Percutaneous sciatic nerve injections with 0 to 9.9 mM capsaicin, 0 to 120 microM tetrodotoxin, or both were administered to male Sprague-Dawley rats. Thermal nociceptive and motor blockade were measured. Data were expressed as medians with 25th and 75th percentiles. RESULTS: Capsaicin produced a transient increase in thermal latency with no effect on motor strength. Tetrodotoxin reduced motor strength for a longer duration than nociception. The interaction between tetrodotoxin and capsaicin was synergistic, as evidenced by (1) supraadditive prolongation of both nociceptive and motor block, with the effect of capsaicin reversed by the vanilloid antagonist capsazepine, and (2) synergism in the frequency that rats achieved maximal block shown by isobolographic analysis. The combination of tetrodotoxin and capsaicin showed less motor predominance than tetrodotoxin did alone. Similar interactions were found between tetrodotoxin and resiniferatoxin (another vanilloid), and between capsaicin and saxitoxin (another site 1 sodium channel blocker), but much less so between bupivacaine and capsaicin. CONCLUSIONS: Site 1 sodium channel blockers and vanilloids have synergistic effects on nerve blockade in vivo. These interactions may be useful in developing prolonged local anesthetics and elucidating mechanisms of functionally selective nerve blockade.     

Sciatic nerve blockade in infant, adolescent, and adult rats: a comparison of ropivacaine with bupivacaine

BACKGROUND: Ropivacaine is a newly introduced local anesthetic. No data are available regarding its safety, efficacy, or sensory-selectivity in children. The sciatic block duration and systemic toxicity of bupivacaine and ropivacaine were compared among infant, adolescent, and adult rats. METHODS: Infant, adolescent, and adult rats received blocks with ropivacaine or bupivacaine. Nociceptive, proprioceptive, and motor blockade were assessed. Systemic effects (contralateral leg analgesia, seizures, respiratory distress, apnea) were quantified. Plasma local anesthetic concentrations were measured at terminal apnea. RESULTS: Nerve blockade for a given absolute dose lasted longer in infants than in older rats for both drugs. Block duration from ropivacaine generally was the same as or slightly shorter than bupivacaine. There was no difference in sensory-selectivity between the drugs. Doses required to induce all systemic toxicity indices were inversely related to age (e.g., the lethal dose in 50% of animals [LD50] of ropivacaine in infants is 155 mg/kg; in adults it is 54 mg/kg). All indices of toxicity occurred at higher doses per kilogram for ropivacaine than bupivacaine, at all ages (e.g., the LD50 of bupivacaine in infants is 92 mg/kg; in adults it is 30 mg/kg). Plasma concentrations at terminal apnea were higher for ropivacaine than for bupivacaine at all ages, and were higher in infants than in older rats. CONCLUSIONS: Ropivacaine resembles bupivacaine in its local anesthetic effects but has a greater margin of safety. For a given absolute dose, sciatic blockade in infant rats lasts longer than in adolescents or adults. Although the doses (in milligrams per kilogram) causing toxicity were much higher in infants than in adults, this probably does not correspond to a wider therapeutic index.     

Computer-assisted adjustment of inspired oxygen concentration improves control of oxygen saturation in newborn infants requiring mechanical ventilation

Open-loop computer control of inspired oxygen concentration was evaluated in 16 newborn infants requiring mechanical ventilation. FIO2 and oxygen saturation were compared for 2-hour periods of computer versus routine manual FIO2 adjustment. During computer-assisted FIO2 adjustment, patients spent more time at the target SaO2 and less time with SaO2 < 90%.