Inosine mediates the protective effect of adenosine in rat astrocyte cultures subjected to combined glucose-oxygen deprivation.

Preliminary evidence suggests adenosine, a neuromodulator, has neuroprotective properties during cerebral ischemia. It is unclear, however, if adenosine has glioprotective effects. We studied the effect of adenosine on cellular injury in astroglial cultures subjected to combined glucose-oxygen deprivation. Adenosine (100-1,000 microM)dramatically reduced astroglial injury, whereas the adenosine agonists 2-chloroadenosine (10 nM-100 microM), N6-cyclopentyladenosine (1 nM-10 microM), 5'-N-ethylcarboxamidoadenosine (10 nM-100 microM), and N6-2-(4-aminophenyl)ethyladenosine (10 nM-100 microM) had no effect. Furthermore, the adenosine antagonists 8-cyclopentyl-1,3-dipropylxanthine (1 nM-1 microM), xanthine amine congener (10 nM-10 microM), and 8-(p-sulfophenyl)-theophylline (10-300 microM) failed to reverse the protective effect of 200 microM adenosine. Next, adenosine degradation products were studied. Inosine proved to be glioprotective at concentrations nearly identical to those of adenosine, but hypoxanthine and ribose had no effect. The protective effect of 200 microM inosine was not reversed by 8-(p-sulfophenyl)theophylline (10-300 microM). Adenosine deaminase (1 unit/ml) had no effect on protection produced by adenosine, whereas erythro-9-(2-hydroxy-3-nonyl)adenine hydrochloride (10 microM) reversed the protective effect of adenosine. Dipyridamole (4 microM) inhibited the protective effect of both adenosine and inosine. We conclude that adenosine dramatically decreases astroglial injury during combined glucose-oxygen deprivation and that this protective effect appears to be mediated by inosine.

Nordihydroguaiaretic acid and RHC 80267 potentiate astroglial injury during combined glucose-oxygen deprivation.

Membrane phospholipid degradation has been proposed to play a key role in hypoxic-ischemic brain injury. We tested the hypotheses that both nordihydroguaiaretic acid, a phospholipase A2 and lipoxygenase inhibitor, and RHC 80267, a diacylglycerol lipase inhibitor, would decrease the release of [3H]arachidonic acid metabolites from prelabeled cultures of astroglia subjected to combined glucose-oxygen deprivation and that these inhibitors would also decrease astroglial injury during combined glucose-oxygen deprivation. Both nordihydroguaiaretic acid and RHC 80267 significantly inhibited the release of [3H]arachidonic acid metabolites during combined glucose-oxygen deprivation. This suggests that two separate enzymic pathways, the phospholipase A2 pathway and the phospholipase C/diacylglycerol lipase pathway, contribute to the release of astroglial [3H]arachidonic acid metabolites during combined glucose-oxygen deprivation. However, both of these lipase inhibitors increased astroglial cell death during combined glucose-oxygen deprivation, probably due to inhibition of arachidonic acid release. We speculate that arachidonic acid release may be a mechanism of astroglial self-preservation during combined glucose-oxygen deprivation.

Clinical uses of fentanyl, sufentanil, and alfentanil.

The pharmacokinetics, pharmacodynamics, and clinical uses of fentanyl, sufentanil, and alfentanil are reviewed. The fentanyl derivatives have reduced or eliminated many of the disadvantages of opioid anesthetics, such as incomplete amnesia and undesirable hemodynamic responses to surgery. Fentanyl is 50-100 times as potent as morphine and was the first of the three to be marketed. Sufentanil is even more potent than fentanyl. Alfentanil has the fastest onset of action, followed by sufentanil and then fentanyl. Alfentanil also has the shortest duration of action of the group. Most studies of these agents have been done to assess their role as anesthetics in cardiac surgery. All three provide cardiovascular stability when administered before noxious surgical stimuli, except when given as a single bolus during the induction of anesthesia. All seem to produce adequate anesthesia, particularly when used in combination with nitrous oxide. Because of its short duration of action, alfentanil is preferred for brief procedures or when rapid changes in the level of consciousness are desired. All three agents have also been used for analgesia; epidural administration provides adequate relief of pain. Fentanyl has been formulated as a transdermal patch that seems to provide the same degree of analgesia as a continuous i.v. infusion. Fentanyl has also been formulated as an investigational lozenge that has shown advantages as a preoperative sedative in children. As more is learned about these agents, their perioperative uses for anesthesia, analgesia, and sedation will continue to be refined.

Lack of effect of short-term passive smoking on the metabolic disposition of theophylline.

To test the hypothesis that involuntary smoking can result in increased drug metabolism, five nonsmoking healthy male volunteers (21-36 y old) were enrolled in a study of single-dose theophylline pharmacokinetics before and after intense environmental tobacco smoke (ETS) exposure. Exposure was provided by spending 3 h/day for five consecutive days in a small room with a smoking apparatus that burned four cigarettes simultaneously, at a rate of 20 cigarettes/h. Measurement of urine continine concentration demonstrated that significant absorption from ETS occurred in all subjects. However, pre- and post-exposure pharmacokinetic parameters for theophylline did not differ significantly: Vz = 0.438 vs 0.440 l.kg-1; t1/2 = 9.19 vs 9.69 h; CL = 34.4 vs 32.6 (ml.kg-1.h-1), respectively. Similarly, 24-hr urinary excretion of theophylline and its metabolites was unchanged by ETS exposure. We conclude that intense short-term passive smoking does not affect theophylline disposition. The possibility of chronic ETS exposure causing alterations in drug metabolism cannot be excluded.

Interlot variability in gentamicin and tobramycin concentration and its possible significance.

Aminoglycoside therapy is routinely monitored at many institutions. It is widely known that serum concentrations of gentamicin and tobramycin may differ markedly among patients receiving the same doses of these drugs. One possible source of this variability may be interlot variation in the concentration of these drugs in commercial preparations. A study was designed to evaluate inter- and intralot variation in gentamicin and tobramycin concentrations at the labeled concentrations of 10 and 40 mg/ml. Multiple samples from six to 10 lots of commercially available gentamicin sulfate injection (Elkins-Sinn, Inc.) and tobramycin sulfate injection (Eli Lilly & Co.) were studied at each concentration. The actual percentage concentration of gentamicin in various lots ranged from 101 to 134% of the labeled concentrations; the actual percentage range was 101-109% at 10 mg/ml and 102-134% at 40 mg/ml labeled concentration. The actual percentage concentration of tobramycin in various lots ranged from 103 to 122% of labeled concentration; the actual percentage range was 107-117% at 10 mg/ml and 103-122% at 40 mg/ml labeled concentration. The intralot variation was less than 4% for both drugs at two concentrations. Based on these results, an 80-mg dose may in fact contain 107 mg of gentamicin or 98 mg of tobramycin. This may be clinically important in the care of patients and may at least in part explain the large variation in serum concentrations and difficulty in prediction of dosage requirements from routine monitoring. Furthermore, the available literature on pharmacokinetics, efficacy, and toxicity has not considered this interlot variation in aminoglycoside concentration.(ABSTRACT TRUNCATED AT 250 WORDS)

Adverse effects of meperidine, promethazine, and chlorpromazine for sedation in pediatric patients.

A combination of meperidine (M) 25 mg/ml, promethazine (P) 6.5 mg/ml, and chlorpromazine (C) 6.5 mg/ml is widely used to produce sedation in pediatric patients. A dose of MPC 0.1 ml/kg is recommended for cardiac catheterization, but no specific guidelines for dosing or frequency of monitoring have been established for patients undergoing other types of procedures. The adverse effects of MPC were studied prospectively in 95 patients undergoing various procedures. MPC was given parenterally at a dose of 0.07-0.11 ml/kg. Four patients developed respiratory depression. In these patients, the lowest respiratory rate ranged from 12 to 20 per minute. The lowest pulse rate ranged from 92 to 102 per minute. Three patients had received recommended or lower than recommended doses of MPC. One who received MPC 0.07 ml/kg developed respiratory arrest within 30 minutes; another required naloxone, and all recovered within 10 hours. These cases suggest the need for frequent monitoring and specific dosing guidelines for MPC use in pediatric patients.