The humidity output and CO, elimination of the Bain circuit were tested on a simulated adult patient. The moisture content of inspired gases was found to be adequate when the circuit was used with a minute volume of 8.4 L/niin and a fresh gas inflow of 4.9 L/min (65 percent relative humidity at room temperature at the onset of experimentation, rising to 100 percent after 80 minutes). However, the mean inspired CO, concentration increased from 0.8 percent to 5.5

BACKGROUND:Currently available local anesthetics have relatively brief durations of action. An ultralong-acting local anesthetic would benefit patients with acute and chronic pain. The authors prepared and characterized a novel liposomal bupivacaine formulation using remote loading of bupivacaine along an ammonium sulfate gradient and assessed its efficacy in humans. METHODS:A large multivesicular liposomal bupivacaine formulation was prepared by subjecting small unilamellar vesicles to successive freeze-and-thaw cycles. Bupivacaine hydrochloride was then remotely loaded into the liposomes along an ammonium sulfate gradient ([(NH4)2SO4)]intraliposome/[(NH4)2SO4)]medium > 1000). The liposomes were then characterized for size distribution; drug-to-phospholipid ratio; in vitro release profile at 4 degree, 21 degree C, and 37 degree C; sterility; and pyrogenicity. Six subjects each received six intradermal injections in the lower back with 0.5 ml of 0.5, 1.0, and 2% liposomal bupivacaine; 0.5% standard bupivacaine; saline; and "empty" liposomes. Duration of analgesia was assessed using pinprick testing of the skin directly over the injection sites. Results were compared using the log-rank test. RESULTS:The mean large multivesicular vesicle size was 2439 +/- 544 nm, with a drug-to-phospholipid ratio of 1.8, fivefold greater than results previously reported. In vitro release was slowest at 4 degree C. The median duration of analgesia with 0.5% standard bupivacaine was 1 h. The median durations of analgesia after 0.5, 1.0, and 2.0% liposomal bupivacaine were 19, 38, and 48 h, respectively. Neither saline nor "empty" liposomes produced analgesia. CONCLUSIONS:This novel liposomal formulation had a favorable drug-to-phospholipid ratio and prolonged the duration of bupivacaine analgesia in a dose-dependent manner. If these results in healthy volunteers can be duplicated in the clinical setting, this formulation has the potential to significantly impact the management of pain.

All of the therapeutic properties of marihuana (analgesic, antiemetic, appetite stimulant, antiglaucoma) have been duplicated by the tetrahydrocannabinol (THC) molecule or its synthetic derivatives. Today, the molecular mechanisms of action of these compounds have led to a general understanding of the pharmacological effects of marihuana and of its therapeutic properties. These mechanisms involve the specific binding of THC to the 7-transmembrane (7TM) domain G protein-linked receptor, a molecular switch which regulates signal transduction in the cell membrane. The natural ligand of the 7TM receptor is an eicosanoid, arachidonylethanolamide (AEA), generated in the membrane and derived from arachidonic acid. THC acts as a substitute ligand to the 7TM receptor site of AEA. THC would deregulate the physiological function of the 7TM receptor and of its ligand AEA. As a result, the therapeutic effects of the drug may not be separated from its adverse psychoactive and cardiovascular effects. The binding of THC to the 7TM receptor site of AEA induces allosteric changes in the receptor sites of neurotransmitter and opiates resulting in variable interactions and pharmacological responses. The pharmacokinetics of THC with its prolonged storage in fat and its slow release result in variable and delayed pharmacological response, which precludes precise dosing to achieve timely therapeutic effects. The experimental use of THC and of its synthetic analogues, agonists, and antagonists has provided novel information in the nature of molecular signaling in the cell membrane. As a result, the relationships between allosteric receptor responsiveness, molecular configuration of proteins, and physiological regulation of cellular and organ function may be further investigated.

We evaluated the intensity of the withdrawal symptoms after the discontinuation of the morphine infusion in rats. Opiate addiction was induced by progressively increasing intraperitoneal morphine infusion rates. The control group (Group 1) received normal saline. The initial morphine rates were 1, 4, and 16 mg kg(-1) h for Groups 2, 3, and 4, respectively. Infusion rates were gradually increased by a factor of 1.4, 2, 2.8, and 4 on the second, third, fourth, and fifth days, respectively. The last rate was used for 48 h and then infusions were disconnected. Weight reduction, food consumption, and water intake were used for evaluation of withdrawal. All morphine groups showed a significant reduction of body weight during the 4 postdiscontinuation days and a decline in food and water intake on the first postdiscontinuation day. All changes were dependent on the morphine infusion concentration. No changes were observed in the control group. We suggest that the rat model used in this study may be utilized for quantification of spontaneous withdrawal.

Objective. Postoperative intravenous (IV) versus epidural morphine patient-controlled analgesia (PCA) were compared regarding maintenance of initial PCA route, pain levels, side effects, and levels of satisfaction. Additionally, the role of preoperative attitudinal expectations in predicting postoperative levels of satisfaction with pain management as well as maintenance of initial PCA route was evaluated.Design. After either abdominal or thoracic surgery, 70 eligible patients were randomized to receive morphine either through an epidural route (n = 37) or an intravenous PCA pump (n = 33).Setting. A large tertiary university teaching hospital in a major northeastern city.Outcome measures. Patients completed visual analogue rating scales 1 week before Surgery regarding attitudes such as expectations of satisfaction with pain management after surgery and expectations of medication efficacy postsurgically. Postoperatively, beginning the day after surgery, patients were asked to complete visual analogue rating scales every 12 hours until they were discharged, for a maximum of 3 postoperative days. The scales evaluated included pain, ability to think, and satisfaction with pain control.Results. There were no significant between-group differences on the postoperative visual analogue scales. Although the overall rate of changing the initial PCA route to which the patients were randomized was identical for both groups (30%), those patients who had thoracic surgery changed their route of PCA administration significantly less when their initial PCA route was epidural (20%) than when their initial PCA route was IV (46%) (P <.05). Patients who were satisfied with pain control postoperatively were more likely to have been started on IV PCA (P =.001), have lower preoperative expectations of postoperative satisfaction with pain (P <.001), and have higher preoperative expectations of medication effects on postoperative pain (P <.001). Additionally, older patients (P =.007) and patients with lower preoperative expectations of postoperative satisfaction with pain (P =.003) were more likely to adhere to their initial treatment protocol.Conclusions. Both techniques, IV and epidural PCA, result in high levels of satisfaction. Satisfaction with PCA can be accurately predicted in nearly three of four patients based on initial PCA route and preoperative attitudes. Additionally, maintaining the initial treatment plan can be accurately predicted based on age and preoperative attitudes. Patient expectations about pain relief should be addressed preoperatively, particularly with younger patients, for optimal results.

Purpose. To evaluate the dehydration-rehydration technique to prepare a formulation of liposomal bupivacaine, and to assess its analgesic efficacy.

We tested the hypothesis that remifentanil-nitrous oxide (N2O) anesthesia shortens postoperative emergence and recovery compared with an isoflurane-N2O-fentanyl combination in elderly patients undergoing spinal surgery. A total of 60 patients (>65 yr old) were randomly assigned to one of two groups for maintenance of anesthesia. After the induction with 3.6 ± 1.2 mg/kg IV thiopental and endotracheal intubation facilitated with 1.4 ± 0.5 mg/kg succinylcholine, patients were maintained with either 0.5%–1.5% isoflurane, 70% N2O, and up to 7 μg/kg fentanyl (iso/fent group) or 48 ± 11 μg/kg remifentanil and 70% N2O (remi group). A mini-mental status examination was used to assess cognitive ability preoperatively, at 15, 30, and 60 min after arrival at the postanesthesia care unit and again 12–24 h postoperatively. The time from the conclusion of anesthesia to spontaneous respiration was similar in both groups. Times to eye opening (4.8 ± 2.6 vs 2.3 ± 1.1 min), extubation (6.8 ± 3.8 vs 3.2 ± 2.1 min), and verbalization (9.9 ± 6.2 vs 3.9 ± 2.6 min) were significantly shorter for the remi group (P < 0.05). Postoperative mini-mental status examination scores were significantly lower in the iso/fent group at 15 (16.3 ± 5.8 vs 23.7 ± 3.3), 30 (20.2 ± 5.2 vs 26.3 ± 2.7), and 60 min (23.5 ± 4.4 vs 27.5 ± 2.0) (P < 0.001); however, the scores equalized after 12 h. Requirements for postoperative analgesics were similar in the two groups. More patients in the remi group were treated with antiemetics (21 vs 7, P = 0.06). Use of remifentanil-N2O for maintenance did not shorten the overall length of stay in the postanesthesia care unit; a stay is often related to multiple administrative issues, rather than cognitive recovery. Implications Maintenance of anesthesia with remifentanil-nitrous oxide (N2O), compared with isoflurane-N2O-fentanyl, can safely shorten postoperative recovery of cognitive function in a geriatric population. Earlier recovery may facilitate postoperative neurological assessment. Use of remifentanil-N2O for maintenance did not shorten the overall length of stay in the postanesthesia care unit, a stay often related to multiple administrative issues, rather than cognitive recovery.

The purpose of our study is to compare haemodynamic responses and the ischaemic potential of commonly used inotropes (dopamine, dobutamine and milrinone) using a computer model of the cardiovascular system. Cardiotropic drugs interact with the model by changing ventricular elastance and resistance of the individual circulation. All three drugs increase cardiac index in a dose-dependent manner. Dopamine at medium and high infusion rates increases heart rate, systemic vascular resistance and arterial blood pressure. The associated increase in coronary blood flow, however, is not sufficient to account for increased oxygen demand. Both dobutamine and milrinone decrease vascular resistance and increase coronary blood flow. The more pronounced increase in heart rate associated with dobutamine, however, results in a higher ischaemic potential for this drug. Our simulation demonstrates that although all the drugs studied improve cardiac function in simulated patients with heart failure, milrinone accomplishes this at a lower energy cost. The computer simulation developed can be used to assess the complex effect of cardiotropic drugs and possibly suggest optimal drug therapy in specific clinical situations.

Background The in vitro adaptive responses of delta opiate receptors (DOR) to chronic ethanol treatment have been well documented. The acute effects of ethanol on these receptors are not well characterized beyond its effect on ligand binding. The aim of this study was to evaluate the acute effects of clinically relevant concentrations of ethanol (50-200 mm) on the saturation binding kinetics, receptor/ligand internalization, and agonist stimulation of G-protein coupling in N18TG2 cells expressing the Flag epitope-tagged mouse DOR. Methods Confocal microscopy was used to localize Flag epitope-tagged DOR in N18TG2 cells. Saturation binding assays at 4 degrees C and 37 degrees C were conducted in the absence or presence of ethanol on cells not pretreated or pretreated with ethanol for 30 min at 37 degrees C. Highly specific delta agonist, DPDPE ([D-Pen2,D-Pen5]enkephalin), was used in these studies. The effect of ethanol on agonist stimulation of G-protein coupling was examined using [35S]GTPgammaS (guanosine-5'-O-(3-thio)triphosphate) binding to membranes. Agonist-mediated receptor internalization was examined using flow cytometry of cells labeled with the antiserum directed against the Flag epitope, and the ligand internalization was examined using [3H]DPDPE. Results Ethanol decreased the binding of the agonist [3H]DPDPE, and not the antagonist [3H]diprenorphine, in a dose-dependent manner. These effects were temperature-dependent. Ethanol reversibly inhibited agonist stimulation of [35S]GTPgammaS binding. In non-pretreated cells, ethanol decreased the rate of receptor/ligand internalization, but this effect was not seen in ethanol pretreated cells. Taken together, these results suggest that pretreatment of N18TG2 cells with ethanol induces compensatory mechanisms that allow the receptor to function efficiently in its presence. Conclusion Acute ethanol decreased the binding, agonist-mediated functional coupling and receptor/ligand internalization in N18TG2 cells expressing epitope-tagged DOR. In these cells, 30-min pretreatment with ethanol was sufficient to reverse these effects.