piperidines and sameridine

Sameridine is a new compound with both local anesthetic and opioid properties (partial micro -opioid receptor agonist). It was intended for intrathecal administration to provide anesthesia for surgery and extended postoperative analgesia. In this double-blinded pharmacodynamic study with a two-parallel-group design, we investigated, during a 24-h period, the effects of intrathecal sameridine and bupivacaine on ventilation at rest and at ventilatory challenges during hypercarbia and hypoxia. Twenty-four healthy volunteers received either 25 mg of sameridine or 15 mg of bupivacaine intrathecally. Ventilation was measured by pneumotachography and in-line capnography. Sedation was rated by a visual analog scale. Segmental spread and development of motor and sensory block were similar in both groups. There was a decrease in tidal volume 2.5 to 6 h after injection in the bupivacaine group. This was seen only at 4 h in the sameridine group. There were no other major ventilatory differences between sameridine and bupivacaine during resting ventilation. Hypercarbic (tidal volume, mean inspiratory flow) and hypoxic (mean inspiratory flow) ventilatory responses were slightly decreased in the sameridine group, but not in the bupivacaine group. We conclude that intrathecal administration of sameridine or bupivacaine in healthy volunteers produces similar, minor effects on ventilatory responses over a 24-h observation period.

Topics: Adult; Algorithms; Anesthetics, Local; Bupivacaine; Carbon Dioxide; Conscious Sedation; Double-Blind Method; Electrocardiography; Female; Humans; Hypoxia; Injections, Spinal; Male; Monitoring, Intraoperative; Motor Neurons; Nerve Block; Neurons, Afferent; Piperidines; Receptors, Opioid, mu; Respiratory Mechanics

Sameridine, a novel molecule, has both local anesthetic and partial mu-opioid receptor properties. The aim of this single, blinded, randomized, four-way cross-over study was to investigate the hypercarbic ventilatory response (HCVR) in 12 healthy volunteers. A 20-min IV infusion of two doses of sameridine 0.15 mg/kg (S-Small) and 0.73 mg/kg (S-Large) were compared with 0.10 mg/kg of morphine and placebo. Ventilation was studied repeatedly for 2 h by pneumotachography and inline capnography. The hypercarbic ventilatory response was measured after addition of 4% CO(2) to inspired air until steady state. A visual analog scale followed sedation. After drug infusion there was a significant rightward shift (on average 4.5 mm Hg) of the ventilatory response curve (HCVR = Delta VE/Delta ETCO(2)) in the S-Large group. There were no changes of HCVR in the other groups. On a molar basis, the S-Large dose was 6.5 times the morphine dose, and such a dose would have been expected to cause a 12 mm Hg rightward shift. This discrepancy in effect is most likely a result of the partial mu-agonist effect of sameridine. Sedation was most pronounced after S-Large and morphine infusions. The authors concluded that a large IV dose of sameridine depressed the hypercarbic ventilatory response, whereas a smaller, clinical dose did not.

Topics: Analgesics, Opioid; Anesthetics, Local; Carbon Dioxide; Cross-Over Studies; Humans; Morphine; Piperidines; Prospective Studies; Respiration; Single-Blind Method

Sameridine has both local anesthetic and partial mu-opioid receptor agonistic properties. The aim of this single-blinded, randomized, three-way cross-over study of 12 subjects was to investigate the effects on resting ventilation of two doses of sameridine: 0.15 mg/kg (S-Small) and 0.73 mg/kg (S-Large) compared with 0.10 mg/kg morphine. Each drug was infused IV over 20 min. Ventilation was measured by pneumotachography and in-line capnography, and sedation was rated by the subjects using a visual analog scale (VAS). Plasma was collected and analyzed for sameridine and morphine. At the end of drug infusion, minute ventilation (VE) and tidal volume (VT) were reduced in the S-Large group, and VE was reduced in the morphine group. End-tidal CO2 increased in both groups (P < 0.05), but respiratory rates remained unchanged. In the S-Small group, no ventilatory changes were recorded. In the S-Large group, the median sedation score was 6.8 cm with corresponding values in the morphine and S-Small groups of 3.3 and 2.5 cm, respectively. There was a relationship between the plasma concentration of sameridine and the depression of ventilation. We conclude that sameridine influences resting ventilation and that this effect is directly related to plasma concentrations of sameridine. From a ventilatory aspect, a clinical dose of sameridine with both local anesthetic and opioid properties seems safe.. Sameridine, a molecule with both local anesthetic and analgesic properties, impaired resting ventilation after a large IV dose (0.73 mg/kg), more so than 0.10 mg/kg IV morphine. A clinical dose of sameridine (0.15 mg/kg) did not have any effects on ventilation.

Topics: Adult; Analgesics; Analgesics, Opioid; Blood Pressure; Carbon Dioxide; Cross-Over Studies; Dose-Response Relationship, Drug; Female; Heart Rate; Humans; Infusions, Intravenous; Male; Middle Aged; Morphine; Piperidines; Pulmonary Ventilation; Rest; Single-Blind Method

Sameridine is a new compound with local anesthetic and analgesic properties when injected intrathecally. We studied the anesthetic and analgesic efficacy of three doses of isobaric sameridine (15, 20, and 23 mg) compared with 100 mg of hyperbaric lidocaine for spinal anesthesia in 140 healthy male patients undergoing inguinal hernia repair. Patients received spinal anesthesia with 4 mL of the study drug injected at the L2-3 or L3-4 interspace in the lateral decubitus position. All three doses of sameridine provided spinal anesthesia similar to lidocaine, with a slightly longer time to reach peak block height. The failure rate was highest in the 15-mg sameridine group, and accrual was discontinued in that group after 35 patients. The duration of blockade was shorter with lidocaine, but the time to voiding and ambulation was similar in all groups. Patients receiving sameridine were less likely to request morphine for postoperative analgesia and were less likely to request any analgesia in the first 4 h after injection of the drug. Use of oral analgesics (hydrocodone and acetaminophen) was similar in all groups after the first 4 h of the 24-h observation. We conclude that, in the three doses studied, sameridine provided spinal anesthesia similar to lidocaine, but with residual analgesia after drug injection that reduced the need for systemic analgesics in the first 4 h postoperatively.. In this clinical trial, we show the potential efficacy of a class of drugs that can produce both spinal anesthesia and postoperative analgesia when used for hernia repair.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Analgesia; Anesthesia, Spinal; Anesthetics, Local; Dose-Response Relationship, Drug; Hernia, Inguinal; Humans; Lidocaine; Male; Middle Aged; Piperidines; Time Factors

A gas chromatographic method was developed and validated for the determination of sameridine in human plasma. Sameridine is a new type of compound with both local anaesthetic and analgesic properties, when administered intrathecally. The method is based on liquid-liquid extraction of sameridine from 1.0 ml of plasma, followed by gas chromatography with nitrogen-phosphorus detection. Method validation results showed that this method is very sensitive, selective and robust. The limit of quantification was 1 nM for 1.0 ml of human plasma in the low-level range (1.00-75.0 nM) and the between-day accuracy and precision were measured at 99-104% of nominal values and 3.4-5.6% (RSD), respectively.

Topics: Analgesics; Anesthetics, Local; Chromatography, Gas; Humans; Nitrogen; Piperidines; Reproducibility of Results; Sensitivity and Specificity

The metabolism of sameridine (LPB) (an amide-type local anesthetic-analgesic agent with a hexyl side chain) to carboxylic acid derivatives by isolated male rat hepatocytes was studied using gradient reversed-phase HPLC and mass spectrometry. Incubation of sameridine with hepatocytes resulted in the formation of numerous different metabolites. Two carboxylic acids, i.e., the C(6) and C(4) carboxylated derivatives of sameridine (LPB-6'-oic acid and LPB-4'-oic acid), were found to be produced from the intermediate omega-hydroxy metabolite (6'-hydroxy-LPB). Shortening of the alkyl chain in LPB-6'-oic acid by two carbon atoms resulted in LPB-4'-oic acid. However, incubation of rat hepatocytes with 5'-hydroxy-LPB [the (omega-1)-hydroxy derivative of sameridine] did not give rise to any carboxylated derivative. Addition of SKF525A inhibited the metabolism of sameridine by rat hepatocytes, indicating that the initial step is catalyzed by cytochrome P450. Furthermore, the metabolism of sameridine to LPB-4'-oic acid was enhanced in hepatocytes isolated from rats treated with clofibrate, an up-regulator of peroxisomal fatty acid beta-oxidation and of microsomal cytochrome P450 4A. L-Carnitine (which increases the rate of mitochondrial fatty acid beta-oxidation) had no effect on the level of LPB-4'-oic acid produced by isolated rat hepatocytes. The metabolism of 6'-hydroxy-LPB to LPB-6'-oic acid was inhibited almost completely by 4-methylpyrazole, an inhibitor of alcohol dehydrogenase. Considered together, our findings suggest that cytochrome P450 4A, cytosolic dehydrogenases, and the enzymes involved in peroxisomal fatty acid beta-oxidation catalyze the metabolism of sameridine to LPB-4'-oic acid.

Topics: Anesthetics, Local; Animals; Anticholesteremic Agents; Clofibrate; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Enzyme Inhibitors; Fomepizole; Liver; Male; Peroxisomes; Piperidines; Proadifen; Pyrazoles; Rats; Rats, Sprague-Dawley

Sameridine is a type of compound with both local anaesthetic and analgesic effects with the clinical intention to be used intrathecally (i.t.) in order to provide both surgical anaesthesia and prolonged postoperative analgesia. Before new drugs are introduced for clinical use, they must be tested for potential toxic effects.. In the present study sameridine (5 or 10 mg/ml), bupivacaine (5 mg/ml) or saline (9 mg/ml) was injected intrathecally in rats twice, daily (at 07:00 and 19:00), 5 days a week for 2 weeks. Thereafter, the rats were anaesthetised, perfused and the spinal cords were prepared for microscopic investigation. A morphologic method, using light and electron microscopic examination of the cross-section of the spinal cord, was combined with a quantitative morphometric analysis of the number and size of neuronal cells in the dorsal horn as a sensitive indicator of neurotoxicity. Using the laser-Doppler flowmetry technique, the effects of saline and sameridine (1, 5 and 10 mg/ml) on spinal cord blood flow (SCBF) was studied.. No signs of neurotoxicity could be seen in any of the animals and no significant differences were seen when comparing the cell number or cell sizes in the groups injected with sameridine, bupivacaine or saline. After i.t. administration of 10 mg/ml sameridine a significant, short-lasting, decrease in SCBF (72% of pre-drug value) was seen.. In conclusion, our studies do not show any signs of neurotoxic effects of i.t. administration of sameridine in the rat. A transient decrease in SCBF was noted after i.t. injection of sameridine 10 mg/ml.

Topics: Analgesics; Anesthesia, Spinal; Anesthetics, Local; Animals; Bupivacaine; Cell Count; Cell Size; Injections, Spinal; Laser-Doppler Flowmetry; Male; Microscopy, Electron; Neurons; Piperidines; Rats; Rats, Sprague-Dawley; Regional Blood Flow; Single-Blind Method; Spinal Cord

Sameridine is a new candidate drug with both local anaesthetic and analgesic properties. The free concentration of sameridine in blood plasma was determined by coupled-column liquid chromatography. Following adjustment of the pH and the temperature of the plasma samples, the free fraction was prepared by ultrafiltration. The coupled-column liquid chromatographic system consisted of a reversed-phase column, a cation-exchange extraction column and a cation-exchange analytical column. Sameridine was detected by UV determination at 205 nm and the system showed high selectivity. The limit of quantification was 1 nM and the within-day precision was 4.6% (R.S.D., n = 10).

Topics: Analgesics; Anesthetics, Local; Chromatography, Liquid; Humans; Piperidines; Proteins; Ultrafiltration

Sameridine, a new substance with both local anesthetic and opioid effects, was administered intrathecally for the first time to humans, i.e. in patients subjected to arthroscopic knee joint surgery.. A dose-escalating (10, 15, 20 and 25 mg), open study was performed in 33 patients. Only two patients were included in the 25 mg group.. Sameridine provided good quality of surgical anesthesia in all patients except those receiving 10 mg. The maximum level of sensory block, Th5-Th7, was reached within 30 min with a median duration of 3.6-3.9 h. The motor block was more profound with increasing dose, but never lasted longer than the sensory block. The influence on heart rate and blood pressure was minor and atropine and ephedrine were needed in four patients. No clinically significant ECG-changes were detected and no arrhythmias were recorded. Oxygen saturation and respiratory rate did not decrease in a clinically significant way and were not affected by concomitant morphine given i.v. postoperatively. There were few side-effects, the most frequent being mild pruritus (10/33).. Sameridine provided clinically adequate anesthesia for the patients receiving the doses of 15, 20 and 25 mg. Further studies are needed to evaluate the substance and it is of great interest to clinically investigate the opioid component with respect to postoperative analgesia.

Topics: Adolescent; Adult; Anesthesia, Spinal; Anesthetics, Local; Arthroscopy; Electrocardiography; Endoscopy; Hemodynamics; Humans; Injections, Spinal; Intraoperative Complications; Knee Joint; Male; Middle Aged; Neuromuscular Blockade; Pain Measurement; Pain, Postoperative; Piperidines; Respiratory Mechanics