No volume effect on retrograde colonic spread of rectally-administered ropivacaine gel.

BACKGROUND: Rectal administration of enemas, foams and suppositories is the most efficient way to deliver locally acting drugs to the distal colon. Ropivacaine, a long-acting local anaesthetic, was chosen as a candidate for a new rectal treatment of ulcerative colitis. AIM: To determine the colonic spread of a rectal ropivacaine formulation. METHODS: In this randomized, incomplete cross-over study, 12 male volunteers were given 200 mg ropivacaine HCl rectally in 20, 40, 60 and 80 mL hydroxypropyl methylcellulose gel. The viscosity of the gel was 1.1 Pa s. The spread of the radiolabelled (99mTc-labelled diethylenetriaminepenta-acetic acid) formulations was assessed by gamma-scintigraphy. Plasma was collected and analysed for ropivacaine base. RESULTS: The retrograde spread was limited to the descending colon and the difference between the studied volumes was not statistically significant. Only the 80-mL volume tended to have a larger distribution, although the 20-mL volume showed the same maximal distribution in two subjects. No distinct relationship between volume, retrograde colonic spread and plasma concentrations could be found. Ropivacaine was well tolerated. CONCLUSIONS: Rectal ropivacaine gel in all volumes between 20 and 80 mL can spread up to the descending colon. There was no relationship between either retrograde colonic spread or the administered volume and the ropivacaine plasma concentrations.

The effects on hypercarbic ventilatory response of sameridine compared to morphine and placebo.

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.

The effects on resting ventilation of intravenous infusions of morphine or sameridine, a novel molecule with both local anesthetic and opioid properties.

UNLABELLED: 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. IMPLICATIONS: 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.

Metabolism of ropivacaine in humans is mediated by CYP1A2 and to a minor extent by CYP3A4: an interaction study with fluvoxamine and ketoconazole as in vivo inhibitors.

BACKGROUND: Potential drug-drug interactions can be identified in vitro by exploring the importance of specific cytochrome P450 (CYP) isozymes for drug metabolism. The metabolism of the local anesthetic ropivacaine to 3-hydroxyropivacaine and (S)-2',6'-pipecoloxylidide was shown in vitro to be dependent on CYP1A2 and 3A4, respectively. In this in vivo model study we quantitated the role of these 2 isozymes for the metabolism of ropivacaine. METHODS: In a randomized, 3-way crossover study, 12 healthy subjects received a single dose of 40 mg ropivacaine intravenously alone or combined either with 25 mg fluvoxamine as a CYP1A2 inhibitor or with 100 mg ketoconazole as a CYP3A4 inhibitor twice daily for 2 days. Venous plasma and urine samples were collected over 10 hours and 24 hours, respectively. The samples were analyzed for ropivacaine base, 3-hydroxyropivacaine, and (S)-2',6'-pipecoloxylidide. RESULTS: Coadministration with fluvoxamine decreased the mean total plasma clearance of ropivacaine from 354 to 112 mL/min (68%), whereas ketoconazole decreased plasma clearance to 302 mL/min (15%). The relative changes in unbound plasma clearance were similar to the changes in total plasma clearance. The ropivacaine half-life (t1/2) of 1.9 hours was almost doubled during fluvoxamine administration and the plasma concentration at the end of infusion increased slightly, whereas the corresponding parameters after ketoconazole administration remained unchanged. Coadministration with ketoconazole almost abolished the (S)-2',6'-pipecoloxylidide concentrations in plasma, whereas fluvoxamine administration increased the (S)-2',6'-pipecoloxylidide levels. The fraction of dose excreted as 3-hydroxyropivacaine in urine decreased during fluvoxamine administration from 39% to 13%. CONCLUSIONS: CYP1A2 is the most important isozyme for the metabolism of ropivacaine. Drug-drug interactions with strong inhibitors of this isozyme could be of clinical relevance during repeated administration. A potent inhibitor of CYP3A4 causes a minor decrease in clearance, which should be of no clinical relevance.

Pharmacokinetics of three doses of epidural ropivacaine during hysterectomy and comparison with bupivacaine.

PURPOSE: Ropivacaine is a new long-acting aminoamide local anaesthetic, structurally related to bupivacaine. The clinical efficacy of 125 mg, 187.5 mg and 250 mg ropivacaine have been reported and compared with 125 mg bupivacaine for epidural analgesia during hysterectomy. In the pharmacokinetic part of this study the objectives were to 1) determine the dose proportionality in the pharmacokinetics of epidural ropivacaine, and 2) compare the pharmacokinetics of 125 mg ropivacaine and 125 mg bupivacaine. METHODS: In a randomized, double-blind controlled study, patients received one of four treatment regimens with ropivacaine (125, 187.5 or 250 mg) or bupivacaine (125 mg) as a 25 ml epidural bolus administered over three minutes. Peripheral venous blood samples were collected over 24 hr for ropivacaine or bupivacaine quantification using gas chromatography with nitrogen sensitive detection. Pharmacokinetic variables were derived from plasma concentration-time curve data. RESULTS: Fifty two women entered the study. Demographic characteristics were similar among groups. Six patients were excluded due to inadequate sensory block or an insufficient number of plasma samples. The peak plasma concentration (Cmax) of ropivacaine and the total area under the plasma concentration-time curve (AUC) increased proportionally with the dose. Apparent plasma clearance (CL) and the terminal half-life (t1/2) were similar in the three ropivacaine groups. When compared with the 125 mg ropivacaine group, the bupivacaine group had a longer terminal half life (P < 0.05). CONCLUSIONS: Epidural ropivacaine displays dose-proportional pharmacokinetic behaviour for doses of 125 mg to 250 mg. Ropivacaine has a shorter terminal half-life than bupivacaine.

Ropivacaine gel in active distal ulcerative colitis and proctitis -- a pharmacokinetic and exploratory clinical study.

BACKGROUND: Local anaesthetics have anti-inflammatory effects as indicated by preclinical and explorative clinical data. OBJECTIVE: To investigate the pharmacokinetics, tolerability and clinical efficacy of the new local anaesthetic ropivacaine in active distal ulcerative colitis. METHODS: Twelve patients were openly given 200 mg ropivacaine gel rectally twice daily for 2 weeks in this open study. RESULTS: Mean peak total plasma concentrations, Cmax, were 1.37, 1.26, 1.03 and 0.99 mg/L on treatment days 1, 3, 7 and 14. The mean unbound plasma concentrations at Cmax were 0.071, 0.058, 0.050 and 0.045 mg/L. The decrease in Cmax (P < 0.01) as well as in the area under the plasma concentration-time curve, AUC (P < 0.01), may be due to a decreased absorption but an increased metabolism cannot be excluded. The median time of Cmax was around 2 h and the mean terminal half-life was around 2.7 h. Mucosal inflammation assessed endoscopically at the most severely affected site decreased after 2 weeks of treatment (P < 0.01; blinded) and there was also a trend towards histological improvement (P = 0.06). Clinical symptoms, including total number of stools, blood in stools and diarrhoea increased (P < 0.05) during the study. The treatment was, in general, well tolerated with few gastrointestinal complaints and there were no unequivocal signs of systemic effects. CONCLUSIONS: Ropivacaine given rectally as a gel, 200 mg twice daily does not accumulate over a 2-week treatment period and carries a low risk for systemic adverse effects. The results suggest a therapeutic efficacy in active distal ulcerative colitis.