No abstract

The relationships between plasma morphine and metabolite (M3G and M6G) concentrations and analgesic efficacy were investigated in an open study of 39 cancer pain patients receiving chronic oral morphine therapy with either morphine sulfate solution or controlled-release morphine tablets. There were no differences in morphine, metabolite kinetics, or analgesic efficacy between equivalent doses of conventional or controlled-release formulations. The increase in morphine plasma concentration after a dose (1 hr for normal release, 2 hr for controlled release) was correlated significantly with the dose of morphine (r = 0.914, P < 0.001). There was a significant reduction in pain intensity (P < 0.05) and increase in pain relief (P < 0.001) after the dose of morphine administration, when compared with the predose score. One-half of the patients had mild and tolerable adverse effects. Patients were classified by mean pain relief between doses as having optimal, moderate, or poor pain control. No simple relationship was found between morphine plasma concentration and pain control. Morphine plus M6G concentrations in the "optimal control" group (751.2 +/- 194 nmol/L), however, were more than twice those found in the "moderate control" group (276.9 +/- 41.9 nmol/L) (P < 0.05), and no patient in the moderate control group had a morphine plus M6G concentration greater than 405 nmol/L. These results support the importance of M6G in morphine analgesia. For these hospitalized patients, there appeared to be a therapeutic range of morphine plus M6G plasma concentrations for optimal pain control with a lower limit of 400 nmol/L predose.

I Secretion of catecholamines (CA) and dopamine-f-hydroxylase (DBH) activity from the retrogradely perfused cat adrenal gland was studied following ouabain infusion. Perfusion with ouabain (10-s M) for 10 min caused a gradual release of CA in the effluent which reached its peak 30 min after the ouabain pulse, and was maintained constant for at least 1 h. The effect of ouabain seemed to be irreversible. 2 Mecamylamine, while blocking the CA secretory effects of acetylcholine (ACh) perfusion, did not affect the secretion of CA evoked by ouabain. In denervated adrenal glands, ouabain-induced CA secretion was similar to that in the contralateral, innervated gland. However, physostigmine perfusion potentiated the CA secretory effects of ouabain. 3 The release of CA evoked by ouabain was accompanied by a proportional release of DBH activity. The time course of appearance of DBH activity followed the pattern of CA release. 4 The CA and DBH outputs in response to a pulse of ouabain were suppressed in the absence of calcium. Calcium reintroduction to a calcium-free perfused, ouabain-treated gland not only restored but greatly potentiated the release of CA and DBH. The amplitude of the secretory response to calcium reintroduction in ouabain-treated glands was proportional to the extracellular calcium concentration, and was antagonized by an external sodium-deficient medium. 5 These data demonstrate that ouabain releases CA from the perfused cat adrenal gland by a calcium-dependent exocytotic mechanism. The secretory effect of ouabain is not secondary to the release of ACh from cholinergic nerve terminals present in the adrenal gland, but due to a direct action on the chromaffin cell itself. In addition, the results suggest that this action is exerted through redistribution of monovalent cations secondary to the inhibition by the glycoside of the sodium pump. Such monovalent cation redistribution may cause a rise of intracellular ionized calcium levels through the activation of an internal sodium-dependent calcium influx system probably located in the chromaffin cell membrane.

SUMMARYAim: To study the pharmacokinetic and metabolism profiles of a single dose of acetaminophen in patients with cirrhosis. Methods: Oral acetaminophen (1000 mg) was administered to seven healthy subjects and 14 patients with cirrhosis (nine Child-Pugh A or B and five Child-Pugh C grade), being five without and nine with oesophageal varices. Plasma levels of acetaminophen and its metabolites were determined by HPLC. Results: Patients showed a higher mean area under the curve concentration-time (67.4 ± 22.4 mg h/L vs. 38.8 ± 4.3 mg h/L; P ¼ 0.01), a lower clearance (166.7 ± 85.0 mL/min vs. 367.8 ± 62.5 mL/min; P ¼ 0.01) and higher elimination half-life (3.8 ± 1.1 h vs. 2.0 ± 0.4 h; P ¼ 0.01) of acetaminophen than healthy volunteers. The appearance in blood and the urinary excretion of metabolites in patients did not differ from healthy subjects. Absorption profile was faster in patients. Patients with lower mean and systolic arterial pressure had lower AUC of acetaminophen, independently of liver dysfunction stage. Conclusions: Patients with cirrhosis had a higher AUC and lower clearance of acetaminophen. Acetaminophen attained earlier therapeutic concentrations in patients with oesophageal varices. Mean and systolic arterial pressures were significantly associated with AUC suggesting the importance of the haemodynamic function on the pharmacokinetics of acetaminophen in patients with cirrhosis.

Screening for opioid use disorder should be considered in chronic non-cancer pain (CNCP) patients with long-term use of opioids. The aim of our study was to assess the effectiveness of an individualized treatment plan (ITP) for prescription opioid dependence that included screening of pharmacogenetic markers. An observational prospective study was performed using prescription opioid-dependent CNCP outpatients (n = 88). Patients were divided into nonresponders, responders, or high responders according to their response to the ITP. Genotyping of OPRM1 (A118G), OPRD1 (T921C), COMT (G472A), ABCB1 (C3435T), and ARRB2 (C8622T) was performed by real-time PCR. Our ITP achieved a significant reduction of the morphine equivalent daily dose (MEDD) in 64% of responders, including 33% of high responders. Nonopioid medication or buprenorphine use was significantly higher at final versus basal visit. 118-AA OPRM1 patients required significantly lower MEDD at basal and final visits. Our ITP showed effectiveness and security in reducing MEDD in opioid-dependent patients, with good conversion to buprenorphine that was more pronounced in 118-AA OPRM1 patients.