Pharmacokinetics of controlled release morphine (MST) in patients with liver carcinoma.

BACKGROUND: There are no studies reported on the pharmacokinetics of controlled release morphine (MST) in patients with hepatocellular carcinoma, the fifth most common cancer in the world. METHODS: We have studied the pharmacokinetic profile of MST (30 mg) in 15 patients with liver carcinoma (eight with primary carcinoma on top of chronic hepatitis C, and seven with secondary metastatic liver malignancy as a result of other primary) compared with our previously published data for 10 healthy controls. Plasma morphine concentrations were measured in venous blood samples at intervals up to 12 h by high-pressure liquid chromatography. Total body clearance (Cl) and systemic bioavailability were estimated using a compartmental method. RESULTS: Morphine bioavailability showed a substantial increase in patients with primary liver and secondary metastatic carcinoma than that of controls (64.8, 62.1, and 16.8%, respectively). The area under the serum concentration-time curve increased 4-fold in primary carcinoma (416 [sem25] microg h(-1) litre(-1)) and 3-fold (303 [21] microg h(-1) litre(-1)) in metastatic liver patients compared with healthy control (92.5 [3] microg h(-1) litre(-1)). No significant difference was found in T(max) between the two malignant groups but C(max) was significantly greater in primary liver carcinoma patients. Impaired morphine elimination was noted in primary carcinoma only (t(1/2) 5.99 [0.39] h). CONCLUSION: Careful administration of morphine is recommended in patients with liver cancer.

Pharmacokinetics of controlled release morphine (MST) in patients with liver cirrhosis.

We have studied the kinetic profile of controlled release morphine (MST) in 12 patients with posthepatitic cirrhosis, caused by HCV and HBsAg, with portal hypertension, given MST 30 mg for endoscopic sclerotherapy and compared the data with those from 10 healthy controls. Plasma drug concentrations were measured in venous blood samples at intervals up to 12 h by high-pressure liquid chromatography (HPLC). Total body clearance (Cl) and systemic availability were estimated using a compartmental method. Patients with cirrhosis had less clearance (0.586 litre h-1) than controls (0.729 litre h-1). Mean residence time (MRT) was prolonged in cirrhotic patients (19.57 h) compared with controls (7.03 h). Elimination half-life in cirrhotic patients (mean 7.36 (SEM 0.45) h) was nearly twice that of controls (4.01 (0.15) h). Serum concentrations were higher at all sampling times in the cirrhotic patients (peak concentration 35.2 (3.2) ng ml-1 compared with 12.8 (0.4) ng ml-1 in controls). For these changes in the kinetic profile of morphine (as MST) in cirrhotic patients, who experienced more sedation than controls, a smaller dose study together with longer dosing intervals is recommended.

Effect of levonorgestrel contraceptive implants, Norplant, on blood coagulation.

A longitudinal study of coagulation parameters was carried out on 47 women using the levonorgestrel subdermal implants, NORPLANT. The study comprised measurement of platelet count, prothrombin time, thrombin time, partial thromboplastin time with kaolin, clotting factors I, II, V and VI through XIII, plasminogen, antithrombin III (AT III), alpha 1 antitrypsin, alpha 2 macroglobulin and fibrinogen degradation products. The tests were done at admission and after one, three and six months of NORPLANT use. Parallel and similar studies were done on two groups of oral contraceptive users; the first group used a pill containing 1 mg norethisterone and 50 micrograms mestranol, and the second a pill consisting of 150 micrograms levonorgestrel and 30 micrograms ethinylestradiol. Results from this ongoing study have indicated that women using NORPLANT implants evidenced lack of effects on most of the parameters tested except for factor VII activity which was increased and AT III concentration which was decreased after six months of use. The combined pill users evidenced marked changes in the platelet count, the screening tests and in most of the coagulation-promoting factors; the changes were apparent after three months of use and became more pronounced after six months. The results demonstrate, with marked contrast, that the implants had less pronounced effects on the blood coagulation system than did the combined pills used in this study.

PIP: The effect of Norplant, a subdermal contraceptive implant containing levonorgestrel, on blood coagulation factors was investigated in 47 healthy women. Coagulation parameters were also measured in 55 subjects who were taking combination type oral contraceptives (OCs) (either a pill containing 1 mg norethisterone and 50 mcg mestranol or a preparation containing 150 mcg levonorgestrel and 30 mcg ethinyl estradiol). Blood sampling was carried out at admission and after 1, 3, and 6 months of contraceptive use. Parameters measured included platelet count, prothrombin time, thrombin time, partial thromboplastin time with kaolin, clotting factors I, II, V, and VI-XIII, plasminogen, antithrombin III, alpha 1 antitrypsin, alpha 2 macroglobulin, and fibrinogen degradation products. Norplant users showed a lack of effect on the factors tested, except for factor VII activity, which was increased, and antithrombin III concentration, which was decreased after 3 months of use. In contrast, the combined OC users evidenced marked changes in platelet count, the screening tests, and most coagulation promoting factors. These changes became more pronounced after 6 months. Women taking the levonorgestrel-ethinyl estradiol OC evidenced less pronounced changes in some coagulation parameters than those taking the norethisterone-mestranol preparation; however, the high dropout rate among OC users limits the conclusions that can be drawn from these results. These results point to a relative lack of effect of Norplant implants on the blood coagulation-fibrinolytic system, presumably due to the absence of estrogen and the low dose of progestogen delivered to the body.