Familial amyloidotic polyneuropathy (FAP) is an autosomal dominant inherited disorder characterized by progressive peripheral and autonomic neuropathy, associated with neural and systemic amyloid deposits. The amyloid fibrils contain a variant transthyretin (TTR) molecule (TTR met30), over 90% of which is produced in the liver. After liver transplantation in two patients with severe symptomatic FAP, only normal TTR was detectable in circulation. The two patients are being monitored at regular intervals, and, although in one patient there was no evidence of reduction in the quantity of amyloid present at 6 months, there had been no further progression of the neuropathy.

1. The oral and intravenous kinetics of morphine were investigated in seven cirrhotic patients with a history of encephalopathy. The plasma concentrations of morphine and its metabolites morphine‐3 (M3G) and morphine‐6 (M6G) were measured by h.p.l.c. 2. The mean terminal elimination half‐life of morphine was 4.2 h (95% CI 3.6‐4.8) the mean volume of distribution was 4.1 l kg‐1 (95% CI 2.9‐5.4) and the mean plasma clearance was 11.4 ml min‐1 kg‐1 (95% CI 8.1‐14.7). The mean oral bioavailability was 101% (95% CI 56‐147). 3. The plasma clearance of morphine was significantly lower, its terminal elimination half‐life longer and its oral bioavailability greater in the cirrhotic patients compared with patients with normal liver function. The metabolic ratio M3G/morphine was significantly lower in the cirrhotic patients than in control subjects after oral dosing, but did not differ after intravenous dosing. 4. The average urinary recoveries of morphine plus M3G and M6G were 49.9% after i.v. and 57.7% after oral administration. There were no statistically significant differences in the urinary recovery between the two routes of administration or between the cirrhotic patients and controls. 5. Specific changes in the EEG pattern could not be detected after intravenous dosage. 6. The metabolism of morphine is impaired significantly in patients with severe cirrhosis. Clinically important findings were a high oral bioavailability and a long elimination half‐life. These findings call for cautious dosing of oral and intravenous morphine in patients with severe end stage liver disease.

Early and accelerated bone loss occurred after liver transplantation. This bone reduction seems to be mainly the result of increased bone resorption, possibly related to corticosteroid therapy.

Chronic treatment with cannabinoid agonists leads to tolerance. One possible mechanism for this is receptor internalization, but tolerance has also been reported with compounds that only cause internalization to a low degree. Furthermore, cannabinoid antagonist administration precipitates a characteristic withdrawal syndrome in tolerant subjects, accompanied by neuronal activation and enhanced release of corticotropin-releasing hormone (CRH) in the central amygdala. The underlying molecular mechanisms are unknown. We examined the role of cannabinoid tolerance and withdrawal for the expression of the cannabinoid 1 (CB1) receptor and of CRH in rats. Tolerance was first established functionally. An acute dose (100 mg/kg) of the CB1 agonist HU-210 suppressed locomotor activity, and had an anxiogenic-like effect on the elevated plus-maze. Both effects were absent following daily treatment with the same agonist or a lower (40 mg/kg) dose for 14 days. Next, withdrawal was reliably precipitated by a single dose (3 mg/kg) of the CB1 antagonist SR141716A in rats treated subchronically with 14-day HU-210. Using in situ hybridization, a robust suppression of CB1 mRNA expression was found in the caudate-putamen, indicating a downregulation of CB1 expression levels as one mechanism for tolerance to the locomotor suppressant effects of HU-210. The CRH transcript was upregulated in the central amygdala in precipitated withdrawal compared to nonwithdrawn tolerant subjects, suggesting that increased gene expression contributes to the previously reported CRH release in withdrawal. Most importantly, this increase occurred from a suppressed level in tolerant subjects, and behavioral signs of withdrawal, presumably mediated by CRH, were seen at the CRH expression that had only returned to normal nontolerant levels. This suggests the possibility of an allostatic shift, as previously proposed on theoretical grounds. The expression of CRH-R1, CRH-R2a, NPY, and its Y1 receptor mRNA was analyzed in search of neural substrates for the allostatic shift observed, but did not seem to contribute to the dysregulated state.

Nine psychotic patients under continuous oral treatment with haloperidol were randomly given a test dose of 1.5-5 mg haloperidol orally and/or intravenously. Serum levels of haloperidol were determined by high performance liquid chromatography and serum concentration data obtained were submitted to pharmacokinetic analysis. The steady state concentration ratio between blood and plasma was determined and found to be 0.79 +/- 0.03. The blood clearance was then calculated to be 550 +/- 133 ml/min. The mean hepatic extraction ratio was intermediate (0.37). Consequently, for a drug mainly eliminated by hepatic metabolism like haloperidol, the total blood clearance and the extent of oral bioavailability can be affected by changes in hepatic blood flow, hepatic enzyme activities and drug binding. During continuous oral treatment with haloperidol, however, it can be shown that changes in the total metabolic capacity of the liver due to hepatic enzyme induction or inhibition should be important for the therapeutic effects of haloperidol. The volume of distribution at steady state (Vdss) was large (7.9 +/- 2.5 l/kg). The terminal half-life was 18.8 h after intravenous and 18.1 h after oral administration. The oral bioavailability (0.60 +/- 0.18) were in accordance with previous results in healthy subjects. A mean lag time after oral dose was 1.3 +/- 1.1 h and a longer absorption half-life (1.9 +/- 1.4 h) was found in the patients compared with healthy volunteers.