Chenodeoxycholic acid stimulated fibroblast growth factor 19 response - a potential biochemical test for bile acid diarrhoea.

BACKGROUND: Bile acid diarrhoea is underdiagnosed and better diagnostic tests are needed. Fasting serum fibroblast growth factor-19 (FGF19) has insufficient diagnostic value, but this may be improved by stimulation. AIM: To explore if an impaired FGF19 response identifies primary bile acid diarrhoea. METHODS: Eight patients with primary bile acid diarrhoea and eight healthy volunteers ingested (i) a meal plus 1250 mg chenodeoxycholic acid (CDCA), (ii) 1250 mg CDCA or (iii) the meal. Blood was sampled at fasting and repeatedly after stimulation. We analysed FGF19 by enzyme-linked immunosorbent assay and bile acids including 7α-hydroxy-4-cholesten-3-one by liquid chromatography-tandem mass spectrometry. RESULTS: Stimulation with the meal plus CDCA increased median FGF19 in healthy volunteers from fasting 62 pg/mL [interquartile range (IQR): 41-138] to 99 pg/mL (IQR: 67-147; P = 0.012) after 90 min and peaked after 150 min at 313 pg/mL (IQR: 54-512). This response was impaired in primary bile acid diarrhoea patients [fasting 56 pg/mL (IQR: 42-79); 90 min: 48 pg/mL [IQR: 37-63); 150 min: 57 pg/mL (48-198)]. Receiver operating characteristics (ROCAUC ) for fasting FGF19 was 0.55 (P = 0.75) and at 90 min 0.84 (P = 0.02). The difference in FGF19 from fasting to 90 min after the meal plus CDCA separated the groups (ROCAUC 1.0; P = 0.001). 7α-hydroxy-4-cholesten-3-one was elevated in primary bile acid diarrhoea (P = 0.038) and not significantly affected by stimulation. CONCLUSIONS: The FGF19 response following chenodeoxycholic acid plus meal is impaired in primary bile acid diarrhoea. This may provide a biochemical diagnostic test.

Long-term Antabuse treatment: tolerance and reasons for withdrawal.

We studied 210 alcoholics, who were re-admitted to a disulfiram treatment programme after having voluntarily discontinued disulfiram therapy, primarily to ascertain whether illness, hospitalization, or serious adverse effects were the cause of the withdrawal. A simple 9-item questionnaire was used. About 70% of the patients gave either "a wish to drink again" or "no need for further treatment" as the reason. Withdrawal in the remaining patients was in no case related to adverse effects of disulfiram. The low incidence of adverse effects was confirmed in another group comprising 93 patients treated under supervision with disulfiram 600-800 mg twice a week for at least a year (i.e. total dose at least 70 g disulfiram). They were monitored by standard laboratory blood and urine tests. There were no clinically significant changes in the measures used. Indeed, many of the patients improved during the year of abstinence. These two studies add weight to the evidence that disulfiram is not a drug with a high incidence of adverse effects.

An early clinical phase II evaluation of paroxetine, a new potent and selective 5HT-uptake inhibitor in patients with depressive illness.

Paroxetine, a new, potent and selective serotonin (5-HT) uptake inhibitor has been evaluated in an open study for its clinical effect as well as its effect on the 5-HT concentration in whole blood in 19 patients with depressive illness. Paroxetine was administered in daily doses of 20 to 60 mg. The global evaluation after six to eight weeks showed a marked improvement in 11 patients, a moderate improvement in four and no change in four patients. Assessment with the Hamilton Rating Scale for Depression in ten patients showed a reduction from a mean score of 22.7 to 6.6 in six weeks. Maximal reduction was, however, first seen in three of the patients after 8 to 12 weeks. No correlation between the antidepressant effect and plasma concentrations of paroxetine was found. The only side effects noted with paroxetine were that two patients complained of dry mouth in the beginning of the treatment and a further patient experienced a burning sensation together with periodical light headache. Generally laboratory examinations did not show any trend towards pathological values except in one patient, where a moderate leucopenia was observed. Crista puncture/biopsy showed, however, no specific bone marrow reaction. The 5-HT concentration in whole blood was reduced to about 0.02 micrograms/ml indicating a total depletion of 5-HT from the thrombocytes. The present study indicates that paroxetine possesses a good antidepressive effect in combination with a very low frequency of side effects.

Reduction of whole blood serotonin in depressed patients treated with a new, selective serotonin-uptake inhibitor, femoxetine.

Femoxetine, a phenylpiperidine derivative with potent serotonin (5-HT)-uptake inhibitory properties, was investigated in 12 depressive patients for its clinical effect as well as its effect on 5-HT concentration in whole blood. The global evaluation after 6 weeks showed a good effect in six patients. The 5-HT concentration was found to be reduced from a mean value of 0.21 to about 0.05 micrograms/ml, indicating a total depletion of 5-HT from the thrombocytes. The steady-state concentrations of femoxetine resulted in reduction of 5-HT to the same level in all patients. No correlation between degree of 5-HT reduction and therapeutic effect was found.